Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 23, 2026.

Rett syndrome: a neurological disorder with metabolic components

Stephanie M. Kyle, Neeti Vashi, Monica J. Justice

Open Biology · 2018 · Review

doi:10.1098/rsob.170216

Abstract

Rett syndrome (RTT) is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 ( MECP2 ), a ubiquitously expressed transcriptional regulator. Despite remarkable scientific progress since its discovery, the mechanism by which MECP2 mutations cause RTT symptoms is largely unknown. Consequently, treatment options for patients are currently limited and centred on symptom relief. Thought to be an entirely neurological disorder, RTT research has focused on the role of MECP2 in the central nervous system. However, the variety of phenotypes identified in Mecp2 mutant mouse models and RTT patients implicate important roles for MeCP2 in peripheral systems. Here, we review the history of RTT, highlighting breakthroughs in the field that have led us to present day. We explore the current evidence supporting metabolic dysfunction as a component of RTT, presenting recent studies that have revealed perturbed lipid metabolism in the brain and peripheral tissues of mouse models and patients. Such findings may have an impact on the quality of life of RTT patients as both dietary and drug intervention can alter lipid metabolism. Ultimately, we conclude that a thorough knowledge of MeCP2's varied functional targets in the brain and body will be required to treat this complex syndrome.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Rett syndrome: clinical features and stages

Rett syndrome (RTT, OMIM #312750) was first described by Andreas Rett, an Austrian paediatric neurologist, after observing two female patients with identical hand-wringing stereotypies in his clinic waiting room. Upon examination, he found that both patients had the same history: normal early development, followed by a period of regression and loss of purposeful hand movements. Intrigued, Dr Rett documented other female patients in his clinic with similar symptoms. Believing the symptoms to be consistent with a metabolic disorder, he called it ‘cerebroatrophic hyperammonaemia’ in a 1966 German publication. However, the disorder did not gain general acceptance among the medical community until its description in English publications 17 years later. RTT is now well known as a progressive neurological disorder that primarily affects girls, occurring in 1: 10 000–15 000 live female births.

The clinical diagnosis of RTT is based on a battery of co-existing and well-defined inclusive and exclusive criteria (summarized in). Following a period of normal neurological and physical development during the first 6–18 months of life, the first features of RTT begin to manifest in early childhood and appear progressively over several stages (figure 1): stagnation (age 6–18 months), rapid regression (age 1–4 years), pseudostationary (age 2–potentially life) and late motor deterioration (age 10–life). Characteristic symptoms of RTT include loss of acquired speech and motor skills, repetitive hand movements, breathing irregularities and seizures. RTT patients may also suffer from sporadic episodes of gastrointestinal problems, hypoplasia, early-onset osteoporosis, bruxism and screaming spells. Despite these impairments, RTT patients are well integrated into their families and enjoy personal contact. The development of new augmentative communication technologies has allowed otherwise non-verbal RTT patients to engage with others and express themselves.

Many children diagnosed with RTT have reduced brain volume compared with healthy individuals, consistent with a smaller head circumference. Reduced brain volume is largely due to small neuronal body size and a denser packing of cells, particularly in layers III and V of the cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus. Patients also have reduced dendritic arborization, indicative of a delay in neuronal maturation. Furthermore, hypopigmentation of the substantia nigra suggests a dysfunction of dopaminergic neurons. RTT patients show evidence of dysregulated neurotransmitters, neuromodulators and transporters, indicating an important role in synaptic function.

Metabolic complications are also common in RTT. A number of patients present with dyslipidaemia, elevated plasma leptin and adiponectin, elevated ammonia and inflammation of the gallbladder, an organ which stores bile for fat digestion. Changes in brain carbohydrate metabolism and neurometabolites associated with cell integrity and membrane turnover have also been reported. Additionally, energy-producing mitochondria have abnormal structure in patient cells. Consistently, altered electron transport chain complex function, increased oxidative stress, and elevated levels of lactate and pyruvate in blood and cerebrospinal fluid have been observed in RTT patients (reviewed in).

Treatment for RTT patients is currently limited to symptom control. With adequate attention to orthopaedic complications, seizure control and nutrition, women with RTT may survive into middle age and older. However, patients have a sudden and unexpected death rate of 26%, much higher than healthy individuals of a similar age, and typically die due to respiratory infection, cardiac instability and respiratory failure.

Mutations in MECP2 cause Rett syndrome

Familial cases were instrumental in determining the genetic cause of typical RTT. Multipoint linkage analysis of a Brazilian RTT family with three affected and three unaffected daughters narrowed the location of the gene to Xq28. Following this breakthrough in 1999, Amir et al. systematically analysed nearly 100 candidate genes located in the Xq28 region for mutations in RTT patients. By screening genomic DNA from sporadic and familial RTT patients, the group identified damaging missense, frameshift and nonsense mutations in the coding region of the gene methyl-CpG-binding protein 2 (MECP2) in seven patients. It is now well established that mutations in MECP2 account for 95% of typical RTT cases and commonly occur de novo. RTT patients are heterozygous for MECP2 mutation, carrying one normal and one mutated copy of MECP2. When a child presents with RTT-like symptoms, but does not fulfil all the diagnostic criteria for RTT, they may be diagnosed with atypical RTT, symptoms of which deviate in age of onset, sequence of clinical profile and/or severity (table 1). Many atypical cases are associated with mutations in X-linked cyclin-dependent kinase-like 5 (CDKL5; OMIM #300203) or Forkhead box G1 (FOXG1; OMIM #164874), but some remain undefined. Mutations in MECP2 have also been associated with intellectual disability, autism and lupus erythematosis.

MeCP2 is an abundant nuclear protein that was originally identified in a screen for proteins with methyl-DNA-specific binding activity. It is ubiquitously expressed throughout all human tissues, but is particularly abundant within neurons. In the central nervous system (CNS), MeCP2 is expressed at low levels prenatally, but progressively increases during neuronal maturation and synaptogenesis reaching its peak in mature, post-migratory neurons, suggesting a role for MeCP2 in maintaining neuronal maturation, activity and plasticity.

MECP2 is encoded by four exons which are expressed as the MeCP2_exon1 (e1) and the MeCP2_exon2 (e2) isoforms (figure 2a). MeCP2_e1 is 10 times more abundant than MeCP2_e2 in human and mouse brain and in mouse thymus and lung, whereas a 1: 1 ratio is seen in mouse testis and liver, suggesting that e1 is the primary functional isoform in the brain. Exon 4 in both mouse and human contains an 8.5 kb 3′UTR, which is one of the longest known in the human genome, and features four polyadenylation (polyA) sites resulting in four differentially expressed transcripts (figure 2a). The 3′UTR may regulate downstream translation of MECP2's transcript by controlling mRNA degradation and stability, nucleocytoplasmic transport, mRNA localization and modulation of translation. The alternate MECP2 transcripts show quantitative differences in expression in different tissues, in different stages of mouse embryonic development and in human post-natal brain development.

MeCP2 consists of four primary functional domains (figure 2b). The binding specificity of MeCP2 is dependent on the presence of methylated DNA and its methyl-binding domain (MBD) located at amino acids 78–162. MeCP2 is different from other methyl-DNA binding proteins because of its ability to interact with a single, symmetrical methylated CpG (mCpG) site. However, recent work by Lagger et al. revealed that MeCP2 also has a high binding affinity for methylated and hydroxymethylated CAC (mCAC and hmCAC, respectively) in neurons, demonstrating that both methylated dinucleotides and trinucleotides can recruit MeCP2 to DNA for transcriptional regulation. A transcriptional repressor domain (TRD) occurs in amino acids 207–310, and contains the NCoR-interaction domain (NID), which facilitates binding of MeCP2 to the NCoR1/SMRT co-repressor complex. The C-terminal domain (CTD) also shows DNA-binding ability, suggesting the presence of a chromatin-interacting domain in the vicinity of the 5′ region of the CTD.

CpG methylation is minimal in invertebrate genomes (10–40%), but very high in vertebrate genomes (60–90%). Methylated DNA sites recruit methyl-DNA-binding proteins like MeCP2, which attract transcriptional regulatory complexes. Consistently, MeCP2 represses transcription in a gene-specific manner, interacting with the co-repressor complexes mSIN3A and NCoR1/SMRT. However, MeCP2 may also facilitate transcriptional activation, chromatin compaction and mRNA splicing, while also interacting with a host of other regulatory proteins involved in a variety of molecular pathways.

Despite having well-defined functional domains, MeCP2 classifies as an intrinsically disordered protein (IDP) and acquires tertiary structure upon interaction with other protein partners or nucleic acids. Disordered structure makes IDPs notoriously promiscuous binding partners. As such, post-translational modifications (PTMs) add an additional layer of regulation to ensure MeCP2 binding to appropriate partners. Accordingly, MeCP2 undergoes many PTMs including acetylation, phosphorylation, ubiquitination and SUMOylation (figure 2b; reviewed in), which strongly regulate interactions. Altogether, multiple studies suggest that genes can be activated or repressed by MeCP2, depending upon the cellular context, suggesting that MeCP2 may be defined as a transcriptional modulator.

Phenotype variation among people with MECP2 mutations

According to the Human Gene Mutation database, 555 RTT-causing mutations have been identified in MECP2. De novo mutations account for 99.5% of the mutations in MECP2, of which approximately 70% are C > T transitions, which typically arise due to hypermutability at mCpG dinucleotides within the MECP2 locus. Unlike the X chromosome in oocytes, the X chromosome in sperm is hypermethylated. It has been speculated that spontaneous deamination of methylated cytosine residues may result in a transition to a thymine, increasing the potential for deleterious mutations at hypermethylated CpG sites. As such, most de novo MECP2 mutations originate from the paternally inherited X chromosome.

The wide spectrum of MECP2 mutations includes point mutations, insertions, duplications, small or large deletions, or whole MECP2 gene deletions. Despite this, only eight missense and nonsense mutations (R106 W, R133C, T158M, R168X, R255X, R270X, R294X and R306C) account for approximately 70% of all mutations in RTT (figure 2c). C-terminal deletions account for another approximately 8%, and large deletions constitute approximately 5%. Mutation types tend to cluster: missense mutations frequently occur in the MBD, while nonsense mutations generally occur downstream of the MBD. Frameshift mutations resulting from small deletions usually occur in the C-terminus (figure 2c). The location of the mutation reduces specific aspects of MeCP2 function. For example, mutations located in the MBD reduce the DNA-binding ability of MeCP2.

In early studies, Hagberg et al. noted that the severity of motor impairment in classic female RTT patients ranged from wheelchair bound before age five to retaining the ability to walk with a Parkinsonian-like gait. Given the wide variety of mutation types and phenotype severity, genotype–phenotype studies have correlated mutation status with clinical features of RTT patients. Early truncating mutations in the MECP2 gene such as R168X, R255X and R270X, and large INDELs, cause the most severe phenotype. Missense mutations such as R133C and R306C, late truncating mutations such as those in R294X, and others in the 3′ end, which keep the MBD and most of the TRD intact, are the mildest. Therefore, MECP2 mutation status is a strong predictor of disease severity, but phenotype variation commonly occurs between individuals with the same MECP2 mutation and is attributed to differences in X chromosome inactivation (XCI).

Female heterozygous RTT patients are mosaic, allowing some cells to express the mutant MECP2, while the others express the wild-type allele. XCI can be skewed preferentially so the mutant X chromosome is more or less expressed than the wild type, resulting in either a relatively more severe or milder presentation of RTT, respectively. The mother of the children in the original Brazilian family presented no symptoms because her X-inactivation footprint skewed 95% of expression from the non-mutated chromosome. Interestingly, several patients with the same mutation may exhibit a broad spectrum of clinical severity despite similar patterns of XCI in peripheral blood, potentially due to second gene mutations (modifiers) that alleviate or enhance the phenotypic outcome of MECP2 mutation.

As an X-linked disorder, RTT was considered to be lethal in males. However, males with clinical features resembling classical RTT were reported even before the discovery of the causal gene. In 1999, Wan et al. described the first mutation in MECP2 in a male patient who died at one year of age from congenital neonatal encephalopathy. This discovery prompted the inclusion of boys in screening for MECP2 mutations, allowing them to be classified into four categories: severe neonatal encephalopathy and infantile death, typical RTT, less severe neuropsychiatric phenotypes or MECP2 duplication syndrome (table 2).

