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Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins

Rivka A Rachel, Tiansen Li, Anand Swaroop

Cilia · 2012 · Review

doi:10.1186/2046-2530-1-22

Abstract

Ciliopathies encompass a broad array of clinical findings associated with genetic defects in biogenesis and/or function of the primary cilium, a ubiquitous organelle involved in the transduction of diverse biological signals. Degeneration or dysfunction of retinal photoreceptors is frequently observed in diverse ciliopathies. The sensory cilium in a photoreceptor elaborates into unique outer segment discs that provide extensive surface area for maximal photon capture and efficient visual transduction. The daily renewal of approximately 10% of outer segments requires a precise control of ciliary transport. Here, we review the ciliopathies with associated retinal degeneration, describe the distinctive structure of the photoreceptor cilium, and discuss mouse models that allow investigations into molecular mechanisms of cilia biogenesis and defects. We have specifically focused on two ciliary proteins – CEP290 and RPGR – that underlie photoreceptor degeneration and syndromic ciliopathies. Mouse models of CEP290 and RPGR disease, and of their multiple interacting partners, have helped unravel new functional insights into cell type-specific phenotypic defects in distinct ciliary proteins. Elucidation of multifaceted ciliary functions and associated protein complexes will require concerted efforts to assimilate diverse datasets from in vivo and in vitro studies. We therefore discuss a possible framework for investigating genetic networks associated with photoreceptor cilia biogenesis and pathology.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

As the field of cilia biology has exploded over the past decade, our understanding has evolved from the initial realization of cilia as important cellular structures to the knowledge that defects in these organelles constitute a unifying framework in numerous syndromic diseases, collectively called ciliopathies. More recently, distinct sets of genes have been identified as causing overlapping symptom clusters, making it possible to link specific genetic mutations to clinical diagnosis. Amidst this rapid progress, confusion arose because disease conditions manifest as a continuum of disorders with varying severity and organ involvement rather than cleanly segregated entities. As a result, even identical gene mutations can give rise to distinct clinical manifestations, while a well-defined clinical syndrome can trace its etiologic origin to a multitude of gene defects. The goal of this review is to focus on the differences among ciliopathies based on molecular and genetic characteristics and on the realization that assigning a specific clinical diagnosis is only the starting point for identifying the culprit gene. In reaching a clear understanding of molecular mechanisms and future therapeutic strategies, correlating specific symptoms to genetic mutation(s) should provide valuable insights.

We have focused on ciliopathies that include retinal degeneration as part of the clinical spectrum in order to provide a comprehensive analysis of their mutations, phenotypes, subcellular localization of the gene products, and functional insights from respective mouse models. In addition to summarizing the current state of knowledge, we have attempted to define gaps in our understanding of cilia biology and suggested approaches for future investigations.

An overview of ciliogenesis and cilia function

Cilia can be categorized as primary, sensory or motile. Nearly all cells develop a primary cilium, which serves either as a precursor to a cluster of motile cilia (in cells such as ventricular ependyma and tracheal epithelium) or remains as an environmental sensor. Given that most primary cilia are now known to enable cells to interact with and respond to their environment, the distinction between primary and sensory cilia has lost much of its meaning. These cilia are highly specialized organelles that have developed to mediate perception of light, sound, odorants, osmolarity, pressure, flow, circulating hormones, and position within the plane of a tissue (via gradients of morphogens); these perceptions are then transmitted into the cell via signaling pathways to mediate distinct responses. For example, photoreceptor outer segments are filled with stacks of membranous discs densely packed with rhodopsin, the receptor molecule that initiates a transduction cascade turning photons into electrical signals. In the cochlea, the kinocilium serves as a transient anchor point for positioning the stereocilia bundles. In olfactory epithelium, the multiple cilia in each cell converge odorant receptors in the membrane and orchestrate G-protein coupled receptor signaling in response to environmental stimuli. Many recent reviews have summarized ciliogenesis and signaling pathways in cilia, motile cilia, mechanosensory cilia mechanics, cilia as stress and flow sensors, and clinical manifestations and diagnosis of neuronal pathology.

Ciliopathies and associated pleiotropic phenotypes

Kartagener’s syndrome was one of the earliest descriptions of a motile cilia disorder. While Bardet–Biedl syndrome (BBS) was recognized as a distinct collection of phenotypes at least 60 years ago and Joubert syndrome (JBTS) as early as 1968, ciliopathies have become recognized to have sensory cilia as a unifying theme only during the last decade. Clinical entities that affect motile cilia only, such as Kartagener’s syndrome/primary ciliary dyskinesia, manifest situs inversus, bronchiectasis and sinus/respiratory complications, but lack other clinical features commonly seen in ciliopathies. The etiology of primary ciliary dyskinesia lies in genetic defects that inactivate selected molecular motors or structures within the cilia critical for motility, usually in dyneins or radial spoke components, thereby explaining more uniform and limited manifestations. Interestingly, defects in the sensory ciliopathies encompass a broader spectrum of gene functions including cilia biogenesis and structure, receptor trafficking and signaling, implying that sensory roles of cilia are more complex and critical to life.

Ciliopathies share an overlapping conglomeration of features, exhibiting retinal degeneration, cognitive impairments, cerebellar dysmorphogenesis, kidney cysts, hepatic fibrosis, polydactyly, situs inversus, obesity, skeletal/thoracic dysmorphology, genitourinary defects, cardiorespiratory abnormalities, neural tube patterning defects, and/or hydrocephalus (Figure 1). Although various syndromes may have unique symptom clusters, the distinction among clinical entities is often blurred. Clinical diagnosis alone thus provides little insight into disease etiology. Adding molecular diagnosis to classical clinical findings can be valuable in clarifying possible pathogenic mechanism(s). For example, the distinction between nephronophthisis (NPHP) and Senior–Løken syndrome (SLSN) depends on the presence of retinal findings in SLSN; however, individuals in NPHP pedigrees can also manifest ocular defects. Similarly, the distinction between COACH syndrome (Joubert syndrome with congenital hepatic fibrosis) and JBTS is blurry. With a goal to establish a link between clinical features, syndromes, and genetic causes, we have summarized relevant details of many ciliopathies and their causative genes based on information from the Online Mendelian Inheritance in Man database in Figure 1.

In contrast to motile cilia, sensory cilia are uniquely modified to carry out a particular function in a specific organ. As each tissue is designed to mediate a different sensory function, the associated pathways are more complex and slow to unravel (see Table 1). To comprehend the significance of cilia involvement, it would be helpful to delineate the pathological process in each tissue; for example, kidneys may have either massive polycystic disease or glomerulonephritis, differing pathologies that probably represent distinct etiologies. Cellular pathology and dysfunction in sensory ciliopathies may result from absent, shortened or otherwise morphologically abnormal cilia; from normal cilia structure but no transport/function; or from different cell types/tissues affected in various conditions. In photoreceptors, for example, mutations in various ciliopathy genes result in a number of distinct phenotypes, ranging from complete failure of connecting cilium formation and curtailed outer segment biogenesis, to abnormalities of disc assembly. All of these defects should eventually be traceable to a stage in ciliogenesis, transport or maintenance. Photoreceptors thus offer a unique opportunity to evaluate the contribution of ciliary proteins.