Animal models inform MECP2 function

MECP2 appears across vertebrate evolution with strong conservation in its functional domains. Drosophila do not possess an orthologue to human MECP2, perhaps because the invertebrate genome is sparsely methylated. In 2013, Pietri et al. isolated the first null mecp2Q63*/Q63* zebrafish model, which does not recapitulate features of the human disorder. Instead, the fish are viable and reproduce normally, but display minor motor abnormalities and a shortened lifespan, possibly due to immune deficiencies. In 2017, Chen et al. published the first analysis of MECP2-mutant cynomolgus monkeys, which exhibit decreased movement, social withdrawal, increased stereotypical behaviour and sleep abnormalities—symptoms common in RTT patients. Overall, the monkeys exhibit CNS and transcriptome changes that are consistent with the human, in spite of being genetically heterogeneous. Therefore, simian models may serve as a robust, albeit expensive, system to study sophisticated features of RTT in the future.

Mecp2 mutant rodents recapitulate many hallmark symptoms of RTT and are the most widely accepted tool to study the disorder. An engineered null rat model of RTT (Mecp2ZFN) shows phenotypic and transcriptomic similarities to mouse models. Although rats would have advantages for physiologic and preclinical testing, they are not used widely, perhaps due to their cost and the lack of genetic tools. Instead, two null mouse alleles are the primary models for Rett syndrome (table 3). The Bird laboratory developed a Mecp2 mutant mouse model by engineering loxP sites flanking Mecp2 exons 3 and 4 to create a ‘floxed’ conditional line. This conditional-ready allele, called Mecp2tm1Bird, is hypomorphic, resulting in mild RTT-like symptoms due to a 50% reduction in MeCP2 expression. A null mouse line lacking any protein product was created by crossing with a germline-deleting Cre driver (Mecp2tm1.1Bird/Y). Simultaneously, the Jaenisch lab designed a Mecp2 mutant mouse by engineering loxP sites flanking exon 3, Mecp2tm1.1Jae. A smaller Mecp2 transcript and protein fragments are present in mutant brain; however, these mice show phenotypes similar to the null Bird allele.

Although RTT predominantly affects girls, the vast majority of published mouse studies take place in hemizygous Mecp2 mutant male mice, because they present with a more consistent phenotype early in life. While female Mecp2 mutant mice are more clinically relevant, random XCI in rodent females causes skewing of gene expression, resulting in large variations in phenotype presentation, making it difficult to separate which phenotypes arise through cell autonomous versus non-autonomous pathways. The most commonly used male mouse models, Mecp2tm1.1Bird and Mecp2tm1.1Jae, consistently display overt phenotypes at four to six weeks of age, and die between 8 and 12 weeks of age. Though Mecp2 null mice are asymptomatic prior to four weeks of age, there are subtle but consistent defects in transcription, ionotropic receptor signalling, and neuronal responsiveness during late embryogenesis and the perinatal period. At four weeks of age, null mice begin to develop uncoordinated gait, hypoactivity, tremors, hindlimb clasping reminiscent of the hand stereotypies seen in RTT patients, and irregular breathing. These phenotypes progress in severity until death. The soma and nuclei of Mecp2 mutant neurons in the hippocampus, cerebral cortex and cerebellum are smaller and more densely packed than in wild-type littermates, probably giving rise to a smaller brain.

Curiously, body weight in Mecp2 null mice differs depending on genetic background; male Mecp2tm1.1Bird/Y mice on a C57BL/6J background are substantially underweight by four weeks of age compared with wild-type littermates. On a 129S6/SvEvTac strain, males show a reverse effect: Mecp2tm1.1Bird/Y mice are the same weight as wild-type littermates until eight weeks of age, when they become significantly heavier than siblings. Lastly, Mecp2tm1.1Bird/Y mice on a CD1 background weigh slightly less than wild type early in life, but reach a normal weight by six to seven weeks of age.

Heterozygous female mice also show no symptoms initially, but become hypoactive and start to hindlimb clasp at three months. By nine months of age, approximately 50% of heterozygous females develop the same phenotypes as their null counterparts, but some females remain asymptomatic at 1 year. Therefore, females have a lifespan that allows for reproduction, suggesting that the heterozygous condition can exhibit long-term stability, as seen in RTT. Interestingly, heterozygous female mice on all genetic backgrounds, as well as female rats, become significantly overweight as they age, although humans with RTT have a wide range in body mass index.

In addition to deletion mouse models, several alleles have been engineered to recapitulate clinically relevant and common MECP2 mutations in human patients. Mice with these alleles tend to display milder and later onset neurological phenotypes compared with the Mecp2tm1.1Bird null allele, and most do not recapitulate the entire disease phenotype (summarized in table 3). In an effort to distinguish the cause of specific phenotypes, Mecp2 has also been conditionally deleted from different cell types and tissues. A number of conditional deletions in different subsets of neurons highlight the essential role of MeCP2 in neuronal function, yet their milder presentation suggests additional roles outside the CNS (reviewed in).

RTT patients show abnormal neuronal morphology, but not neuronal death, giving legitimacy to the possibility that defective MeCP2-deficient cells can recover. In a landmark study, Guy et al. achieved symptom reversal in Mecp2 mutant mice following the onset of motor dysfunction and neurological deficits. The Mecp2tm2Bird ‘FloxedStop’ allele, in which a loxP-STOP-Neo-loxP cassette was inserted into the intron upstream of endogenous Mecp2 exon 3, was crossed with mice carrying a Cre recombinase fused to the oestrogen receptor (OR). Injection of tamoxifen (TM) caused Cre-ER to translocate to the nucleus and delete the FloxedStop cassette to reactivate the Mecp2 gene. FloxedStop/Y male mice behaved like Mecp2tm1.1Bird/Y mice, developed RTT-like symptoms between four and six weeks of age, and survived for approximately 10 weeks on average. TM injections in mice with advanced neurological symptoms and breathing abnormalities restored Mecp2 expression to 80% of wild-type levels. Remarkably, restoration of MeCP2 expression reversed symptoms: neurological assessments and overall health improved and 80% of TM-treated animals survived beyond 30 weeks of age (end of study). Similarly, symptomatic FloxedStop/+ heterozygous female mice showed significant symptom improvement upon TM injection, including a reduction in body weight. This pivotal finding showed that developmental absence of MeCP2 does not irreversibly damage neurons, instilling hope that symptom reversal is possible in RTT patients.

MeCP2 modulates transcription by bridging DNA with regulatory complexes

In 2001, Kokura et al. first demonstrated that MeCP2 binds to the NCoR1/SMRT co-repressor complex. NCoR1 and SMRT are highly homologous proteins that are recruited to chromatin to repress transcription by acting as a scaffold protein for other nuclear receptors, DNA-binding proteins and histone deacetylases. One role of the NCoR1/SMRT complex is to recruit histone deacetylase 3 (HDAC3) to DNA, which removes histone acetyl marks, resulting in a closed chromatin state. Other members of this complex include G protein pathway suppressor 2 (GPS2), transducin beta-like 1 (TBL1) and transducin beta-like 1 related (TBLR1). The interaction of MeCP2 with the NCoR1/SMRT complex was re-examined over a decade later when Lyst et al. sought to identify binding partners of MeCP2. MeCP2 protein was purified from the brains of reporter mice with an enhanced green fluorescent protein (eGFP) inserted in the 3′ UTR of the Mecp2 gene (Mecp2tm3.1Bird) and mass spectrometry was used to identify associated proteins. Remarkably, five of the seven MeCP2 protein interactors identified were subunits of the NCoR1/SMRT co-repressor complex. Furthermore, this group found that the interaction between MeCP2 and the NCoR1/SMRT complex was facilitated by the NCoR1/SMRT interaction domain (NID) located at MeCP2 amino acids 285–309. MeCP2 binds to complex members TBL1 and TBLR1 at these residues via a WD40 domain, unlike other NCoR1/SMRT recruiters which interact with the NCoR1/SMRT scaffold proteins directly. These findings have led to a model wherein MeCP2 serves as a bridge between methylated DNA and the corepressor complex, anchoring the NCoR1/SMRT complex to DNA via its NID and MBD, respectively. It is hypothesized that disruption of this bridge leads to histone hyperacetylation and an open chromatin state, thereby increasing the transcription of target genes (figure 3). Even so, transcriptional profiling studies using whole brain Mecp2/Y mice have not revealed dramatic gene expression changes, perhaps because the highly heterogeneous nature of the brain masks significant perturbations in subpopulations of cells.

RTT-causing missense mutations cluster in the MBD and NID, highlighting the importance of these two regions of MECP2 in RTT pathology. Within the NID is a mutational hotspot of MeCP2 between amino acids 302 and 306. R306C is one of the more common RTT mutations, and this allele was modelled in mice to determine the biological relevance of the NCoR1 corepressor complex in RTT (table 3). By six weeks of age, male Mecp2R306C mice develop tremors, hypoactivity, hindlimb clasping and motor activity defects. Fifty per cent of Mecp2R306 mice fail to survive past 18-weeks of age and all die by 25 weeks. The R306C mutant MeCP2 has an intact MBD, which binds to methylated heterochromatin. However, the mutation disables the NID, preventing MeCP2 from binding TBL1 or TBLR1, and thus the complex that contains NCoR1 and HDAC3, which disrupts MeCP2-mediated transcriptional repression. This suggests that the interruption of the MeCP2-NCoR1/SMRT complex interaction alone is capable of causing RTT-like phenotypes.

To test the primary role of the MeCP2-NCoR/SMRT1 interaction, the effect of a radically truncated MeCP2 protein was examined for symptom reversal in mice. Mice were generated expressing a MeCP2 protein consisting of only the MBD, NID and short linker regions, while all other amino acid sequences of MeCP2 were removed. Remarkably, mice expressing this truncated protein develop only mild RTT-like symptoms and have a normal life span. Additionally, genetic re-activation or virus-mediated delivery of this minimal MeCP2 protein prevents or ameliorates symptoms in Mecp2-deficient pre-symptomatic or post-symptomatic mice, respectively. This suggests that a very important role of MeCP2 is to link DNA to the NCoR1/SMRT complex.

A mouse mutagenesis screen links MeCP2 to lipid metabolism

While Mecp2 mutant mice are an excellent model for RTT, elimination of MeCP2 affects the expression of a profound number of pathways in the CNS, making it difficult to pinpoint which ones play a key role in pathology. For this reason, Buchovecky et al. employed an unbiased forward genetic suppressor screen in Mecp2 null mice to identify mutations that alleviate RTT symptoms, which could be exploited as potential treatment targets. Genetic screening is a powerful tool to detect pathways involved in disease aetiology independent of a priori assumptions. Curiously, a dominant nonsense mutation was found in squalene epoxidase (Sqle), a monooxygenase and rate-limiting cholesterol biosynthesis enzyme, which requires an electron donor from mitochondria for its function. This mutation in Sqle improved RTT-like motor phenotypes, overall health and lifespan in Mecp2 null male mice. This sparked the question: is cholesterol metabolism perturbed in Mecp2 mutant mice?

Cholesterol is a fundamental component of all cells. While the liver is the primary manufacturer of cholesterol for the body, cholesterol is also a major component of the brain, where it functions in membrane trafficking, signal transduction, myelin formation, dendrite remodelling, neuropeptide formation and synaptogenesis. Importantly, cholesterol cannot cross the blood–brain barrier (BBB), so any cholesterol that the brain requires must be synthesized in situ. Therefore, the brain has complex and tightly regulated cholesterol synthesis pathways with multiple axes of self-regulation; too much or too little cholesterol is detrimental, and imparts negative consequences on cognition, memory and motor skills. To maintain homeostasis, cholesterol can be converted into the oxysterol 24(S)-hydroxycholesterol (24S-OHC) by the neuron-specific enzyme CYP46A1 (figure 4a). Oxysterols can pass lipophilic membranes more easily than cholesterol, allowing for one-way egress across the BBB and into the body.