Photoreceptor structure, modified cilium and transport

The dense stacks of rhodopsin-laden discs in photoreceptor outer segments represent a highly complex and unique example of sensory cilia specialization, enlarged to house the machinery of phototransduction. As the vast majority of photoreceptors in mouse and human retina are rods, our remarks are directed primarily towards rod photoreceptors. Four ciliary compartments can be defined in photoreceptors, based on expression and other studies (Figure 2 and legend); these include the distal cilium (operationally defined as the domain occupied by Rp1 and Mak), the proximal cilium or transition zone (known in photoreceptors as the connecting cilium), the basal body, and the periciliary ridge complex or periciliary membrane complex, which is analogous to what is referred to as the ciliary pocket in general cilia literature. Expression of ciliopathy-associated proteins is generally restricted to one of these four domains (Figure 2). Thus, it is now possible to divide ciliopathy proteins by discrete anatomical localization and to contemplate understanding molecular mechanisms based on precise expression data from confocal images. These proteins are identified as being expressed in specific compartments. Axo: INV/NPHP2, NPHP3, NPHP9/NEK8, RP1, SDCCAG8, MAK; TZ/CC: NPHP1, NPHP4, NPHP8/RPGRIP1L, NPHP5/IQCB1, NPHP6/CEP290, RPGR RPGRIP1, AHI1, RP2, Lebercilin, IFT88; BB: BBS1, BBS2, BBS3, BBS4, BBS5, BBS7, BBS9, MKKS/BBS6; PC/PCC: USH2A/usherin, DFNB31/USH2D/whirlin,, VLGR1. Having immuno-electron micrograph images of protein expression in relationship to microtubule bundles, basal body, and transition zone will further advance our understanding of protein function.

Compartment 1, the distal cilium or axoneme, contains proteins that primarily modulate cilium length; these include MAK, RP1, RP1L1 and IFT20. In photoreceptors, compartment 1 delineates the base of the outer segment (Figure 2B,E). Compartment 2 is referred to as the connecting cilium in photoreceptors and is equivalent to the transition zone of motile and primary cilia. Proteins in this zone include CEP290, RPGR, RPGRIP1, RPGRIP1L, IFT88, KIF3A, KIF7, and LCA5/Lebercilin. Although intraflagellar transport proteins mediate ciliary transport along the length of the cilium, antibody localization via immunohistochemistry identifies them in specific compartments. We believe that the appearance of being concentrated in a particular subzone may reflect a bottleneck in transit. Compartment 3 comprises the basal bodies and the pericentriolar material. The proteins in this domain include BBS1, BBS4, BBS3, MKKS, TTC8/BBS8, and RAB8A. In addition to these three core compartments, a peripheral component contributing to ciliopathies is the periciliary ridge (Compartment 4). The analogous structure in non-photoreceptor cells is the ciliary pocket. The periciliary ridge was originally described in frog photoreceptors by scanning electron microscopy. The same structure is not visible in mammalian photoreceptors; however, three USH2 proteins (usherin, whirlin and VLGR1) mark a functionally equivalent region, referred to as the periciliary membrane complex, to indicate a highly specialized membrane microdomain. Distal to the basal body are structures called rootlets, which provide support for the basal bodies and cilia. A notable protein in this compartment is CROCC (rootletin). While several not strictly ciliary proteins have been included in the list of ciliopathy proteins (Figure 1) as mutations in these cause cilia-related phenotypes, a number of cilia proteins are not included – for example, trafficked cargos that are integral for outer segment function or cytoskeletal proteins that are general features of all ciliated cells.

Knowing the compartmental localization of individual proteins within the cilium will lead to new insights into cilia biogenesis and function. For example, groups of cilia proteins expressed in the same compartment, such as CEP290 and RPGR, may function in related pathways (Figure 3). Other documented interactions between proteins expressed in adjacent compartments (CEP290 and MKKS; NPHP1 and NPHP4; RPGR and USH2) might provide clues to how proteins in different compartments cooperate in mediating transport or signaling. Interesting and non-exclusive possibilities are: the expression patterns indicate pools of protein accumulation rather than absolute boundaries; a system of protein relays transports cargo or signaling from the cell body to the cilia and back; interacting proteins are part of larger multi-protein complexes with overlapping boundaries; and/or discrete molecules of a given protein (for example, CEP290) form complexes within its primary compartment (transition zone), while other CEP290 domains interact with separate complexes in other compartments (for example, basal body). Given the predicted three-dimensional structure of CEP290 as a long, fibrillar coiled-coil protein, and the plethora of its interactors (Figure 3), a central role in transport and communication is suspected.

Retinal degeneration in clinical ciliopathies

Loss or dysfunction of photoreceptors is a moderately penetrant phenotype in ciliopathies. In the clinic, the retinal defect is called retinitis pigmentosa (RP), and in cases with an early childhood onset clinicians frequently give the diagnosis of Leber congenital amaurosis (LCA). Differences among ciliopathy phenotypes reflect both the causative gene and specific mutations within each gene. Retinal degeneration in BBS tends to be slower compared with other ciliopathies. Patients with Meckel–Gruber syndrome have severe neural tube closure defects and early lethality; vision is thus not generally assessed in these patients. Many JBTS patients develop a degree of childhood vision impairment. Alstrom syndrome patients develop vision loss in young adulthood. Like JBTS cases, patients with SLSN tend to exhibit early vision loss. Visual impairment in a child can be the presenting feature of Jeune syndrome (Jeune asphyxiating thoracic dystrophy).

Mouse models of human ciliopathies with retinal degeneration

Integration of biochemical, cell biologic, protein interactions and human genetic/clinical datasets with genetic mutations in mice provides deeper insight into each gene function as it relates to cilia and pathogenic processes. Animal studies can also explain the pleiotropic nature of ciliopathies and apparent variability in clinical and disease manifestations; these may include spatial/temporal expression pattern differences, functional redundancies and variations in genetic background. Moreover, cell-based and gene-based therapies can be evaluated for toxicity and therapeutic value before moving to larger animal (dog, primate) and human studies. A large number of ciliopathy mouse models with retinal degeneration have been reported and are summarized in Table 2. Here, we focus on two ciliopathy genes involved in retinal dystrophy: CEP290, mutations in which cause up to 15 to 25% of LCA; and RPGR, the most common cause of X-linked RP and one of the most frequent causes of all forms of RP.

CEP290 mutations lead to a range of ciliopathy syndromes with variable clinical manifestations in humans (Figure 1). Many patients present with full-spectrum ciliopathy yet select alleles cause only rapid photoreceptor degeneration (LCA). A hypomorphic allele of Cep290, rd16, has been described in mice; Cep290rd16/rd16 mice show rapid degeneration of rod photoreceptors beginning around postnatal day 14 and leaving only residual cones by postnatal day 28. Slower cone loss and preservation of central pathways in Cep290rd16 mice provide opportunities for therapy. Aside from the vision loss, the Cep290rd16/rd16 mice reveal defective olfactory transport of G proteins leading to anosmia and deafness caused by cochlear hair cell dysfunction. A possible mechanism of photoreceptor cell death in Cep290rd16 mice may involve abnormal accumulation of RKIP, the Raf-1 kinase inhibitor, which inhibits cilia formation. Examination of the retinal phenotype of Rkip-knockout mice should shed further light on this question. The Cep290rd16 allele is probably hypomorphic, given the expression of the protein with an in-frame deletion and a milder phenotype. Based on the human data, a null allele of Cep290 is expected to have a severe, full-spectrum ciliopathy phenotype, which has recently been confirmed in mice (Rachel RA, Yamamoto EA, Dong L, Swaroop A, unpublished data).

In contrast to CEP290, RPGR mutations primarily cause retinal degeneration (with a few leading to syndromic phenotypes). The RPGR gene produces multiple alternatively spliced transcripts, all of which encode an N-terminal RCC1-like domain that is structurally similar to the RCC1 protein. One major constitutive isoform spans exons 1 through 19 (RPGRex1-19) and carries a C-terminal isoprenylation site. The other major variant contains exons 1 to 14 and terminates with a large, alternative ORF15 exon (RPGRorf15). The RPGR-ORF15 isoform is expressed predominantly in photoreceptors with some exceptions, concentrated in the connecting cilia, and appears to be the functionally important in the retina as all disease-causing mutations are present in this variant. Conventional gene targeting that disrupted the RCC1-like domain abolished the expression of both types of variants in Rpgr-knockout mice; however, unlike human patients, the retinal degeneration in this mutant is slow despite defective localization of opsins to photoreceptor outer segments. An abbreviated form of Rpgr-orf15 transgene seems to reverse the disease phenotype in this line. A naturally occurring mutant mouse (rd9) was shown to affect only the orf15 exon of the Rpgr gene, mimicking a majority of human patients. The retinal degeneration in the rd9 mutation is also somewhat slow. Interestingly, a recently reported mouse conditional knockout (cko) mutant exhibited relatively earlier onset of retinal disease compared to Rpgr-ko and rd9. The phenotypes in these mouse mutants are closer to what is expected in patients with RPGRorf15 mutations.

Mouse models have been generated for RPGR and CEP290 interactors and related ciliary proteins such as RPGRIP1, NPHP and BBS proteins (Figure 3). Retinal degeneration has been demonstrated in all of these models (Table 2). The retina in these mice reveal ultrastructural defects and provide insights into how cilia proteins contribute to ciliogenesis, the sequence of events in ciliogenesis, and functional interactions among specific proteins. Moreover, we can evaluate the effects of an individual allele on a uniform genetic background in mice. Such a feature allows the engineering of triple and quadruple mutants on a less variable genetic background to enable examination of the contribution of each allele to the phenotype. Unexpectedly, such studies have begun to reveal surprising results. Rather than combinations of ciliopathy alleles necessarily resulting in a more severe phenotype, genetic findings reveal more complex relationships among different ciliary proteins. For example, loss of Dync2h1, involved in retrograde cilia trafficking, disrupts Sonic hedgehog signaling and cilia formation, yet combining this mutation with heterozygous loss of Ift172, an anterograde motor, results in a milder phenotype. A priori this would suggest that neutralizing two opposite forces restores equilibrium; however, reduction of the Ift122 retrograde motor also represses the Dync2h1 phenotype. Another indication of complexity in the biogenesis and function of cilia comes from the interaction of Cep290 and Mkks, a BBS chaperonin protein. In this scenario, loss of Mkks ameliorates the sensory cilia defects in Cep290rd16 mutant mice, and vice versa. Together these findings suggest a dynamic and delicate equilibrium among opposing forces in cilia function.

Mouse models with long-term photoreceptor survival and intermediate rates of disease progression should provide optimal opportunities for designing and evaluating therapies. Those with extremely rapid degeneration may not allow sufficient time for gene-based or cell-based therapy to show benefit (see, however, results on Aipl1ko/ko), whereas those with very slow degeneration are impractical because of the required time and resource commitment. The Rpgr-cko and Nrlko/ko/Cep290rd16/rd16 double mutants display appropriate characteristics for designing treatments of retinal disease caused by RPGR and CEP290 mutations. Nrlko/ko/Cep290rd16/rd16 mice have the Cep290rd16 mutation on the background of an all-cone photoreceptor retina due to the loss of Nrl; in this model, the cones survive longer than rapidly degenerating rods, allowing a longer window for treatment. The Rpgr-cko model displays retinal degeneration that begins during the first months of life, allowing time for treatment options to be tested and evaluated.

For most ciliopathies, mouse models fail to completely recapitulate the human phenotype. For example, mouse Rpgr mutants exhibit a milder phenotype. At least nine genes have been identified as underlying Usher syndrome; yet most mouse mutants (except whirlin and usherin that cause type II Usher syndrome) bearing one of these mutations develop hearing deficits but not visual dysfunction. In addition, many BBS mouse models do not, in general, develop polydactyly, unlike their human counterparts.

Sources of complexity in ciliopathy classification

Confusion in the nomenclature of ciliopathies originates from pleiotropy of phenotypes and from variations introduced at multiple levels, including transcriptional/translational regulation, protein–protein interactions, and cellular function. Tissue-specific expression of different splice variants or protein isoforms and their subcellular localization contribute to this complexity (see Figure 2), as in the case of RPGR. If a gene is required for cilia formation or function in all tissues, one would expect a full-spectrum ciliopathy or prenatal lethality. However, functional redundancy and tissue/cell type selectivity (for example, of RPGRorf15 transcript primarily in photore-ceptors) would result in a more restricted phenotypic spectrum that is also susceptible to modifier effects. In the sense that a complete disruption of ciliogenesis is incompatible with life, many ciliopathy genes would appear to be only partially required for ciliogenesis or function. Different alleles of the same gene (null vs. hypomorph vs. dominant negative) might exhibit varying severity because of the specific functional modules that are impacted. Functional redundancy in genes causing a specific syndrome and phenotypic overlap among syndromes contribute greatly to complexity (Figure 1 and Table 2). Modifier genetic variants that do not cause disease on their own could modulate phenotypic spectrum of a disease-causing allele in a genetically diverse (outbred) population (such as humans) by combining alleles of different genes. This phenomenon seems to occur in particular with BBS.

Basing diagnosis on a combination of molecular definition and clinical symptoms can help as it would clear up some of the confusion resulting from diagnosis based strictly on phenotypic manifestations. Some ciliopathies are caused by mutations in genes that are primarily associated with non-ciliopathy syndromes (for example, TRIM32/BBS11, NPHP3, and KIF7). These genes are specifically associated with pathology in certain organs; for example, NPHP3 is associated with renal–hepatic–pancreatic dysplasia, BBS11/TRIM32 causes limb girdle muscular dystrophy, and KIF7 causes acrocallosal syndrome – none of these is considered a ciliopathy. Additionally, different signaling pathways and mechanisms may operate in distinct tissues. Exceptions also exist to the rule of motile cilia having a 9 + 2 microtubule configuration and sensory cilia having a 9 + 0 structure. Identifying these various sources and levels of complexity are essential. NPHP and SLSN both have kidney disease, but SLSN includes retinal degeneration; however, some patients with NPHP also have retinal disease. Mutations in only two proteins causing NPHP are so far known to also cause SLSN – that is, only mutations in those two proteins, SDCCAG8 and NPHP4, can cause RP/LCA symptoms in addition to isolated renal pathology (Figure 1). Examining whether these two proteins have retina-specific isoforms would be of interest.