Abnormalities in brain lipid homeostasis are associated with developmental disorders and diseases of ageing. Neimann–Pick type C patients accumulate cholesterol in the brain and peripheral tissues, and present with symptoms similar to RTT such as loss of acquired verbal skills and lack of motor coordination. Patients with Smith–Lemli–Opitz syndrome develop microcephaly, cleft lip/palate, liver defects and autistic behaviours due to a deficiency in 7-dehydrocholesterol, allowing for the toxic build-up of cholesterol intermediates. Furthermore, aberrant cholesterol homeostasis has been implicated in Fragile X syndrome, amyotrophic lateral sclerosis, Alzheimer's, Parkinson's and Huntington's diseases. However, lipid anomalies had never before been described in RTT and whether cholesterol played a primary role in the pathology of the disease was unknown.

Strikingly, Buchovecky et al. found that cholesterol homeostasis is perturbed in the Mecp2 null mouse brain. Pre-symptomatically, Mecp2 null whole brain cholesterol is elevated, and Cyp46a1 expression is increased 38% over wild-type levels, indicating a heightened need for cholesterol turnover in neurons (figure 4b). Post-symptomatically, the overproduction of cholesterol decreases sterol synthesis in Mecp2 null brains due to regulatory feedback (figure 4c).

Notably, metabolic phenotypes differ in Mecp2 null mice across genetic backgrounds. While both 129.Mecp2tm1.1Bird mice and B6.Mecp2tm1.1Jae mice show decreased sterol synthesis in the brain, elevated cholesterol and triglycerides in the serum and liver are observed only in 129.Mecp2tm1.1Bird mice. Additionally, CD1.Mecp2tm1.1Bird mice have an increase in serum triglycerides with no corresponding change in serum cholesterol. The C57BL/6 J inbred strain and the 129/Sv substrains manage peripheral cholesterol metabolism differently, presumably due to differences in the transport of cholesterol breakdown products. Together, these data suggest that perturbed brain cholesterol synthesis is a common feature of Mecp2 null mice; however, it is likely that genetic background contributes to the Mecp2 null peripheral metabolic phenotype.

These differential findings in mice suggested that peripheral lipid markers would not be elevated in all patients. Consistently, only a subset of RTT patients exhibit increased serum cholesterol and/or triglycerides. Outside of the CNS, sterols are the precursors of steroid hormones, bile acids and vitamin D. Interestingly, some RTT patients have bone abnormalities, severe gastrointestinal problems and biliary tract disorders. As perturbations in lipid homeostasis may influence both neurological and non-neurological RTT symptoms, the measurement of lipid parameters may serve as a non-invasive and inexpensive biomarker to identify RTT patients who may benefit from treatments that target lipid metabolism.

MeCP2 regulates lipid metabolism with NCoR1/SMRT-HDAC3

Notably, the NCoR1/SMRT corepressor complex is an important component in regulating the diurnal control of energy metabolism. During the fasting cycle, the NCoR1/SMRT-HDAC3 complex maximally occupies hepatocyte chromatin, repressing the expression of genes involved in lipid synthesis and sequestration. However, during the feeding cycle, it releases chromatin, allowing for expression of its targeted loci. This binding oscillation governs the switch between lipid and glucose utilization in hepatocytes. Mice with a liver-specific deletion of Hdac3 display an increased expression of de novo lipogenesis enzymes due to a constitutively active transcriptional environment, resulting in fatty liver disease and elevated serum cholesterol. Overall, the NCoR1/SMRT-HDAC3 complex orchestrates lipogenesis, and its disruption leads to perturbed lipid homeostasis. Therefore, it was expected that loss of MeCP2, the functional bridge between NCoR1/SMRT-HDAC3 and DNA, would lead to transcriptional dysregulation of lipogenesis and metabolic perturbations in mice. In support of this, Sqle, the suppressor of RTT-like phenotypes in mice, is a target of HDAC3, and its transcription increases approximately 170-fold in response to Hdac3 liver deletion.

Indeed, Kyle et al. showed that Mecp2 mutant mice develop severe dyslipidaemia due to aberrant transcription of lipogenesis enzymes in the liver, because MeCP2 interacts with the NCoR1/SMRT-HDAC3 complex to repress lipogenic gene transcription. Loss of MeCP2 decreases HDAC3 binding to DNA, resulting in hyperacetylated histones, and increases transcription of numerous lipid-regulating genes. Interestingly, liver-specific deletion of Mecp2 (B6.Mecp2tm1Bird/Y;Alb-Cre) also results in an increase in lipogenic enzyme transcription. Similar to Mecp2 null mice and a liver-specific deletion of Hdac3, these mice develop dyslipidaemia, fatty liver and metabolic disease. These results support a hepatocyte-autonomous role for Mecp2 in co-ordinating repression of enzymes of the cholesterol and triglyceride biosynthesis pathways and show that loss of Mecp2 from the liver is sufficient to cause metabolic disease in mice. Notably, background strain is unlikely to influence MeCP2's role in regulating liver lipid synthesis as both 129.Mecp2tm1.1Bird and B6.Mecp2tm1Bird/Y; Alb-Cre mice showed perturbed lipid metabolism.

Cholesterol-lowering statin drugs may be repurposed to treat RTT

Considering that cholesterol metabolism is perturbed in Mecp2 mice, it was possible that pharmacological treatment with cholesterol-lowering drugs (statins) would improve symptoms. The primary mechanism of action for statin drugs is to competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a rate-limiting step in cholesterol biosynthesis, effectively reducing the endogenous production of cholesterol. Owing to the prominent role of cholesterol in cardiovascular disease, statins are medically prescribed to prevent atherosclerosis. However, statins are associated with other disease-improving side-effects, such as reducing inflammation, and negative side-effects, such as muscle weakness and acute memory loss. Owing to their relative safety, recent studies have explored how statin drugs can be repurposed to treat non-cardiovascular diseases including Fragile X syndrome and neurofibromatosis Type I.

Remarkably, treatment with either fluvastatin or lovastatin improves subjective health scores, motor performance (measured by rotarod and open field activity) and increases lifespan in 129.Mecp2tm1.1Bird male and female mutant mice when compared with control mice receiving a vehicle. Lovastatin is the more lipophilic of these statins, increasing the likelihood of crossing the BBB and entering the brain. Even so, treatment with either statin improves cholesterol homeostasis in the brains of Mecp2 mutant mice, lowers serum cholesterol and ameliorates lipid accumulation in the liver. Interestingly, lovastatin does not have a strong therapeutic effect on B6.Mecp2tm1.1Bird male mice, supporting the idea that elevated peripheral lipids may be a biomarker for those patients who may respond to statin drugs. Nevertheless, these findings support the idea that lipid metabolism, a pathway that has many opportunities for drug or dietary intervention, could be exploited for symptom improvement in a subset of RTT patients. Importantly, these findings led to a phase 2 clinical trial for the pharmacological treatment of RTT with lovastatin (NCT02563860).

Implications for understanding and treating childhood neurological disorders

Rett syndrome remains a difficult disorder to understand and treat, largely because MeCP2 is central to the regulation of gene expression in many tissues and cell types. More than 60 years after the description of RTT as a metabolic disease of the nervous system, we have finally come to an understanding of some of the metabolic aspects of pathology (summarized in figure 5). Despite this, metabolic parameters vary greatly within the RTT patient population and among different mouse strains indicating that genetic variation may play a large role in the penetrance of metabolic symptoms.

In neurons, MeCP2 serves as a bridge between the NCoR1/SMRT-HDAC3 complex and DNA to facilitate transcriptional repression, and mutations that affect MeCP2 binding to the complex cause RTT. While both Ncor1 and Hdac3 null mice die as embryos, a neuron-specific deletion of Hdac3 produces viable mice that gradually develop a phenotype very similar to that of Mecp2 null mice including abnormal motor coordination, reduced sociability and cognitive defects. These data suggest that at least a subset of RTT-like phenotypes in Mecp2 mutant mice are caused by the loss of HDAC3 in neurons. Moreover, the role of the NCoR1/SMRT-HDAC3 in regulating lipogenesis in the Mecp2 mouse liver raises interesting questions about the role of this complex in regulating lipids in the brain. Biochemistry studies have largely failed to find definitive gene regulatory targets, in part, because MeCP2 binds DNA at levels rivalling histone octamers. Moreover, the brain is a complex organ with many different cell types in various stages of activity, making whole brain studies difficult to interpret. It is likely that at certain times and in specific cells, MeCP2 is required to anchor the NCoR1/SMRT-HDAC3 complex to DNA, regulating lipid production in some cells in the brain as in the liver.

As cholesterol synthesis is a resource-expensive process, current data suggest that newborn neurons must produce cholesterol in a cell-autonomous manner, but as they mature they outsource production to astrocytes (reviewed in). Interestingly, wild-type neurons have abnormal dendritic morphology when co-cultured with MeCP2-deficient astrocytes, yet MeCP2-deficient neurons have normal dendritic morphology when co-cultured with wild-type astrocytes. Moreover, deletion of MeCP2 from glial cells induces a RTT-like phenotype, and re-introducing MeCP2 to astrocytes of Mecp2 null mice using GFAP-Cre improves symptoms and restores dendritic morphology. These data could be explained by the hypothesis that at some point during development, cholesterol synthesis is reduced in a subset of neurons, and is provided instead by astrocytes; in the RTT brain, this downregulation does not occur, leading to lipid accumulation. Certainly, this possibility may also explain the difference in timing of onset of symptoms in mice and humans, because the downregulation of cholesterol synthesis in neurons shortly precedes the onset of RTT-like symptoms in mice. New approaches provided by single-cell genomic technologies may provide definitive answers to this possibility.

Metabolic dysregulation in RTT and other diseases may impart substantial consequences on downstream systems. When one arm of metabolism is perturbed, it affects each connecting pathway, including glucose, lipid, amino acid, nitrogen and mitochondrial respiratory metabolism. Not surprisingly, both RTT patients and Mecp2 mutant mice have abnormal responses to glucose tolerance tests, and mutant mice are also insulin-resistant. Because Mecp2 mice preferentially metabolize fat rather than glucose as their primary energy source, it is likely that other energy-sensing systems are affected. Specifically, energy metabolism affects the post-translational modification of proteins with O-linked N-acetylglucosamine (O-GlcNAc), a nutrient-driven epigenetic regulator. The regulation of O-GlcNAc is required for many proteins involved in neurogenesis, and perturbation of O-GlcNAc protein modification has already been associated with many neurological diseases, including Alzheimer's. Abnormal brain glucose-lipid homeostasis is also associated with oxidative stress in Alzheimer's. RTT patients have increased oxidative burden and abnormal mitochondrial structure, while RTT animal models have defects in the mitochondrial respiratory chain and oxidative changes in the brain. Additionally, abnormal lipid metabolism is directly linked to inflammation, which is a component of pathology in both typical and atypical cases of RTT. Notably, MeCP2 directly represses Irak1 and downregulation of the NF-κβ pathway improves symptoms in Mecp2 null mice.

The understanding of metabolic aspects of RTT pathology reveals potential therapeutic interventions. Statin drugs account for only one family of numerous metabolic modulators being developed to treat lipid accumulation or insulin resistance in Type II diabetes, which may be repurposed to treat RTT. Every year, new drug treatments are tested in Mecp2 animal models that rescue different aspects of RTT phenotypes. For example, the treatment of Mecp2 null mice with a protein-tyrosine phosphatase 1B (PTP1B) antagonist that was developed to treat Type II diabetes extended lifespan, decreased hindlimb clasping and improved motor performance. Similarly, Trolox, a vitamin E derivative, normalized blood glucose levels, reduced oxidative stress and improved exploratory behaviour in Mecp2 mice. Additionally, insulin-like growth factor (IGF-1) partially rescued locomotor activity, respiratory function and heart rate in Mecp2 mice. In addition to statins, phase 2 clinical trials for RTT are in progress for a list of potential therapies including IGF-1 (NCT01777542), EPI-743 (NCT01822249), triheptanoin (NCT03059160) and NNZ-2566 (NCT01703533). However, despite this progress, no single treatment has yet fixed every phenotype in Mecp2 mice or yet proved to effectively treat RTT symptoms.