Perspectives and future directions

In this review we have discussed differences between human ciliopathies and their respective mouse models, focusing on CEP290, RPGR and their interactors. We have highlighted the importance of distinct compartments within cilia showing unique patterns of protein expression and their frequent interactions with proteins in the same or adjacent compartments. Given the complexity of these interactions, precise localization and function of each protein should provide valuable insights and testable hypotheses related to disease mechanisms. We believe that uniform analysis of tissue expression patterns is critical for elucidating the role for each gene in the retina and other relevant cell types. Expression of each isoform should be determined relative to a distinct ciliary compartment. At this stage, it is unclear for most cilia proteins whether a specific isoform is expressed in the same ciliary compartment in each tissue/cell type and whether similar mechanisms and signaling pathways are involved. Standard identifiers should thus be used to illustrate various ciliary components in colocalization studies. Commonly used markers are acetylated α-tubulin and RP1 for the distal cilium and more proximal structures, γ-tubulin for the basal body, Ush2 for the periciliary ridge complex, and rootletin (Crocc) for striated rootlets. Standardizing the data collected for each mutant and in every affected tissue/cell type will allow comparative functional analysis of specific genes. Documenting the histology of the retina with emphasis on the photoreceptor layer is required at distinct stages of degeneration. Electron microscopy in longitudinal sections and cross-sections of the junction between inner and outer segments would be helpful in determining the defects caused by mutations in a specific protein or isoform (see Figure 2). Moreover, a detailed expression pattern with respect to previously defined proteins of specific ciliary compartments will allow more precise localization.

As awareness has grown of the pivotal role of cilia in sensory signaling, various questions persist. Are activated signaling pathways specific for each ciliated tissue or cell type? Do similar multiprotein complexes play similar roles in various tissues? For example, does the composition of BBSome and NPHP–JBTS–MKS complexes change in response to microenvironment or required cellular functions in cultured cells versus different tissues? What causes variability in genotype–phenotype correlations? For example, why do only some BBS gene mutations cause both BBS and isolated retinal dystrophy (Figure 1)? Why do only selected NPHP genes additionally cause retinal dystrophy? Do such mutations provide information about which domains of each protein may have tissue-specific functions? CEP290 and RPGR co-localize and both cause LCA/RP. Why then is only CEP290 associated with other syndromic ciliopathies even though RPGR is ubiquitously expressed?

Next-generation sequencing and new proteomics-based approaches are likely to have a major impact on the progress in this field. First, detailed analysis of ciliary localization for each protein in cultured cells and in specific tissues with relevant markers of distinct compartments will refine our understanding of cilia structure and function. Ultrastructural evaluation of photoreceptor basal bodies and connecting cilia and in other ciliated cells in mouse models will provide key information about the role of each protein. With the identification of clusters of interacting proteins, these interaction networks can be used to define relevant signaling cascades and final common pathways using biochemical and genomic techniques. A better elucidation of ciliary protein networks, their precise functional interactions and downstream signaling events would be relevant for designing therapeutic approaches that are applicable to multiple ciliopathies and pertinent for more than one specific mutation.

Conclusions

Linking clinical diagnosis and nomenclature of ciliopathies with molecular identification depends on understanding how mutations in individual cilia genes contribute to distinct clinical phenotypes. This remains an important area of investigation. Using CEP290 and RPGR as examples of central proteins in the connecting cilium of the photoreceptor, we discuss the clinical phenotypes of mutations in these genes and in those of their interactors to illustrate this principle. We draw attention to the important conclusion that the cilium is comprised of four distinct compartments, each with discrete localization of proteins. By mapping the known interacting partners for CEP290 and RPGR, we find that hubs and disease networks, such as NPHP, BBS, and others, are concentrated in a single ciliary compartment, yet interact with members of other networks in adjacent compartments. A remaining mystery is to understand the significance of discrete localization of proteins (such as intraflagellar transport proteins) that are known to function across compartments, and the manner in which discrete networks (such as BBS and NPHP) interact with each other. These insights provide clues to the sources of complexity and confusion in the study of ciliopathies. We summarize by suggesting avenues of future pursuit that will clarify and expand the current knowledge in the field.

Abbreviations

BB: Basal body; BBS: Bardet–Biedl syndrome; CEP290: Centrosomal protein 290 kDa; Cko: Conditional knockout; COACH: Joubert syndrome with congenital hepatic fibrosis; IFT: Intraflagellar transport; JBTS: Joubert syndrome; LCA: Leber congenital amaurosis; NPHP: Nephronophthisis; RPGR: Retinitis pigmentosa G-protein regulator; SLSN: Senior–Løken syndrome.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

All authors wrote the paper and designed the figures. All authors read and approved the final version of the manuscript.

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    Not in our library10.1136/jmg.2009.066613

  29. 29.

    Sun X Pawlyk B Xu X Liu X Bulgakov OV Adamian M Sandberg MA Khani SC Tan MH Smith AJ Ali RR Li T Gene therapy with a promoter targeting both rods and cones rescues retinal degeneration caused by AIPL1 mutationsGene Ther2010 17117131

    Not in our library10.1038/gt.2009.104

  30. 30.

    Chang B Khanna H Hawes N Jimeno D He S Lillo C Parapuram SK Cheng H Scott A Hurd RE Sayer JA Otto EA Attanasio M O'Toole JF Jin G Shou C Hildebrandt F Williams DS Heckenlively JR Swaroop A In-frame deletion in a novel centrosomal/ciliary protein CEP290/NPHP6 perturbs its interaction with RPGR and results in early-onset retinal degeneration in the rd16 mouseHum Mol Genet2006 1518471857

    Not in our library10.1093/hmg/ddl107

  31. 31.

    Rachel RA May-Simera HL Veleri S Gotoh N Choi BY Murga-Zamalloa C McIntyre JC Marek J Lopez I Hackett AN Brooks M den Hollander AI Beales PL Li T Jacobson SG Sood R Martens JR Liu P Friedman TB Khanna H Koenekoop RK Kelley MW Swaroop A Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesisJ Clin Investig2012 12212331245

    Not in our library10.1172/jci60981

  32. 32.

    Mockel A Perdomo Y Stutzmann F Letsch J Marion V Dollfus H Retinal dystrophy in Bardet–Biedl syndrome and related syndromic ciliopathiesProg Retin Eye Res2011 30258274

    Not in our library10.1016/j.preteyeres.2011.03.001

  33. 33.

    Ramamurthy V Cayouette M Development and disease of the photoreceptor ciliumClin Genet2009 76137145

    Not in our library10.1111/j.1399-0004.2009.01240.x

  34. 34.

    Adams NA Awadein A Toma HS The retinal ciliopathiesOphthalmic Genet2007 28113125

    Not in our library10.1080/13816810701537424

  35. 35.

    Domire JS Green JA Lee KG Johnson AD Askwith CC Mykytyn K Dopamine receptor 1 localizes to neuronal cilia in a dynamic process that requires the Bardet–Biedl syndrome proteinsCell Mol Life Sci2011 6829512960

    Not in our library10.1007/s00018-010-0603-4

  36. 36.

    Green JA Mykytyn K Neuronal ciliary signaling in homeostasis and diseaseCell Mol Life Sci2010 6732873297

    Not in our library10.1007/s00018-010-0425-4

  37. 37.

    Doherty D Joubert syndrome: insights into brain development, cilium biology, and complex diseaseSemin Pediatr Neurol2009 16143154

    Not in our library10.1016/j.spen.2009.06.002

  38. 38.

    Whitfield JF The neuronal primary cilium – an extrasynaptic signaling deviceCell Signal2004 16763767

    Not in our library10.1016/j.cellsig.2003.12.002

  39. 39.

    Whitfield JF Chakravarthy BR The neuronal primary cilium: driver of neurogenesis and memory formation in the hippocampal dentate gyrus?Cell Signal2009 2113511355

    Not in our library10.1016/j.cellsig.2009.02.013

  40. 40.

    Louie CM Gleeson JG Genetic basis of Joubert syndrome and related disorders of cerebellar developmentHum Mol Genet2005 14235242

    Not in our library10.1093/hmg/ddi264

  41. 41.

    Millen KJ Gleeson JG Cerebellar development and diseaseCurr Opin Neurobiol2008 181219

    Not in our library10.1016/j.conb.2008.05.010

  42. 42.

    Spassky N Han YG Aguilar A Strehl L Besse L Laclef C Ros MR Garcia-Verdugo JM Alvarez-Buylla A Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor poolDev Biol2008 317246259

    Not in our library10.1016/j.ydbio.2008.02.026

  43. 43.

    Shiba D Yokoyama T The ciliary transitional zone and nephrocystinsDifferentiation2012 83S91S96Epub 2011 Dec 12

    Not in our library10.1016/j.diff.2011.11.006

  44. 44.

    Winyard P Jenkins D Putative roles of cilia in polycystic kidney diseaseBiochim Biophys Acta2011 181212561262

    Not in our library10.1016/j.bbadis.2011.04.012

  45. 45.

    Takiar V Caplan MJ Polycystic kidney disease: pathogenesis and potential therapiesBiochim Biophys Acta2011 181213371343

    Not in our library10.1016/j.bbadis.2010.11.014

  46. 46.

    D'Angelo A Franco B The primary cilium in different tissues-lessons from patients and animal modelsPediatr Nephrol2011 26655662

    Not in our library10.1007/s00467-010-1650-7

  47. 47.

    Dalagiorgou G Basdra EK Papavassiliou AG Polycystin-1: function as a mechanosensorInt J BiochemCell Biol2010 4216101613

    Not in our library10.1016/j.biocel.2010.06.017

  48. 48.

    Hurd TW Hildebrandt F Mechanisms of nephronophthisis and related ciliopathiesNephron Exp Nephrol2011 118e9e14

    Not in our library10.1159/000320888

  49. 49.

    Hildebrandt F Attanasio M Otto E Nephronophthisis: disease mechanisms of a ciliopathyJ Am Soc Nephrol2009 202335

    Not in our library10.1681/asn.2008050456

  50. 50.

    Lancaster MA Louie CM Silhavy JL Sintasath L Decambre M Nigam SK Willert K Gleeson JG Impaired Wnt-beta-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathyNat Med2009 1510461054

    Not in our library10.1038/nm.2010

  51. 51.

    Gunay-Aygun M Liver and kidney disease in ciliopathiesAm J Med Genet C Semin Med Genet2009 151C296306

    Not in our library10.1002/ajmg.c.30225

  52. 52.

    Larusso NF Masyuk TV The role of cilia in the regulation of bile flowDig Dis2011 29612

    Not in our library10.1159/000324121

  53. 53.

    Masyuk T Masyuk A LaRusso N Cholangiociliopathies: genetics, molecular mechanisms and potential therapiesCurr Opin Gastroenterol2009 25265271

    Not in our library10.1097/mog.0b013e328328f4ff

  54. 54.

    Masyuk AI Masyuk TV LaRusso NF Cholangiocyte primary cilia in liver health and diseaseDev Dyn2008 23720072012

    Not in our library10.1002/dvdy.21530

  55. 55.

    Masyuk AI Gradilone SA Banales JM Huang BQ Masyuk TV Lee SO Splinter PL Stroope AJ Larusso NF Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptorsAm J Physiol Gastrointest Liver Physiol2008 295G725G734

    Not in our library10.1152/ajpgi.90265.2008

  56. 56.

    Gradilone SA Masyuk AI Splinter PL Banales JM Huang BQ Tietz PS Masyuk TV Larusso NF Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretionProc Natl Acad Sci U S A2007 1041913819143

    Not in our library10.1073/pnas.0705964104

  57. 57.

    Masyuk AI Masyuk TV Splinter PL Huang BQ Stroope AJ LaRusso NF Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signalingGastroenterology2006 131911920

    Not in our library10.1053/j.gastro.2006.07.003

  58. 58.

    Bimonte S De Angelis A Quagliata L Giusti F Tammaro R Dallai R Ascenzi MG Diez-Roux G Franco B Ofd1 is required in limb bud patterning and endochondral bone developmentDev Biol2011 349179191

    Not in our library10.1016/j.ydbio.2010.09.020

  59. 59.

    Marion V Stutzmann F Gerard M De Melo C Schaefer E Claussmann A Helle S Delague V Souied E Barrey C Verloes A Stoetzel C Dollfus H Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet–Biedl syndrome with situs inversus and insertional polydactylyJ Med Genet2012 4931721Epub 2012 Apr 17

    Not in our library10.1136/jmedgenet-2012-100737

  60. 60.

    Berbari NF Johnson AD Lewis JS Askwith CC Mykytyn K Identification of ciliary localization sequences within the third intracellular loop of G protein-coupled receptorsMol Biol Cell2008 1915401547

    Not in our library10.1091/mbc.e07-09-0942

  61. 61.

    Anderson CT Castillo AB Brugmann SA Helms JA Jacobs CR Stearns T Primary cilia: cellular sensors for the skeletonAnat Rec2008 29110741078

    Not in our library10.1002/ar.20754

  62. 62.

    Malone AM Anderson CT Stearns T Jacobs CR Primary cilia in boneJ MusculoskeletNeuronal Interact2007 7301

    Not in our library

  63. 63.

    Malone AM Anderson CT Tummala P Kwon RY Johnston TR Stearns T Jacobs CR Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanismProc Natl Acad Sci U S A2007 1041332513330

    Not in our library10.1073/pnas.0700636104

  64. 64.

    Haycraft CJ Zhang Q Song B Jackson WS Detloff PJ Serra R Yoder BK Intraflagellar transport is essential for endochondral bone formationDevelopment2007 134307316

    Not in our library10.1242/dev.02732

  65. 65.

    Liu A Wang B Niswander LA Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factorsDevelopment2005 13231033111

    Not in our library10.1242/dev.01894

  66. 66.

    Weatherbee SD Niswander LA Anderson KV A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signalingHum Mol Genet2009 1845654575

    Not in our library10.1093/hmg/ddp422

  67. 67.

    Cattaneo I Condorelli L Terrinoni AR Antiga L Sangalli F Remuzzi A Shear stress reverses dome formation in confluent renal tubular cellsCell Physiol Biochem2011 28673682

    Not in our library10.1159/000335813

  68. 68.

    Clement CA Kristensen SG Mollgard K Pazour GJ Yoder BK Larsen LA Christensen ST The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiationJ Cell Sci2009 122Pt 1730703082

    Not in our library10.1242/jcs.049676

  69. 69.

    You Y Huang T Richer EJ Schmidt JE Zabner J Borok Z Brody SL Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cellsAm J Physiol Lung Cell Mol Physiol2004 286L650L657

    Not in our library10.1152/ajplung.00170.2003

  70. 70.

    Patel AC Brody SL Stappenbeck TS Holtzman MJ Tracking cell lineage to rediscover (again) the switch from ciliated to mucous cellsAmer J Respir Cell Mol Biol2011 44261263

    Not in our library10.1165/rcmb.2010-0468ed

  71. 71.

    Brody SL Yan XH Wuerffel MK Song SK Shapiro SD Ciliogenesis and left-right axis defects in forkhead factor HFH-4-null miceAm J Respir Cell Mol Biol2000 234551

    Not in our library10.1165/ajrcmb.23.1.4070

  72. 72.