While MeCP2 has been largely studied in CNS development and maturation, some clinically significant aspects of RTT may arise independently of MECP2 deficiency in the nervous system, and should be considered when planning any treatment strategy. Given the association between MeCP2 and HDAC3, non-specific HDAC inhibitors, commonly prescribed for seizure maintenance, should be approached cautiously as a treatment in RTT. Additionally, both RTT patients and Mecp2 mutant mice present with metabolic syndrome, oxidative stress, cardiac defects, decreased bone density and urological dysfunction. As CNS-targeted gene therapy becomes a more realistic therapeutic approach, peripheral deficiency of MeCP2 must be considered more than ever as these symptoms are likely to persist following targeted genetic treatment to the brain.

Furthermore, mutations in members of the NCoR1/SMRT-HDAC3 complex should be examined for roles in other childhood neurological diseases. Already, mutations in other components of the complex, TBLR1 and TBL1, have been associated with autism, intellectual disability, Pierpont syndrome, a disorder characterized by developmental delay and abnormal fat distribution in the distal limbs, and West syndrome, a disorder with RTT-like features. Notably, six of these mutations in TBLR1 mapped to the WD40 domain of the protein and disrupted MeCP2-binding. Therefore, the transcriptional function of the NCoR1/SMRT complex could represent a shared mechanism for autism spectrum disorders and other neurological conditions. Comparing the transcriptome of mice with genetic deletions of Mecp2 and members of the NCoR1/SMRT-HDAC3 complex may offer a comprehensive list of genes regulated by this interaction that can be studied to better understand disease pathology and exploited to develop potential treatments. Altogether, the progress in understanding the mechanistic basis for RTT pathology will continue to inform other neurological diseases and complex epigenetic mechanisms.

References 219

  1. 1.

    Rett A 1966 On a unusual brain atrophy syndrome in hyperammonemia in childhood. Wien. Med. Wochenschr. 1946, 723–726.

    Not in our library

  2. 2.

    Hagberg B, Aicardi J, Dias K, Ramos O 1983 A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471–479. (doi:10.1002/ana.410140412)

    Not in our library10.1002/ana.410140412

  3. 3.

    Burd L, Randall T, Martsolf JT, Kerbeshian J 1991 Rett syndrome symptomatology of institutionalized adults with mental retardation: comparison of males and females. Am. J. Ment. Retard. 95, 596–601.

    Not in our library

  4. 4.

    Hagberg B 2002 Clinical manifestations and stages of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8, 61–65. (doi:10.1002/mrdd.10020)

    Not in our library10.1002/mrdd.10020

  5. 5.

    Hagberg B, Witt-Engerström I, Opitz JM, Reynolds JF 1986 Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am. J. Med. Genet. 25, 47–59. (doi:10.1002/ajmg.1320250506)

    Not in our library10.1002/ajmg.1320250506

  6. 6.

    Neul JL et al. 2010 Rett syndrome: revised diagnostic criteria and nomenclature. Ann. Neurol. 68, 944–950. (doi:10.1002/ana.22124)

    Not in our library10.1002/ana.22124

  7. 7.

    Haas RH 1988 The history and challenge of Rett syndrome. J. Child Neurol. 3, S3–S5. (doi:10.1177/088307388800300102)

    Not in our library10.1177/0883073888003001s02

  8. 8.

    Townend GS, Marschik PB, Smeets E, van de Berg R, van den Berg M, Curfs LMG 2016 Eye gaze technology as a form of augmentative and alternative communication for individuals with Rett syndrome: experiences of families in the Netherlands. J. Dev. Phys. Disabil. 28, 101–112. (doi:10.1007/s10882-015-9455-z)

    Not in our library10.1007/s10882-015-9455-z

  9. 9.

    Jellinger K, Seitelberger F, Opitz JM, Reynolds JF 1986 Neuropathology of Rett syndrome. Am. J. Med. Genet. 25, 259–288. (doi:10.1002/ajmg.1320250528)

    Not in our library10.1002/ajmg.1320250528

  10. 10.

    Jellinger K, Armstrong D, Zoghbi HY, Percy AK 1988 Neuropathology of Rett syndrome. Acta Neuropathol.. 76, 142–158. (doi:10.1007/BF00688098)

    Not in our library10.1007/bf00688098

  11. 11.

    Armstrong DD 1992 The neuropathology of the Rett syndrome. Brain Dev. 14, S89–S98.

    Not in our library

  12. 12.

    Kaufmann WE, Moser HW 2000 Dendritic anomalies in disorders associated with mental retardation. Cereb. Cortex 10, 981–991. (doi:10.1093/cercor/10.10.981)

    Not in our library10.1093/cercor/10.10.981

  13. 13.

    Taneja P, Ogier M, Brooks-Harris G, Schmid DA, Katz DM, Nelson SB 2009 Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J. Neurosci. 29, 12 187–12 195. (doi:10.1523/JNEUROSCI.3156-09.2009)

    Not in our library10.1523/jneurosci.3156-09.2009

  14. 14.

    Zoghbi HY, Milstien S, Butler IJ, Smith EOB, Kaufman S, Glaze DG, Percy AK 1989 Cerebrospinal fluid biogenic amines and biopterin in rett syndrome. Ann. Neurol. 25, 56–60. (doi:10.1002/ana.410250109)

    Not in our library10.1002/ana.410250109

  15. 15.

    Justice MJ, Buchovecky CM, Kyle SM, Djukic A 2013 A role for metabolism in Rett syndrome pathogenesis: new clinical findings and potential treatment targets. Rare Dis. 1, e27265 (doi:10.4161/rdis.27265)

    Not in our library10.4161/rdis.27265

  16. 16.

    Segatto M, Trapani L, Di Tunno I, Sticozzi C, Valacchi G, Hayek J, Pallottini V 2014 Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients. PLoS ONE 9, e104834 (doi:10.1371/journal.pone.0104834)

    Not in our library10.1371/journal.pone.0104834

  17. 17.

    Acampa M, Guideri F, Hayek J, Blardi P, De Lalla A, Zappella M, Auteri A 2008 Sympathetic overactivity and plasma leptin levels in Rett syndrome. Neurosci. Lett. 432, 69–72. (doi:10.1016/j.neulet.2007.12.030)

    Not in our library10.1016/j.neulet.2007.12.030

  18. 18.

    Blardi P, De Lalla A, D'Ambrogio T, Vonella G, Ceccatelli L, Auteri A, Hayek J 2009 Long-term plasma levels of leptin and adiponectin in Rett syndrome. Clin. Endocrinol. 70, 706–709. (doi:10.1111/j.1365-2265.2008.03386.x)

    Not in our library10.1111/j.1365-2265.2008.03386.x

  19. 19.

    Freilinger M et al. 2014 Prevalence, clinical investigation, and management of gallbladder disease in Rett syndrome. Dev. Med. Child Neurol. 56, 756–762. (doi:10.1111/dmcn.12358)

    Not in our library10.1111/dmcn.12358

  20. 20.

    Matsuishi T, Urabe F, Percy AK, Komori H, Yamashita Y, Schultz RS, Ohtani Y, Kuriya N, Kato H 1994 Abnormal carbohydrate metabolism in cerebrospinal fluid in Rett syndrome. J. Child Neurol. 9, 26–30. (doi:10.1177/088307389400900105)

    Not in our library10.1177/088307389400900105

  21. 21.

    Hanefeld F, Christen HJ, Holzbach U, Kruse B, Frahm J, Hanicke W 1995 Cerebral proton magnetic resonance spectroscopy in Rett syndrome. Neuropediatrics 26, 126–127. (doi:10.1055/s-2007-979742)

    Not in our library10.1055/s-2007-979742

  22. 22.

    Horska A, Naidu S, Herskovits EH, Wang PY, Kaufmann WE, Barker PB 2000 Quantitative 1H MR spectroscopic imaging in early Rett syndrome. Neurology 54, 715–722. (doi:10.1212/WNL.54.3.715)

    Not in our library10.1212/wnl.54.3.715

  23. 23.

    Eeg-Olofsson O, Al-Zuhair AG, Teebi AS, Al-Essa MM 1988 Abnormal mitochondria in the Rett syndrome. Brain Dev.. 10, 260–262. (doi:10.1016/S0387-7604(88)80010-X)

    Not in our library10.1016/s0387-7604(88)80010-x

  24. 24.

    Eeg-Olofsson O, Al-Zuhair AG, Teebi AS, Daoud AS, Zaki M, Besisso MS, Al-Essa MM 1990 Rett syndrome: a mitochondrial disease?. J. Child Neurol. 5, 210–214. (doi:10.1177/088307389000500311)

    Not in our library10.1177/088307389000500311

  25. 25.

    Wakai S, Kameda K, Ishikawa Y, Miyamoto S, Nagaoka M, Okabe M, Minami R, Tachi N 1990 Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities. Pediatr. Neurol. 6, 339–343. (doi:10.1016/0887-8994(90)90028-Y)

    Not in our library10.1016/0887-8994(90)90028-y

  26. 26.

    Cardaioli E, Dotti MT, Hayek G, Zappella M, Federico A 1999 Studies on mitochondrial pathogenesis of Rett syndrome: ultrastructural data from skin and muscle biopsies and mutational analysis at mtDNA nucleotides 10463 and 2835. J. Submicrosc. Cytol. Pathol. 31, 301–304.

    Not in our library

  27. 27.

    Haas RH, Nasirian F, Hua X, Nakano K, Hennessy M 1995 Oxidative metabolism in Rett syndrome. 2. Biochemical and molecular studies. Neuropediatrics 26, 95–99. (doi:10.1055/s-2007-979735)

    Not in our library10.1055/s-2007-979735

  28. 28.

    Sierra C, Vilaseca MA, Brandi N, Artuch R, Mira A, Nieto M, Pineda M 2001 Oxidative stress in Rett syndrome. Brain Dev. 23(Suppl 1), S236–S239. (doi:10.1016/S0387-7604(01)00369-2)

    Not in our library10.1016/s0387-7604(01)00369-2

  29. 29.

    De Felice C et al. 2009 Systemic oxidative stress in classic Rett syndrome. Free Radic. Biol. Med. 47, 440–448. (doi:10.1016/j.freeradbiomed.2009.05.016)

    Not in our library10.1016/j.freeradbiomed.2009.05.016

  30. 30.

    Leoncini S, De Felice C, Signorini C, Pecorelli A, Durand T, Valacchi G, Ciccoli L, Hayek J 2011 Oxidative stress in Rett syndrome: natural history, genotype, and variants. Redox Rep. 16, 145–153. (doi:10.1179/1351000211Y.0000000004)

    Not in our library10.1179/1351000211y.0000000004

  31. 31.

    Shulyakova N, Andreazza AC, Mills LR, Eubanks JH 2017 Mitochondrial dysfunction in the pathogenesis of Rett syndrome: implications for mitochondria-targeted therapies. Front. Cell. Neurosci. 11, 58 (doi:10.3389/fncel.2017.00058)

    Not in our library10.3389/fncel.2017.00058

  32. 32.

    Kerr AM, Armstrong DD, Prescott RJ, Doyle D, Kearney DL 1997 Rett syndrome: analysis of deaths in the British survey. Eur. Child Adolesc. Psychiat. 6(Suppl 1), 71–74.

    Not in our library

  33. 33.

    Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, Williamson S, Leonard H 2006 Rett syndrome in Australia: a review of the epidemiology. J. Pediatr. 148, 347–352. (doi:10.1016/j.jpeds.2005.10.037)

    Not in our library10.1016/j.jpeds.2005.10.037

  34. 34.
    Twenty years of surveillance in Rett syndrome: what does this tell us? · 2014
    No notice
  35. 35.

    Sirianni N, Naidu S, Pereira J, Pillotto RF, Hoffman EP 1998 Rett syndrome: confirmation of X-linked dominant inheritance, and localization of the gene to Xq28. Am. J. Hum. Genet. 63, 1552–1558. (doi:10.1086/302105)

    Not in our library10.1086/302105

  36. 36.

    Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY 1999 Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl- CpG-binding protein 2. Nat. Genet. 23, 185–188. (doi:10.1038/13810)

    Not in our library10.1038/13810

  37. 37.

    Wan M et al. 1999 Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65, 1520–1529. (doi:10.1086/302690)

    Not in our library10.1086/302690

  38. 38.

    Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, Zoghbi H, Percy A, Glaze DG 2008 Specific mutations in Methyl-CpG-Binding Protein 2 confer different severity in Rett syndrome. Neurology 70, 1313–1321. (doi:10.1212/01.wnl.0000291011.54508.aa)

    Not in our library10.1212/01.wnl.0000291011.54508.aa

  39. 39.

    Weaving LS et al. 2004 Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am. J. Hum. Genet. 75, 1079–1093. (doi:10.1086/426462)

    Not in our library10.1086/426462

  40. 40.

    Tao J et al. 2004 Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am. J. Hum. Genet. 75, 1149–1154. (doi:10.1086/426460)

    Not in our library10.1086/426460

  41. 41.

    Scala E et al. 2005 CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. J. Med. Genet. 42, 103–107. (doi:10.1136/jmg.2004.026237)

    Not in our library10.1136/jmg.2004.026237

  42. 42.

    Sartori S, Di Rosa G, Polli R, Bettella E, Tricomi G, Tortorella G, Murgia A 2009 A novel CDKL5 mutation in a 47,XXY boy with the early-onset seizure variant of Rett syndrome. Am. J. Med. Genet. Part A 149, 232–236. (doi:10.1002/ajmg.a.32606)

    Not in our library10.1002/ajmg.a.32606

  43. 43.

    Fehr S et al. 2013 The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur. J. Hum. Genet. 21, 266–273. (doi:10.1038/ejhg.2012.156)

    Not in our library10.1038/ejhg.2012.156

  44. 44.

    Guerrini R, Parrini E 2012 Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia 53, 2067–2078. (doi:10.1111/j.1528-1167.2012.03656.x)

    Not in our library10.1111/j.1528-1167.2012.03656.x

  45. 45.

    Ariani F et al. 2008 FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 83, 89–93. (doi:10.1016/j.ajhg.2008.05.015)

    Not in our library10.1016/j.ajhg.2008.05.015

  46. 46.

    Mencarelli MA et al. 2010 Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J. Med. Genet. 47, 49–53. (doi:10.1136/jmg.2009.067884)

    Not in our library10.1136/jmg.2009.067884

  47. 47.

    Philippe C, Amsallem D, Francannet C, Lambert L, Saunier A, Verneau F, Jonveaux P 2010 Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J. Med. Genet. 47, 59–65. (doi:10.1136/jmg.2009.067355)

    Not in our library10.1136/jmg.2009.067355

  48. 48.

    Sung Jae LS et al. 2001 Spectrum of MECP2 mutations in Rett syndrome. Brain Dev. 23(Suppl. 1), S138–S143. (doi:10.1016/S0387-7604(01)00339-4)

    Not in our library10.1016/s0387-7604(01)00339-4

  49. 49.

    Zappella M 1992 The Rett girls with preserved speech. Brain Dev. 14, 98–101. (doi:10.1016/S0387-7604(12)80094-5)

    Not in our library10.1016/s0387-7604(12)80094-5

  50. 50.

    Koelsch KA, Webb R, Jeffries M, Dozmorov MG, Frank MB, Guthridge JM, James JA, Wren JD, Sawalha AH 2013 Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse. J. Autoimmun. 41, 168–174. (doi:10.1016/j.jaut.2012.12.012)

    Not in our library10.1016/j.jaut.2012.12.012

  51. 51.

    Schönewolf-Greulich B et al. 2016 The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. Clin. Genet. 89, 733–738. (doi:10.1111/cge.12769)

    Not in our library10.1111/cge.12769

  52. 52.

    Tate P, Skarnes W, Bird A 1996 The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nat. Genet. 12, 205–208. (doi:10.1038/ng0296-205)

    Not in our library10.1038/ng0296-205

  53. 53.

    Lewis JD et al. 1992 Purification, sequence, and cellular localization of a novel chromosomal protein that binds to Methylated DNA. Cell 69, 905–914. (doi:10.1016/0092-8674(92)90610-O)

    Not in our library10.1016/0092-8674(92)90610-o

  54. 54.

    Cohen DRS, Matarazzo V, Palmer AM, Tu Y, Jeon O-H, Pevsner J, Ronnett GV 2003 Expression of MeCP2 in olfactory receptor neurons is developmentally regulated and occurs before synaptogenesis. Mol. Cell. Neurosci. 22, 417–429. (doi:10.1016/S1044-7431(03)00026-5)

    Not in our library10.1016/s1044-7431(03)00026-5

  55. 55.

    Jung BP, Jugloff DGM, Zhang G, Logan R, Brown S, Eubanks JH 2003 The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J. Neurobiol. 55, 86–96. (doi:10.1002/neu.10201)

    Not in our library10.1002/neu.10201

  56. 56.

    Samaco RC, Nagarajan RP, Braunschweig D, LaSalle JM 2004 Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders. Hum. Mol. Genet. 13, 629–639. (doi:10.1093/hmg/ddh063)

    Not in our library10.1093/hmg/ddh063

  57. 57.

    Kishi N, Macklis JD 2005 Dissecting MECP2 function in the central nervous system. J. Child Neurol. 20, 753–759. (doi:10.1177/08830738050200091001)

    Not in our library10.1177/08830738050200091001

  58. 58.

    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler AD 2002 The Human Genome Browser at UCSC. Genome Res.. 12, 996–1006. (doi:10.1101/gr.229102)

    Not in our library10.1101/gr.229102

  59. 59.

    Mnatzakanian GN et al. 2004 A previously unidentified MECP2 open reading frame defines a new protein isoform relevant to Rett syndrome. Nat. Genet. 36, 339–341. (doi:10.1038/ng1327)

    Not in our library10.1038/ng1327

  60. 60.

    Kriaucionis S, Bird A 2004 The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 32, 1818–1823. (doi:10.1093/nar/gkh349)

    Not in our library10.1093/nar/gkh349

  61. 61.

    Olson CO, Zachariah RM, Ezeonwuka CD, Liyanage VRB, Rastegar M 2014 Brain region-specific expression of MeCP2 isoforms correlates with DNA methylation within Mecp2 regulatory elements. PLoS ONE 9, e90645 (doi:10.1371/journal.pone.0090645)

    Not in our library10.1371/journal.pone.0090645

  62. 62.

    Pelka GJ, Watson CM, Christodoulou J, Tam PPL 2005 Distinct expression profiles of Mecp2 transcripts with different lengths of 3′UTR in the brain and visceral organs during mouse development. Genomics 85, 441–452. (doi:10.1016/j.ygeno.2004.12.002)

    Not in our library10.1016/j.ygeno.2004.12.002

  63. 63.

    Coy JF, Sedlacek Z, Bächner D, Delius H, Poustka A 1999 A complex pattern of evolutionary conservation and alternative polyadenylation within the long 3′ untranslated region of the methyl-CpG-binding protein 2 gene (MeCP2) suggests a regulatory role in gene expression. Hum. Mol. Genet. 8, 1253–1262. (doi:10.1093/hmg/8.7.1253)

    Not in our library10.1093/hmg/8.7.1253

  64. 64.

    D'Esposito M, Quaderi NA, Ciccodicola A, Bruni P, Esposito T, D'Urso M, Brown SDM 1996 Isolation, physical mapping, and Northern analysis of the X-linked human gene encoding methyl CpG-binding protein, MECP2. Mamm. Genome 7, 533–535. (doi:10.1007/s003359900157)

    Not in our library10.1007/s003359900157

  65. 65.

    McGowan H, Pang ZP 2015 Regulatory functions and pathological relevance of the MECP2 3′UTR in the central nervous system. Cell Regen. 4, 9 (doi:10.1186/s13619-015-0023-x)

    Not in our library10.1186/s13619-015-0023-x

  66. 66.

    Nan X, Meehan RR, Bird A 1993 Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886–4892. (doi:10.1093/nar/21.21.4886)

    Not in our library10.1093/nar/21.21.4886

  67. 67.
    MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain · 2017
    No notice
  68. 68.

    Nan X, Campoy FJ, Bird A 1997 MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481. (doi:10.1016/S0092-8674(00)81887-5)

    Not in our library10.1016/s0092-8674(00)81887-5

  69. 69.

    Nan X, Tate P, Li E, Bird A 1996 DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421. (doi:10.1128/MCB.16.1.414)

    Not in our library10.1128/mcb.16.1.414

  70. 70.

    Lyst MJ et al. 2013 Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902. (doi:10.1038/nn.3434)

    Not in our library10.1038/nn.3434

  71. 71.

    Ebert DH et al. 2013 Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341–345. (doi:10.1038/nature12348)

    Not in our library10.1038/nature12348

  72. 72.

    Chandler SPSP, Guschin D, Landsberger N, Wolffe APAP 1999 The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA. Biochemistry 38, 7008–7018. (doi:10.1021/bi990224y)

    Not in our library10.1021/bi990224y

  73. 73.

    Bird A, Tweedie S 1995 Transcriptional noise and the evolution of gene number. Phil. Trans. R. Soc. B. 349, 249–253. (doi:10.1098/rstb.1995.0109)

    Not in our library10.1098/rstb.1995.0109

  74. 74.

    Tweedie S, Charlton J, Clark V, Bird A 1997 Methylation of genomes and genes at the invertebrate-vertebrate boundary. Mol. Cell. Biol. 17, 1469–1475. (doi:10.1128/MCB.17.3.1469)

    Not in our library10.1128/mcb.17.3.1469

  75. 75.

    Stein R, Razin A, Cedar H 1982 In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells. Proc. Natl Acad. Sci. USA 79, 3418–3422. (doi:10.1073/pnas.79.11.3418)

    Not in our library10.1073/pnas.79.11.3418

  76. 76.

    Nan X, Ng H-HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A 1998 Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389. (doi:10.1038/30764)

    Not in our library10.1038/30764

  77. 77.

    Chahrour M, Jung SYY, Shaw C, Zhou X, Wong STCTC, Qin J, Zoghbi HYY 2008 MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229. (doi:10.1126/science.1153252)

    Not in our library10.1126/science.1153252

  78. 78.

    Georgel PT, Horowitz-Scherer RA, Adkins N, Woodcock CL, Wade PA, Hansen JC 2003 Chromatin compaction by human MeCP2: asssembly of novel secondary chromatin structures in the absence of DNA methylation. J. Biol. Chem. 278, 32 181–32 188. (doi:10.1074/jbc.M305308200)

    Not in our library10.1074/jbc.m305308200

  79. 79.

    Baker SA, Chen L, Wilkins AD, Yu P, Lichtarge O, Zoghbi HY 2013 An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984–996. (doi:10.1016/j.cell.2013.01.038)

    Not in our library10.1016/j.cell.2013.01.038

  80. 80.

    Li R et al. 2016 Misregulation of alternative splicing in a mouse model of Rett syndrome. PLoS Genet. 12, e1006129 (doi:10.1371/journal.pgen.1006129)

    Not in our library10.1371/journal.pgen.1006129

  81. 81.

    Young JI et al. 2005 Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc. Natl Acad. Sci. USA 102, 17 551–17 558. (doi:10.1073/pnas.0507856102)

    Not in our library10.1073/pnas.0507856102

  82. 82.

    Kimura H, Shiota K 2003 Methyl-CpG-binding protein, MeCP2, is a target molecule for maintenance DNA methyltransferase, Dnmt1. J. Biol. Chem. 278, 4806–4812. (doi:10.1074/jbc.M209923200)

    Not in our library10.1074/jbc.m209923200

  83. 83.

    Kokura K, Kaul SC, Wadhwa R, Nomura T, Khan MM, Shinagawa T, Yasukawa T, Colmenares C, Ishii S 2001 The Ski protein family is required for MeCP2-mediated transcriptional repression. J. Biol. Chem. 276, 34 115–34 121. (doi:10.1074/jbc.M105747200)

    Not in our library10.1074/jbc.m105747200

  84. 84.

    Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis S, Bird A 2007 Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc. Natl Acad. Sci. USA 104, 2709–2714. (doi:10.1073/pnas.0608056104)

    Not in our library10.1073/pnas.0608056104

  85. 85.

    Adams VH, McBryant SJ, Wade PA, Woodcock CL, Hansen JC 2007 Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2. J. Biol. Chem. 282, 15 057–15 064. (doi:10.1074/jbc.M700855200)

    Not in our library10.1074/jbc.m700855200

  86. 86.
    Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment · 2016
    No notice
  87. 87.

    Ausió J, de Paz AM, Esteller M 2014 MeCP2: the long trip from a chromatin protein to neurological disorders. Trends Mol. Med. 20, 487–498. (doi:10.1016/j.molmed.2014.03.004)

    Not in our library10.1016/j.molmed.2014.03.004

  88. 88.
    MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis? · 2014
    Not checked
  89. 89.

    Ben-Shachar S, Chahrour M, Thaller C, Shaw CA, Zoghbi HY 2009 Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum. Mol. Genet. 18, 2431–2442. (doi:10.1093/hmg/ddp181)

    Not in our library10.1093/hmg/ddp181

  90. 90.

    Pacheco NL, Heaven MR, Holt LM, Crossman DK, Boggio KJ, Shaffer SA, Flint DL, Olsen ML 2017 RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome. Mol. Autism 8, 56 (doi:10.1186/s13229-017-0174-4)

    Not in our library10.1186/s13229-017-0174-4

  91. 91.

    Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NST, Abeysinghe S, Krawczak M, Cooper DN 2003 Human Gene Mutation Database (HGMD): 2003 update. Hum. Mutat. 21, 577–581. (doi:10.1002/humu.10212)

    Not in our library10.1002/humu.10212

  92. 92.

    Goto T, Monk M 1998 Regulation of X-chromosome inactivation in development in mice and humans. Microbiol. Mol. Biol. Rev. 62, 362–378.

    Not in our library10.1128/mmbr.62.2.362-378.1998

  93. 93.

    Millar CB 2002 Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297, 403–405. (doi:10.1126/science.1073354)

    Not in our library10.1126/science.1073354

  94. 94.

    Trappe R, Laccone F, Cobilanschi J, Meins M, Huppke P, Hanefeld F, Engel W 2001 MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am. J. Hum. Genet. 68, 1093–1101. (doi:10.1086/320109)

    Not in our library10.1086/320109

  95. 95.

    Bienvenu T et al. 2000 MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum. Mol. Genet. 9, 1377–1384. (doi:10.1093/HMG/9.9.1377)

    Not in our library10.1093/hmg/9.9.1377

  96. 96.

    Cuddapah VA et al. 2014 Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J. Med. Genet. 51, 152–158. (doi:10.1136/jmedgenet-2013-102113)

    Not in our library10.1136/jmedgenet-2013-102113

  97. 97.

    Knudsen GPS, Neilson TCS, Pedersen J, Kerr A, Schwartz M, Hulten M, Bailey MES, Ørstavik KH 2006 Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers. Eur. J. Hum. Genet. 14, 1189–1194. (doi:10.1038/sj.ejhg.5201682)

    Not in our library10.1038/sj.ejhg.5201682

  98. 98.

    Ishii T, Makita Y, Ogawa A, Amamiya S, Yamamoto M, Miyamoto A, Oki J 2001 The role of different X-inactivation pattern on the variable clinical phenotype with Rett syndrome. Brain Dev. 23(Suppl. 1), S161–S164. (doi:10.1016/S0387-7604(01)00344-8)

    Not in our library10.1016/s0387-7604(01)00344-8

  99. 99.

    Hoffbuhr KC, Moses LM, Jerdonek MA, Naidu S, Hoffman EP 2002 Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype. Ment. Retard. Dev. Disabil. Res. Rev. 8, 99–105. (doi:10.1002/mrdd.10026)

    Not in our library10.1002/mrdd.10026

  100. 100.

    Ben Zeev B, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, Vecsler M, Vecksler M, Christodoulou J 2009 The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology 72, 1242–1247. (doi:10.1212/01.wnl.0000345664.72220.6a)

    Not in our library10.1212/01.wnl.0000345664.72220.6a

  101. 101.

    Zeev BB, Yaron Y, Schanen NC, Wolf H, Brandt N, Ginot N, Shomrat R, Orr-Urtreger A 2002 Rett syndrome: clinical manifestations in males with MECP2 mutations. J. Child Neurol. 17, 20–24. (doi:10.1177/088307380201700105)

    Not in our library10.1177/088307380201700105

  102. 102.

    Jülich K, Horn D, Burfeind P, Erler T, Auber B 2009 A novel MECP2 mutation in a boy with neonatal encephalopathy and facial dysmorphism. J. Pediatr. 155, 140–143. (doi:10.1016/j.jpeds.2009.01.035)

    Not in our library10.1016/j.jpeds.2009.01.035

  103. 103.

    Imessaoudene B, Bonnefont JP, Royer G, Cormier-Daire V, Lyonnet S, Lyon G, Munnich A, Amiel J 2001 MECP2 mutation in non-fatal, non-progressive encephalopathy in a male. J. Med. Genet. 38, 171–174. (doi:10.1136/jmg.38.3.171)

    Not in our library10.1136/jmg.38.3.171

  104. 104.

    Topçu M, Akyerli C, Sayi A, Törüner GA, Koçoğlu SR, Cimbiş M, Ozçelik T 2002 Somatic mosaicism for a MECP2 mutation associated with classic Rett syndrome in a boy. Eur. J. Hum. Genet. 10, 77–81. (doi:10.1038/sj.ejhg.5200745)

    Not in our library10.1038/sj.ejhg.5200745

  105. 105.

    Schwartzman JS, Bernardino A, Nishimura A, Gomes RR, Zatz M 2001 Rett syndrome in a boy with a 47,XXY karyotype confirmed by a rare mutation in the MECP2 gene. Neuropediatrics 32, 162–164. (doi:10.1055/s-2001-16620)

    Not in our library10.1055/s-2001-16620

  106. 106.

    Meloni I et al. 2000 A mutation in the rett syndrome gene, MECP2, causes X-linked mental retardation and progressive spasticity in males. Am. J. Hum. Genet. 67, 982–985. (doi:10.1086/303078)

    Not in our library10.1086/303078

  107. 107.

    Van Esch H et al. 2005 Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453. (doi:10.1086/444549)

    Not in our library10.1086/444549

  108. 108.

    Ramocki MB et al. 2009 Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann. Neurol. 66, 771–782. (doi:10.1002/ana.21715)

    Not in our library10.1002/ana.21715

  109. 109.

    Hendrich B, Tweedie S 2003 The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19, 269–277. (doi:10.1016/S0168-9525(03)00080-5)

    Not in our library10.1016/s0168-9525(03)00080-5

  110. 110.

    Pietri T, Roman A-C, Guyon N, Romano SA, Washbourne P, Moens CB, de Polavieja GG, Sumbre G 2013 The first mecp2-null zebrafish model shows altered motor behaviors. Front. Neural Circuits 7, 118 (doi:10.3389/fncir.2013.00118)

    Not in our library10.3389/fncir.2013.00118

  111. 111.

    Cortelazzo A et al. 2017 Proteomic analysis of the Rett syndrome experimental model mecp2Q63X mutant zebrafish. J. Proteomics 154, 128–133. (doi:10.1016/j.jprot.2016.12.010)

    Not in our library10.1016/j.jprot.2016.12.010

  112. 112.

    van der V, Svoboda O, Weijts BG, Espin-Palazon R, Sapp V, Pietri T, Bagnat M, Muotri AR, Traver D 2017 Mecp2 regulates tnfa during zebrafish embryonic development and acute inflammation. Dis. Model. Mech. 19, 1439–1451. (doi:10.1242/dmm.026922)

    Not in our library10.1242/dmm.026922

  113. 113.

    Chen Y et al. 2017 Modeling Rett syndrome ising TALEN-Edited MECP2 mutant cynomolgus monkeys. Cell 169, 945–955. (doi:10.1016/j.cell.2017.04.035)

    Not in our library10.1016/j.cell.2017.04.035

  114. 114.

    Patterson KC, Hawkins VE, Arps KM, Mulkey DK, Olsen ML 2015 MeCP2 deficiency results in robust Rett-like behavioural and motor deficits in male and female rats. Hum. Mol. Genet. 25, 3303–3320. (doi:10.1093/hmg/ddw179)

    Not in our library10.1093/hmg/ddw179

  115. 115.

    Veeraragavan S et al. 2015 Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome. Hum. Mol. Genet. 25, 3284–3302. (doi:10.1093/hmg/ddw178)

    Not in our library10.1093/hmg/ddw178

  116. 116.

    Wu Y, Zhong W, Cui N, Johnson CM, Xing H, Zhang S, Jiang C 2016 Characterization of Rett syndrome-like phenotypes in Mecp2-knockout rats. J. Neurodev. Disord. 8, 23 (doi:10.1186/s11689-016-9156-7)

    Not in our library10.1186/s11689-016-9156-7

  117. 117.

    Guy J, Hendrich B, Holmes M, Martin JE, Bird A 2001 A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326. (doi:10.1038/85899)

    Not in our library10.1038/85899

  118. 118.

    Kerr B, Alvarez-saavedra M, Sáez MA, Saona A, Young JI 2008 Defective body-weight regulation, motor control and abnormal social interactions in Mecp2 hypomorphic mice. Hum. Mol. Genet. 17, 1707–1717. (doi:10.1093/hmg/ddn061)

    Not in our library10.1093/hmg/ddn061

  119. 119.

    Samaco RC, Fryer JD, Ren J, Fyffe S, Chao HT, Sun Y, Greer JJ, Zoghbi HY, Neul JL 2008 A partial loss of function allele of Methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727. (doi:10.1093/hmg/ddn062)

    Not in our library10.1093/hmg/ddn062

  120. 120.

    Chen RZ, Akbarian S, Tudor M, Jaenisch R 2001 Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331. (doi:10.1038/85906)

    Not in our library10.1038/85906

  121. 121.

    Katz DM et al. 2012 Preclinical research in Rett syndrome: setting the foundation for translational success. Dis. Model. Mech. 5, 733–745. (doi:10.1242/dmm.011007)

    Not in our library10.1242/dmm.011007

  122. 122.

    Bedogni F et al. 2016 Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb. Cortex 26, 2517–2529. (doi:10.1093/cercor/bhv078)

    Not in our library10.1093/cercor/bhv078

  123. 123.

    Santos M, Silva-Fernandes A, Oliveira P, Sousa N, Maciel P 2007 Evidence for abnormal early development in a mouse model of Rett syndrome. Genes Brain Behav. 6, 277–286. (doi:10.1111/j.1601-183X.2006.00258.x)

    Not in our library10.1111/j.1601-183x.2006.00258.x

  124. 124.

    Chao H-TT, Zoghbi HYY, Rosenmund C 2007 MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65. (doi:10.1016/j.neuron.2007.08.018)

    Not in our library10.1016/j.neuron.2007.08.018

  125. 125.

    Gigli CC, Scaramuzza L, Gandaglia A, Bellini E, Gabaglio M, Parolaro D, Kilstrup-Nielsen C, Landsberger N, Bedogni F 2016 MeCP2 related studies benefit from the use of CD1 as genetic background. PLoS ONE 11, e0153473 (doi:10.1371/journal.pone.0153473)

    Not in our library10.1371/journal.pone.0153473

  126. 126.

    Shahbazian MD, Young JI, Yuva-Paylor LA, Spencer CM, Antalffy BA, Noebels JL, Armstrong DL, Paylor R, Zoghbi HY 2002 Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243–254. (doi:10.1016/S0896-6273(02)00768-7)

    Not in our library10.1016/s0896-6273(02)00768-7

  127. 127.

    Lawson-Yuen A, Liu D, Han L, Jiang ZI, Tsai GE, Basu AC, Picker J, Feng J, Coyle JT 2007 Ube3a mRNA and protein expression are not decreased in Mecp2R168X mutant mice. Brain Res. 1180, 1–6. (doi:10.1016/j.brainres.2007.08.039)

    Not in our library10.1016/j.brainres.2007.08.039

  128. 128.