    Horner VL Caspary T Disrupted dorsal neural tube BMP signaling in the cilia mutant Arl13b hnn stems from abnormal Shh signalingDev Biol2011 3554354

    Not in our library10.1016/j.ydbio.2011.04.019

  73. 73.

    Murdoch JN Copp AJ The relationship between sonic Hedgehog signaling, cilia, and neural tube defectsBirth Defects Res A Clin Mol Teratol2010 88633652

    Not in our library10.1002/bdra.20686

  74. 74.

    Ross AJ May-Simera H Eichers ER Kai M Hill J Jagger DJ Leitch CC Chapple JP Munro PM Fisher S Tan PL Phillips HM Leroux MR Henderson DJ Murdoch JN Copp AJ Eliot MM Lupski JR Kemp DT Dollfus H Tada M Katsanis N Forge A Beales PL Disruption of Bardet–Biedl syndrome ciliary proteins perturbs planar cell polarity in vertebratesNat Genet2005 3711351140

    Not in our library10.1038/ng1644

  75. 75.
    Ablation of Whirlin Long Isoform Disrupts the USH2 Protein Complex and Causes Vision and Hearing Loss · 2010
    No notice
  76. 76.

    Peters KR Palade GE Schneider BG Papermaster DS Fine structure of a periciliary ridge complex of frog retinal rod cells revealed by ultrahigh resolution scanning electron microscopyJ Cell Biol1983 96265276

    Not in our library10.1083/jcb.96.1.265

  77. 77.

    Ghossoub R Molla-Herman A Bastin P Benmerah A The ciliary pocket: a once-forgotten membrane domain at the base of ciliaBiol Cell2011 103131144

    Not in our library10.1042/bc20100128

  78. 78.

    Otto EA Hurd TW Airik R Chaki M Zhou W Stoetzel C Patil SB Levy S Ghosh AK Murga-Zamalloa CA van Reeuwijk J Letteboer SJ Sang L Giles RH Liu Q Coene KL Estrada-Cuzcano A Collin RW McLaughlin HM Held S Kasanuki JM Ramaswami G Conte J Lopez I Washburn J Macdonald J Hu J Yamashita Y Maher ER Guay-Woodford LM Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal–renal ciliopathyNat Genet2010 42840850

    Not in our library10.1038/ng.662

  79. 79.

    Omori Y Chaya T Katoh K Kajimura N Sato S Muraoka K Ueno S Koyasu T Kondo M Furukawa T Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survivalProc Natl Acad Sci U S A2010 1072267122676

    Not in our library10.1073/pnas.1009437108

  80. 80.

    Hong DH Yue G Adamian M Li T Retinitis pigmentosa GTPase regulator (RPGRr)-interacting protein is stably associated with the photoreceptor ciliary axoneme and anchors RPGR to the connecting ciliumJ Biol Chem2001 276151209112099

    Not in our library10.1074/jbc.m009351200

  81. 81.

    Pawlyk BS Smith AJ Buch PK Adamian M Hong DH Sandberg MA Ali RR Li T Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIPInvest Ophthalmol Vis Sci2005 4630393045

    Not in our library10.1167/iovs.05-0371

  82. 82.

    Zhao Y Hong DH Pawlyk B Yue G Adamian M Grynberg M Godzik A Li T The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesisProc Natl Acad Sci U S A2003 10039653970

    Not in our library10.1073/pnas.0637349100

  83. 83.

    Westfall JE Hoyt C Liu Q Hsiao YC Pierce EA Page-McCaw PS Ferland RJ Retinal degeneration and failure of photoreceptor outer segment formation in mice with targeted deletion of the Joubert syndrome gene, Ahi1J Neurosci2010 3087598768

    Not in our library10.1523/jneurosci.5229-09.2010

  84. 84.

    Holopainen JM Cheng CL Molday LL Johal G Coleman J Dyka F Hii T Ahn J Molday RS Interaction and localization of the retinitis pigmentosa protein RP2 and NSF in retinal photoreceptor cellsBiochemistry2010 4974397447

    Not in our library10.1021/bi1005249

  85. 85.

    Boldt K Mans DA Won J van Reeuwijk J Vogt A Kinkl N Letteboer SJ Hicks WL Hurd RE Naggert JK Texier Y den Hollander AI Koenekoop RK Bennett J Cremers FP Gloeckner CJ Nishina PM Roepman R Ueffing M Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and miceJ Clin Invest2011 12121692180

    Not in our library10.1172/jci45627

  86. 86.

    Chuang JZ Zhao Y Sung CH SARA-regulated vesicular targeting underlies formation of the light-sensing organelle in mammalian rodsCell2007 1303535547

    Not in our library10.1016/j.cell.2007.06.030

  87. 87.

    Kulaga HM Leitch CC Eichers ER Badano JL Lesemann A Hoskins BE Lupski JR Beales PL Reed RR Katsanis N Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouseNat Genet2004 369994998

    Not in our library10.1038/ng1418

  88. 88.

    Sedmak T Wolfrum U Intraflagellar transport molecules in ciliary and nonciliary cells of the retinaJ Cell Biol2010 189171186

    Not in our library10.1083/jcb.200911095

  89. 89.

    Cideciyan AV Rachel RA Aleman TS Swider M Schwartz SB Sumaroka A Roman AJ Stone EM Jacobson SG Swaroop A Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathyHum Mol Genet2011 2014111423

    Not in our library10.1093/hmg/ddr022

  90. 90.

    McEwen DP Koenekoop RK Khanna H Jenkins PM Lopez I Swaroop A Martens JR Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neuronsProc Natl Acad Sci U S A2007 1041591715922

    Not in our library10.1073/pnas.0704140104

  91. 91.

    Murga-Zamalloa CA Ghosh AK Patil SB Reed NA Chan LS Davuluri S Peranen J Hurd TW Rachel RA Khanna H Accumulation of the Raf-1 kinase inhibitory protein (Rkip) is associated with Cep290-mediated photoreceptor degeneration in ciliopathiesJ Biol Chem2011 2862827628286

    Not in our library10.1074/jbc.m111.237560

  92. 92.

    Hong DH Pawlyk B Sokolov M Strissel KJ Yang J Tulloch B Wright AF Arshavsky VY Li T RPGR isoforms in photoreceptor connecting cilia and the transitional zone of motile ciliaInvest Ophthalmol Vis Sci2003 4424132421

    Not in our library10.1167/iovs.02-1206

  93. 93.

    Brunner S Skosyrski S Kirschner-Schwabe R Knobeloch KP Neidhardt J Feil S Glaus E Luhmann UF Ruther K Berger W Cone versus rod disease in a mutant Rpgr mouse caused by different genetic backgroundsInvest Ophthalmol Vis Sci2010 5111061115

    Not in our library10.1167/iovs.08-2742

  94. 94.

    Hong DH Pawlyk BS Adamian M Sandberg MA Li T A single, abbreviated RPGR-ORF15 variant reconstitutes RPGR function in vivoInvest Ophthalmol Vis Sci2005 46435441

    Not in our library10.1167/iovs.04-1065

  95. 95.
    A retinitis pigmentosa GTPase regulator (RPGR)- deficient mouse model for X-linked retinitis pigmentosa (RP3) · 2000
    Not checked
  96. 96.

    Hosch J Lorenz B Stieger K RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapyOphthalmic Genet2011 32111

    Not in our library10.3109/13816810.2010.535889

  97. 97.