    Wegener E et al. 2014 Characterization of the MeCP2R168X knockin mouse model for Rett syndrome. PLoS ONE 9, e115444 (doi:10.1371/journal.pone.0115444)

    Not in our library10.1371/journal.pone.0115444

  129. 129.

    Tao J et al. 2009 Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function. Proc. Natl Acad. Sci. USA 106, 4882–4887. (doi:10.1073/pnas.0811648106)

    Not in our library10.1073/pnas.0811648106

  130. 130.

    Jentarra GM, Olfers SL, Rice SG, Srivastava N, Homanics GE, Blue M, Naidu S, Narayanan V 2010 Abnormalities of cell packing density and dendritic complexity in the MeCP2 A140 V mouse model of Rett syndrome/X-linked mental retardation. BMC Neurosci. 11, 19 (doi:10.1186/1471-2202-11-19)

    Not in our library10.1186/1471-2202-11-19

  131. 131.

    Cohen S et al. 2011 Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85. (doi:10.1016/j.neuron.2011.08.022)

    Not in our library10.1016/j.neuron.2011.08.022

  132. 132.

    Goffin D et al. 2011 Rett syndrome mutation MeCP2 T1 58A disrupts DNA binding, protein stability and ERP responses. Nat. Neurosci. 15, 274–283. (doi:10.1038/nn.2997)

    Not in our library10.1038/nn.2997

  133. 133.

    Itoh M, Tahimic CGT, Ide S, Otsuki A, Sasaoka T, Noguchi S, Oshimura M, Goto YI, Kurimasa A 2012 Methyl CpG-binding protein isoform MeCP2-e2 is dispensable for Rett syndrome phenotypes but essential for embryo viability and placenta development. J. Biol. Chem. 287, 13 859–13 867. (doi:10.1074/jbc.M111.309864)

    Not in our library10.1074/jbc.m111.309864

  134. 134.

    Yasui DH et al. 2014 Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome. Hum. Mol. Genet. 23, 2447–2458. (doi:10.1093/hmg/ddt640)

    Not in our library10.1093/hmg/ddt640

  135. 135.

    Brown K et al. 2016 The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum. Mol. Genet. 25, 558–570. (doi:10.1093/hmg/ddv496)

    Not in our library10.1093/hmg/ddv496

  136. 136.

    Pitcher MR, Herrera JA, Buffington SA, Kochukov MY, Merritt JK, Fisher AR, Schanen NC, Costa-Mattioli M, Neul JL 2015 Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. Hum. Mol. Genet. 24, 2662–2672. (doi:10.1093/hmg/ddv030)

    Not in our library10.1093/hmg/ddv030

  137. 137.

    Lamonica JM, Kwon DY, Goffin D, Fenik P, Johnson BS, Cui Y, Guo H, Veasey S, Zhou Z 2017 Elevating expression of MeCP2T158M rescues DNA binding and Rett syndrome-like phenotypes. J. Clin. Invest. 127, 1889–1904. (doi:10.1172/JCI90967)

    Not in our library10.1172/jci90967

  138. 138.

    Johnson BS et al. 2017 Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nat. Med. 23, 1203–1214. (doi:10.1038/nm.4406)

    Not in our library10.1038/nm.4406

  139. 139.

    Fyffe SL et al. 2008 Deletion of Mecp2 in Sim1-expressing neurons reveals a critical role for MeCP2 in feeding behavior, aggression, and the response to stress. Neuron 59, 947–958. (doi:10.1016/j.neuron.2008.07.030)

    Not in our library10.1016/j.neuron.2008.07.030

  140. 140.

    He LJ, Liu N, Cheng TL, Chen XJ, Li YD, Shu YS, Qiu ZL, Zhang XH 2014 Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. Nat. Commun. 5, 5036 (doi:10.1038/ncomms6036)

    Not in our library10.1038/ncomms6036

  141. 141.

    Conti V et al. 2015 MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms. PLoS ONE 10, e0130183 (doi:10.1371/journal.pone.0130183)

    Not in our library10.1371/journal.pone.0130183

  142. 142.

    Ito-Ishida A, Ure K, Chen H, Swann JW, Zoghbi HY 2015 Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron 88, 651–658. (doi:10.1016/j.neuron.2015.10.029)

    Not in our library10.1016/j.neuron.2015.10.029

  143. 143.

    Li W 2012 Beyond widespread Mecp2 deletions to model Rett syndrome: conditional spatio-temporal knockout, single-point mutations and transgenic rescue mice. Autism Open Access 2012(Suppl. 1), 5 (doi:10.4172/2165-7890.S1-005)

    Not in our library10.4172/2165-7890.s1-005

  144. 144.

    Armstrong D, Dunn JK, Antalffy B, Trivedi R 1995 Selective dendritic alterations in the cortex of Rett syndrome. J. Neuropathol. Exp. Neurol. 54, 195–201. (doi:10.1097/00005072-199503000-00006)

    Not in our library10.1097/00005072-199503000-00006

  145. 145.

    Guy J, Gan J, Selfridge J, Cobb S, Bird A 2007 Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147. (doi:10.1126/science.1138389)

    Not in our library10.1126/science.1138389

  146. 146.

    Li J, Wang J, Wang J, Nawaz Z, Liu JM, Qin J, Wong J 2000 Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350. (doi:10.1093/emboj/19.16.4342)

    Not in our library10.1093/emboj/19.16.4342

  147. 147.

    Yoon H-G, Chan DW, Reynolds AB, Qin J, Wong J 2003 N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol. Cell 12, 723–734. (doi:10.1016/j.molcel.2003.08.008)

    Not in our library10.1016/j.molcel.2003.08.008

  148. 148.

    Fischle W, Dequiedt F, Hendzel MJ, Guenther MG, Lazar MA, Voelter W, Verdin E 2002 Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57. (doi:10.1016/S1097-2765(01)00429-4)

    Not in our library10.1016/s1097-2765(01)00429-4

  149. 149.

    Mottis A, Mouchiroud L, Auwerx J 2013 Emerging roles of the corepressors NCoR1 and SMRT in homeostasis. Genes Dev. 27, 819–835. (doi:10.1101/gad.214023.113)

    Not in our library10.1101/gad.214023.113

  150. 150.

    Kruusvee V, Lyst MJ, Taylor C, Tarnauskaitė Ž, Bird AP, Cook AG 2017 Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc. Natl. Acad. Sci. USA 114, E3243–E3250. (doi:10.1073/pnas.1700731114)

    Not in our library10.1073/pnas.1700731114

  151. 151.

    Tudor M, Akbarian S, Chen RZ, Jaenisch R 2002 Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl Acad. Sci. USA 99, 15 536–15 541. (doi:10.1073/pnas.242566899)

    Not in our library10.1073/pnas.242566899

  152. 152.

    Jordan C, Li HH, Kwan HC, Francke U 2007 Cerebellar gene expression profiles of mouse models for Rett syndrome reveal novel MeCP2 targets. BMC Med. Genet. 8, 36 (doi:10.1186/1471-2350-8-36)

    Not in our library10.1186/1471-2350-8-36

  153. 153.

    Lyst MJ, Bird A 2015 Rett syndrome: a complex disorder with simple roots. Nat. Rev. Genet. 16, 261–275. (doi:10.1038/nrg3897)

    Not in our library10.1038/nrg3897

  154. 154.

    Heckman LDD, Chahrour MHH, Zoghbi HYY 2014 Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife 3, e02676 (doi:10.7554/eLife.02676)

    Not in our library10.7554/elife.02676

  155. 155.

    Tillotson R, Selfridge J, Koerner MV, Gadalla KKE, Guy J, De Sousa D, Hector RD, Cobb SR, Bird A 2017 Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature 550, 398–401. (doi:10.1038/nature24058)

    Not in our library10.1038/nature24058

  156. 156.

    Buchovecky CM et al. 2013 A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome. Nat. Genet. 45, 1013–1020. (doi:10.1038/ng.2714)

    Not in our library10.1038/ng.2714

  157. 157.

    Porter TD 2012 New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology. Acta Pharm. Sin. B 2, 102–106. (doi:10.1016/j.apsb.2012.02.002)

    Not in our library

  158. 158.

    Osono Y, Woollett LA, Herz J, Dietschy JM 1995 Role of the low density lipoprotein receptor in the flux of cholesterol through the plasma and across the tissues of the mouse. J. Clin. Invest. 95, 1124–1132. (doi:10.1172/JCI117760)

    Not in our library10.1172/jci117760

  159. 159.

    Van Der Wulp MYM, Verkade HJ, Groen AK 2013 Regulation of cholesterol homeostasis. Mol. Cell. Endocrinol. 368, 1–16. (doi:10.1016/j.mce.2012.06.007)

    Not in our library10.1016/j.mce.2012.06.007

  160. 160.

    Pfrieger FW, Ungerer N 2011 Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 50, 357–371. (doi:10.1016/j.plipres.2011.06.002)

    Not in our library10.1016/j.plipres.2011.06.002

  161. 161.

    Zlokovic BV 2008 The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201. (doi:10.1016/j.neuron.2008.01.003)

    Not in our library10.1016/j.neuron.2008.01.003

  162. 162.

    Lund EG, Xie C, Kotti T, Turley SD, Dietschy JM, Russell DW 2003 Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J. Biol. Chem. 278, 22 980–22 988. (doi:10.1074/jbc.M303415200)

    Not in our library10.1074/jbc.m303415200

  163. 163.

    Lund EG, Guileyardo JM, Russell DW 1999 cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc. Natl Acad. Sci. USA 96, 7238–7243. (doi:10.1073/pnas.96.13.7238)

    Not in our library10.1073/pnas.96.13.7238

  164. 164.

    Bi X, Liao G 2010 Cholesterol in Niemann–Pick type C disease. Subcell. Biochem. 51, 319–335. (doi:10.1007/978-90-481-8622-8_11)

    Not in our library10.1007/978-90-481-8622-8_11

  165. 165.

    Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G 1994 Defective cholesterol biosynthesis associated with the Smith–Lemli–Opitz syndrome. N. Engl. J. Med. 330, 107–113. (doi:10.1056/NEJM199401133300205)

    Not in our library10.1056/nejm199401133300205

  166. 166.

    Berry-Kravis E, Levin R, Shah H, Mathur S, Darnell JC, Ouyang B 2015 Cholesterol levels in Fragile X syndrome. Am. J. Med. Genet. Part A 167, 379–384. (doi:10.1002/ajmg.a.36850)

    Not in our library10.1002/ajmg.a.36850

  167. 167.
    Defective cholesterol metabolism in amyotrophic lateral sclerosis · 2017
    No notice
  168. 168.

    Puglielli L, Tanzi RE, Kovacs DM 2003 Alzheimer's disease: the cholesterol connection. Nat. Neurosci. 6, 345–351. (doi:10.1038/nn0403-345)

    Not in our library10.1038/nn0403-345

  169. 169.

    De Lau LML, Koudstaal PJ, Hofman A, Breteler MMB 2006 Serum cholesterol levels and the risk of Parkinson's disease. Am. J. Epidemiol. 164, 998–1002. (doi:10.1093/aje/kwj283)

    Not in our library10.1093/aje/kwj283

  170. 170.

    Karasinska JM, Hayden MR 2011 Cholesterol metabolism in Huntington disease. Nat. Rev. Neurol. 7, 561–572. (doi:10.1038/nrneurol.2011.132)

    Not in our library10.1038/nrneurol.2011.132

  171. 171.

    Lopez AM, Chuang J-C, Posey KS, Turley SD 2017 Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis. Brain Res. 1654A, 77–84. (doi:10.1016/j.brainres.2016.10.021)

    Not in our library10.1016/j.brainres.2016.10.021

  172. 172.

    Dietschy JM 2009 Central nervous system: cholesterol turnover, brain development and neurodegeneration. Biol. Chem. 390, 287–293. (doi:10.1515/BC.2009.035)

    Not in our library10.1515/bc.2009.035

  173. 173.