    Kirschner R Rosenberg T Schultz-Heienbrok R Lenzner S Feil S Roepman R Cremers FP Ropers HH Berger W RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosaHum Mol Genet1999 815711578

    Not in our library10.1093/hmg/8.8.1571

  98. 98.

    Mavlyutov TA Zhao H Ferreira PA Species-specific subcellular localization of RPGR and RPGRIP isoforms: implications for the phenotypic variability of congenital retinopathies among speciesHum Mol Genet2002 1118991907

    Not in our library10.1093/hmg/11.16.1899

  99. 99.

    Murga-Zamalloa C Swaroop A Khanna H Multiprotein complexes of Retinitis Pigmentosa GTPase regulator (RPGR), a ciliary protein mutated in X-linked Retinitis Pigmentosa (XLRP)Adv Exp Med Biol2010 664105114

    Not in our library10.1007/978-1-4419-1399-9_13

  100. 100.

    Arts HH Doherty D van Beersum SE Parisi MA Letteboer SJ Gorden NT Peters TA Marker T Voesenek K Kartono A Ozyurek H Farin FM Kroes HY Wolfrum U Brunner HG Cremers FP Glass IA Knoers NV Roepman R Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndromeNat Genet2007 39882888

    Not in our library10.1038/ng2069

  101. 101.

    Brancati F Travaglini L Zablocka D Boltshauser E Accorsi P Montagna G Silhavy JL Barrano G Bertini E Emma F Rigoli L Dallapiccola B Gleeson JG Valente EM RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disordersClin Genet2008 74164170

    Not in our library10.1111/j.1399-0004.2008.01047.x

  102. 102.

    Delous M Baala L Salomon R Laclef C Vierkotten J Tory K Golzio C Lacoste T Besse L Ozilou C Moutkine I Hellman NE Anselme I Silbermann F Vesque C Gerhardt C Rattenberry E Wolf MT Gubler MC Martinovic J Encha-Razavi F Boddaert N Gonzales M Macher MA Nivet H Champion G Bertheleme JP Niaudet P McDonald F Hildebrandt F The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndromeNat Genet2007 39875881

    Not in our library10.1038/ng2039

  103. 103.

    Khanna H Davis EE Murga-Zamalloa CA Estrada-Cuzcano A Lopez I den Hollander AI Zonneveld MN Othman MI Waseem N Chakarova CF Maubaret C Diaz-Font A MacDonald I Muzny DM Wheeler DA Morgan M Lewis LR Logan CV Tan PL Beer MA Inglehearn CF Lewis RA Jacobson SG Bergmann C Beales PL Attie-Bitach T Johnson CA Otto EA Bhattacharya SS Hildebrandt F A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathiesNat Genet2009 41739745

    Not in our library10.1038/ng.366

  104. 104.

    Liu L Zhang M Xia Z Xu P Chen L Xu T Caenorhabditis elegans ciliary protein NPHP-8, the homologue of human RPGRIP1L, is required for ciliogenesis and chemosensationBiochem Biophys Res Commun2011 410626631

    Not in our library10.1016/j.bbrc.2011.06.041

  105. 105.

    Wolf MT Saunier S O'Toole JF Wanner N Groshong T Attanasio M Salomon R Stallmach T Sayer JA Waldherr R Griebel M Oh J Neuhaus TJ Josefiak U Antignac C Otto EA Hildebrandt F Mutational analysis of the RPGRIP1L gene in patients with Joubert syndrome and nephronophthisisKidney Int2007 7215201526

    Not in our library10.1038/sj.ki.5002630

  106. 106.

    Pazour GJ Baker SA Deane JA Cole DG Dickert BL Rosenbaum JL Witman GB Besharse JC The intraflagellar transport protein, IFT88, is essential for vertebrate photoreceptor assembly and maintenanceJ Cell Biol2002 157103113

    Not in our library10.1083/jcb.200107108

  107. 107.

    Sukumaran S Perkins BD Early defects in photoreceptor outer segment morphogenesis in zebrafish ift57, ift88 and ift172 intraflagellar transport mutantsVision Res2009 49479489

    Not in our library10.1016/j.visres.2008.12.009

  108. 108.

    Tsujikawa M Malicki J Intraflagellar transport genes are essential for differentiation and survival of vertebrate sensory neuronsNeuron2004 42703716

    Not in our library10.1016/s0896-6273(04)00268-5

  109. 109.

    Whitehead JL Wang SY Bost-Usinger L Hoang E Frazer KA Burnside B Photoreceptor localization of the KIF3A and KIF3B subunits of the heterotrimeric microtubule motor kinesin II in vertebrate retinaExp Eye Res1999 69491503

    Not in our library10.1006/exer.1999.0724

  110. 110.

    Dafinger C Liebau MC Elsayed SM Hellenbroich Y Boltshauser E Korenke GC Fabretti F Janecke AR Ebermann I Nurnberg G Nurnberg P Zentgraf H Koerber F Addicks K Elsobky E Benzing T Schermer B Bolz HJ Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamicsJ Clin Invest2011 12126622667

    Not in our library10.1172/jci43639

  111. 111.

    Gerdes JM Liu Y Zaghloul NA Leitch CC Lawson SS Kato M Beachy PA Beales PL DeMartino GN Fisher S Badano JL Katsanis N Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt responseNat Genet2007 3913501360

    Not in our library10.1038/ng.2007.12

  112. 112.

    Pretorius PR Baye LM Nishimura DY Searby CC Bugge K Yang B Mullins RF Stone EM Sheffield VC Slusarski DC Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoformPLoS Genet2010 6e1000884

    Not in our library10.1371/journal.pgen.1000884

  113. 113.

    Kim JC Ou YY Badano JL Esmail MA Leitch CC Fiedrich E Beales PL Archibald JM Katsanis N Rattner JB Leroux MR MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet–Biedl syndrome, is a novel centrosomal component required for cytokinesisJ Cell Sci2005 118Pt 510071020

    Not in our library10.1242/jcs.01676

  114. 114.

    Ansley SJ Badano JL Blacque OE Hill J Hoskins BE Leitch CC Kim JC Ross AJ Eichers ER Teslovich TM Mah AK Johnsen RC Cavender JC Lewis RA Leroux MR Beales PL Katsanis N Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndromeNature2003 425628633

    Not in our library10.1038/nature02030

  115. 115.

    Lim YS Chua CE Tang BL Rabs and other small GTPases in ciliary transportBiol Cell2011 103209221

    Not in our library10.1042/bc20100150

  116. 116.

    Liu X Bulgakov OV Darrow KN Pawlyk B Adamian M Liberman MC Li T Usherin is required for maintenance of retinal photoreceptors and normal development of cochlear hair cellsProc Natl Acad Sci U S A2007 10444134418

    Not in our library10.1073/pnas.0610950104

  117. 117.

    Yang J Liu X Yue G Adamian M Bulgakov O Li T Rootletin, a novel coiled-coil protein, is a structural component of the ciliary rootletJ Cell Biol2002 159431440

    Not in our library10.1083/jcb.200207153

  118. 118.

    Wright RN Hong DH Perkins B RpgrORF15 connects to the Usher protein network through direct interactions with multiple whirlin isoformsInvest Ophthalmol Vis Sci2012 53151929Print 2012 Mar

    Not in our library10.1167/iovs.11-8845

  119. 119.