    Sticozzi C et al. 2013 Scavenger receptor B1 post-translational modifications in Rett syndrome. FEBS Lett. 587, 2199–2204. (doi:10.1016/j.febslet.2013.05.042)

    Not in our library10.1016/j.febslet.2013.05.042

  174. 174.

    Shapiro JR et al. 2010 Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations. Pediatr. Res. 68, 446–451. (doi:10.1203/PDR.0b013e3181f2edd2)

    Not in our library10.1203/pdr.0b013e3181f2edd2

  175. 175.

    Motil KJ et al. 2011 Vitamin D deficiency is prevalent in girls and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 53, 569–574. (doi:10.1097/MPG.0b013e3182267a66)

    Not in our library10.1097/mpg.0b013e3182267a66

  176. 176.

    Motil KJ et al. 2012 Gastrointestinal and nutritional problems occur frequently throughout life in girls and women with Rett syndrome. J. Pediatr. Gastroenterol. Nutr. 55, 292–298. (doi:10.1097/MPG.0b013e31824b6159)

    Not in our library10.1097/mpg.0b013e31824b6159

  177. 177.

    Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, Liu XS, Lazar MA 2011 A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331, 1315–1319. (doi:10.1126/science.1198125)

    Not in our library10.1126/science.1198125

  178. 178.

    Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW 2008 Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 27, 1017–1028. (doi:10.1038/emboj.2008.51)

    Not in our library10.1038/emboj.2008.51

  179. 179.

    Sun Z et al. 2012 Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 18, 934–942. (doi:10.1038/nm.2744)

    Not in our library10.1038/nm.2744

  180. 180.

    Kyle SM, Saha PK, Brown HM, Chan LC, Justice MJ 2016 MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex. Hum. Mol. Genet. 25, 3029–3041. (doi:10.1093/hmg/ddw156)

    Not in our library10.1093/hmg/ddw156

  181. 181.

    Istvan ES, Deisenhofer J 2001 Structural mechanism for statin inhibition of HMG-CoA reductase. Science 292, 1160–1164. (doi:10.1126/science.1059344)

    Not in our library10.1126/science.1059344

  182. 182.

    Weitz-Schmidt G 2002 Statins as anti-inflammatory agents. Trends Pharmacol. Sci. 23, 482–486. (doi:10.1016/S0165-6147(02)02077-1)

    Not in our library10.1016/s0165-6147(02)02077-1

  183. 183.

    Jain MK, Ridker PM 2005 Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat. Rev. Drug Discov. 4, 977–987. (doi:10.1038/nrd1901)

    Not in our library10.1038/nrd1901

  184. 184.

    Abd TT, Jacobson TA 2011 Statin-induced myopathy: a review and update. Expert Opin. Drug Saf. 10, 373–387. (doi:10.1517/14740338.2011.540568)

    Not in our library10.1517/14740338.2011.540568

  185. 185.

    Strom BL, Schinnar R, Karlawish J, Hennessy S, Teal V, Bilker WB 2015 Statin therapy and risk of acute memory impairment. JAMA Intern. Med. 175, 1399 (doi:10.1001/jamainternmed.2015.2092)

    Not in our library10.1001/jamainternmed.2015.2092

  186. 186.

    Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RKS, Bear MF 2013 Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77, 243–250. (doi:10.1016/j.neuron.2012.01.034)

    Not in our library10.1016/j.neuron.2012.01.034

  187. 187.

    Ardern-Holmes SL, North KN 2011 Therapeutics for childhood neurofibromatosis type 1 and type 2. Curr. Treat. Options Neurol. 13, 529–543. (doi:10.1007/s11940-011-0142-9)

    Not in our library10.1007/s11940-011-0142-9

  188. 188.
    Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice · 2016
    Not checked
  189. 189.

    Nott A et al. 2016 Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat. Neurosci. 19, 1497–1505. (doi:10.1038/nn.4347)

    Not in our library10.1038/nn.4347

  190. 190.

    Skene PJ, Illingworth RS, Webb S, Kerr ARW, James KD, Turner DJ, Andrews R, Bird AP 2010 Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468. (doi:10.1016/j.molcel.2010.01.030)

    Not in our library10.1016/j.molcel.2010.01.030

  191. 191.

    Pfrieger FW 2003 Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 25, 72–78. (doi:10.1002/bies.10195)

    Not in our library10.1002/bies.10195

  192. 192.

    Ballas N, Lioy DT, Grunseich C, Mandel G 2009 Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology. Nat. Neurosci. 12, 311–317. (doi:10.1038/nn.2275)

    Not in our library10.1038/nn.2275

  193. 193.

    Lioy DT et al. 2011 A role for glia in the progression of Rett's syndrome. Nature 475, 497–500. (doi:10.1038/nature10214)

    Not in our library10.1038/nature10214

  194. 194.

    Nguyen MVC, Felice CA, Du F, Covey MV, Robinson JK, Mandel G, Ballas N 2013 Oligodendrocyte lineage cells contribute unique features to Rett syndrome neuropathology. J. Neurosci. 33, 18 764–18 774. (doi:10.1523/JNEUROSCI.2657-13.2013)

    Not in our library10.1523/jneurosci.2657-13.2013

  195. 195.

    Cooke DW, Naidu S, Plotnick L, Berkovitz GD 1995 Abnormalities of thyroid function and glucose control in subjects with Rett syndrome. Horm. Res. 43, 273–278. (doi:10.1159/000184309)

    Not in our library10.1159/000184309

  196. 196.

    Ogawa M, Sawaguchi S, Furukawa K, Okajima T 2015 N-acetylglucosamine modification in the lumen of the endoplasmic reticulum. Biochim. Biophys. Acta. 1850, 1319–1324. (doi:10.1016/j.bbagen.2015.03.003)

    Not in our library10.1016/j.bbagen.2015.03.003

  197. 197.

    Olivier-Van Stichelen S, Hanover JA 2015 You are what you eat: O-linked N-acetylglucosamine in disease, development and epigenetics. Curr. Opin. Clin. Nutr. Metab. Care 18, 339–345. (doi:10.1097/MCO.0000000000000188)

    Not in our library10.1097/mco.0000000000000188

  198. 198.

    Ma X, Li H, He Y, Hao J 2017 The emerging link between O-GlcNAcylation and neurological disorders. Cell. Mol. Life Sci. 74, 3667–3686. (doi:10.1007/s00018-017-2542-9)

    Not in our library10.1007/s00018-017-2542-9

  199. 199.

    Rojas-Gutierrez E, Muñoz-Arenas G, Treviño S, Espinosa B, Chavez R, Rojas K, Flores G, Díaz A, Guevara J 2017 Alzheimer's disease and metabolic syndrome: a link from oxidative stress and inflammation to neurodegeneration. Synapse 71, e21990 (doi:10.1002/syn.21990)

    Not in our library10.1002/syn.21990

  200. 200.

    Kriaucionis S, Paterson A, Curtis J, Guy J, MacLeod N, Bird A 2006 Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome. Mol. Cell. Biol. 26, 5033–5042. (doi:10.1128/MCB.01665-05)

    Not in our library10.1128/mcb.01665-05

  201. 201.

    Gold WA, Williamson SL, Kaur S, Hargreaves IP, Land JM, Pelka GJ, Tam PPL, Christodoulou J 2014 Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT): implications for the disease phenotype. Mitochondrion 15, 10–17. (doi:10.1016/j.mito.2014.02.012)

    Not in our library10.1016/j.mito.2014.02.012

  202. 202.

    Müller M, Can K 2014 Aberrant redox homoeostasis and mitochondrial dysfunction in Rett syndrome. Biochem. Soc. Trans. 42, 959–964. (doi:10.1042/BST20140071)

    Not in our library10.1042/bst20140071

  203. 203.

    De Felice C et al. 2014 Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol. Dis. 68, 66–77. (doi:10.1016/j.nbd.2014.04.006)

    Not in our library10.1016/j.nbd.2014.04.006

  204. 204.

    Schulman IG 2017 Liver X receptors link lipid metabolism and inflammation. FEBS Lett. 591, 2978–2991. (doi:10.1002/1873-3468.12702)

    Not in our library10.1002/1873-3468.12702

  205. 205.

    Leoncini S et al. 2015 Cytokine dysregulation in MECP2- and CDKL5-related Rett syndrome: relationships with aberrant redox homeostasis, inflammation, and ω-3 PUFAs. Oxid. Med. Cell. Longev. 2015, 421624 (doi:10.1155/2015/421624)

    Not in our library10.1155/2015/421624

  206. 206.

    Kishi N, MacDonald JL, Ye J, Molyneaux BJ, Azim E, Macklis JD 2016 Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat. Commun. 7, 10520 (doi:10.1038/ncomms10520)

    Not in our library10.1038/ncomms10520

  207. 207.

    Krishnan N, Krishnan K, Connors CR, Choy MS, Page R, Peti W, Van Aelst L, Shea SD, Tonks NK 2015 PTP1B inhibition suggests a therapeutic strategy for Rett syndrome. J. Clin. Invest. 125, 3163–3177. (doi:10.1172/JCI80323)

    Not in our library10.1172/jci80323

  208. 208.
    Systemic radical scavenger treatment of a mouse model of Rett syndrome: merits and limitations of the vitamin E derivative Trolox · 2016
    Not checked
  209. 209.

    Castro J, Garcia RI, Kwok S, Banerjee A, Petravicz J, Woodson J, Mellios N, Tropea D, Sur M 2014 Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 9941–9946. (doi:10.1073/pnas.1311685111)

    Not in our library10.1073/pnas.1311685111

  210. 210.

    Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Flannery R, Jaenisch R, Sur M 2009 Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029–2034. (doi:10.1073/pnas.0812394106)

    Not in our library10.1073/pnas.0812394106

  211. 211.

    Hara M et al. 2015 Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias. Sci. Rep. 5, e11204 (doi:10.1038/srep11204)

    Not in our library10.1038/srep11204

  212. 212.

    Crosson J et al. 2017 Evaluation of QTc in Rett syndrome: correlation with age, severity, and genotype. Am. J. Med. Genet. 173, 1495–1501. (doi:10.1002/ajmg.a.38191)

    Not in our library10.1002/ajmg.a.38191

  213. 213.

    O'Connor RD, Zayzafoon M, Farach-Carson MC, Schanen NC 2009 Mecp2 deficiency decreases bone formation and reduces bone volume in a rodent model of Rett syndrome. Bone 45, 346–356. (doi:10.1016/j.bone.2009.04.251)

    Not in our library10.1016/j.bone.2009.04.251

  214. 214.

    Ward CS et al. 2016 Loss of MeCP2 causes urological dysfunction and contributes to death by kidney failure in mouse models of Rett syndrome. PLoS ONE 11, e0165550 (doi:10.1371/journal.pone.0165550)

    Not in our library10.1371/journal.pone.0165550

  215. 215.

    Assadi F, Crowe C, Rouhi O 2006 Hyperkalemic distal renal tubular acidosis associated with Rett syndrome. Pediatr. Nephrol. 21, 588–590. (doi:10.1007/s00467-006-0029-2)

    Not in our library10.1007/s00467-006-0029-2

  216. 216.
    An X chromosome-wide association study in autism families identifies <it>TBL1X </it>as a novel autism spectrum disorder candidate gene in males · 2011
    Not checked
  217. 217.

    Pons L, Cordier MP, Labalme A, Till M, Louvrier C, Schluth-Bolard C, Lesca G, Edery P, Sanlaville D 2015 A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Am. J. Med. Genet. Part A 167, 164–168. (doi:10.1002/ajmg.a.36759)

    Not in our library10.1002/ajmg.a.36759

  218. 218.

    Heinen CA et al. 2016 A specific mutation in TBL1XR1 causes Pierpont syndrome. J. Med. Genet. 53, 330–337. (doi:10.1136/jmedgenet-2015-103233)

    Not in our library10.1136/jmedgenet-2015-103233

  219. 219.

    Saitsu H et al. 2014 A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. J. Hum. Genet. 59, 1–3. (doi:10.1038/jhg.2014.71)

    Not in our library10.1038/jhg.2014.71

Cited by papers we hold 2

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.