    Katsanis N Ansley SJ Badano JL Eichers ER Lewis RA Hoskins BE Scambler PJ Davidson WS Beales PL Lupski JR Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorderScience2001 29322562259

    Not in our library10.1126/science.1063525

  120. 120.

    Doherty D Parisi MA Finn LS Gunay-Aygun M Al-Mateen M Bates D Clericuzio C Demir H Dorschner M van Essen AJ Gahl WA Gentile M Gorden NT Hikida A Knutzen D Ozyurek H Phelps I Rosenthal P Verloes A Weigand H Chance PF Dobyns WB Glass IA Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)J Med Genet2010 47821

    Not in our library10.1136/jmg.2009.067249

  121. 121.

    Leitch CC Zaghloul NA Davis EE Stoetzel C Diaz-Font A Rix S Alfadhel M Lewis RA Eyaid W Banin E Dollfus H Beales PL Badano JL Katsanis N Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet–Biedl syndromeNat Genet2008 40443448

    Not in our library10.1038/ng.97

  122. 122.

    Karska-Basta I Kubicka-Trzaska A Filemonowicz-Skoczek A Romanowska-Dixon B Kobylarz J Alstrom syndrome – a case report and literature reviewKlin Oczna2008 110188192

    Not in our library

  123. 123.

    Helou J Otto EA Attanasio M Allen SJ Parisi MA Glass I Utsch B Hashmi S Fazzi E Omran H O'Toole JF Sayer JA Hildebrandt F Mutation analysis of NPHP6/CEP290 in patients with Joubert syndrome and Senior-Loken syndromeJournal of Medical Genetics2007 4410657663

    Not in our library10.1136/jmg.2007.052027

  124. 124.

    Roepman R Letteboer SJ Arts HH van Beersum SE Lu X Krieger E Ferreira PA Cremers FP Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis or Leber congenital amaurosis-associated mutationsProc Natl Acad Sci U S A2005 1021852018525

    Not in our library10.1073/pnas.0505774102

  125. 125.

    Stone EM Cideciyan AV Aleman TS Scheetz TE Sumaroka A Ehlinger MA Schwartz SB Fishman GA Traboulsi EI Lam BL Fulton AB Mullins RF Sheffield VC Jacobson SG Variations in NPHP5 in patients with nonsyndromic leber congenital amaurosis and Senior–Loken syndromeArch Ophthalmol2011 1298187

    Not in our library10.1001/archophthalmol.2010.330

  126. 126.

    Casteels I Demandt E Legius E Visual loss as the presenting sign of Jeune syndromeEur J Paediatr Neurol2000 4243247

    Not in our library10.1053/ejpn.2000.0313

  127. 127.

    den Hollander AI Roepman R Koenekoop RK Cremers FP Leber congenital amaurosis: genes, proteins and disease mechanismsProg Retin Eye Res2008 27391419

    Not in our library10.1016/j.preteyeres.2008.05.003

  128. 128.

    Vervoort R Lennon A Bird AC Tulloch B Axton R Miano MG Meindl A Meitinger T Ciccodicola A Wright AF Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosaNat Genet2000 25462466

    Not in our library10.1038/78182

  129. 129.

    Breuer DK Yashar BM Filippova E Hiriyanna S Lyons RH Mears AJ Asaye B Acar C Vervoort R Wright AF Musarella MA Wheeler P MacDonald I Iannaccone A Birch D Hoffman DR Fishman GA Heckenlively JR Jacobson SG Sieving PA Swaroop A A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosaAm J Hum Genet2002 7015451554

    Not in our library10.1086/340848

  130. 130.

    Jimeno D Feiner L Lillo C Teofilo K Goldstein LS Pierce EA Williams DS Analysis of kinesin-2 function in photoreceptor cells using synchronous Cre-loxP knockout of Kif3a with RHO-CreInvest Ophthalmol Vis Sci2006 4750395046

    Not in our library10.1167/iovs.06-0032

  131. 131.

    Marszalek JR Liu X Roberts EA Chui D Marth JD Williams DS Goldstein LS Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptorsCell2000 102175187

    Not in our library10.1016/s0092-8674(00)00023-4

  132. 132.

    Won J Shi LY Hicks W Wang J Hurd R Naggert JK Chang B Nishina PM Mouse model resources for vision researchJ Ophthalmol2011 391384Epub 2010 Oct 31

    Not in our library10.1155/2011/391384

  133. 133.

    Liu Q Saveliev A Pierce EA The severity of retinal degeneration in Rp1h gene-targeted mice is dependent on genetic backgroundInvest Ophthalmol Vis Sci2009 5015661574

    Not in our library10.1167/iovs.08-2776

  134. 134.

    Liu J Huang Q Higdon J Liu W Xie T Yamashita T Cheon K Cheng C Zuo J Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutationsHum Mol Genet2005 1429452958

    Not in our library10.1093/hmg/ddi325

  135. 135.

    Gao J Cheon K Nusinowitz S Liu Q Bei D Atkins K Azimi A Daiger SP Farber DB Heckenlively JR Pierce EA Sullivan LS Zuo J Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) geneProc Natl Acad Sci U S A2002 9956985703

    Not in our library10.1073/pnas.042122399

  136. 136.

    Schwartz SB Aleman TS Cideciyan AV Swaroop A Jacobson SG Stone EM De novo mutation in the RP1 gene (Arg677ter) associated with retinitis pigmentosaInvest Ophthalmol Vis Sci2003 4435933597

    Not in our library10.1167/iovs.03-0155

  137. 137.

    Cideciyan AV Aleman TS Jacobson SG Khanna H Sumaroka A Aguirre GK Schwartz SB Windsor EA He S Chang B Stone EM Swaroop A Centrosomal-ciliary gene CEP290/NPHP6 mutations result in blindness with unexpected sparing of photoreceptors and visual brain: implications for therapy of Leber congenital amaurosisHum Mutat2007 2810741083

    Not in our library10.1002/humu.20565

  138. 138.

    Louie CM Caridi G Lopes VS Brancati F Kispert A Lancaster MA Schlossman AM Otto EA Leitges M Grone HJ Lopez I Gudiseva HV O'Toole JF Vallespin E Ayyagari R Ayuso C Cremers FP den Hollander AI Koenekoop RK Dallapiccola B Ghiggeri GM Hildebrandt F Valente EM Williams DS Gleeson JG AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisisNat Genet2010 42175180

    Not in our library10.1038/ng.519

  139. 139.

    Lancaster MA Gopal DJ Kim J Saleem SN Silhavy JL Louie CM Thacker BE Williams Y Zaki MS Gleeson JG Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndromeNat Med2011 17726731

    Not in our library10.1038/nm.2380

  140. 140.

    Collin GB Won J Hicks WL Cook SA Nishina PM Naggert JK Meckelin is necessary for photoreceptor intraciliary transport and outer segment morphogenesisInvest Ophthalmol Vis Science2012 53967974Print 2012 Feb

    Not in our library10.1167/iovs.11-8766

  141. 141.

    Bhowmick R Li M Sun J Baker SA Insinna C Besharse JC Photoreceptor IFT complexes containing chaperones, guanylyl cyclase 1 and rhodopsinTraffic2009 10648663

    Not in our library10.1111/j.1600-0854.2009.00896.x

  142. 142.

    Liem KF Jr He M, Ocbina PJ, Anderson KV: Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signalingProc Natl Acad Sci U S A2009 1061337713382

    Not in our library10.1073/pnas.0906944106

  143. 143.

    Chapple JP Hardcastle AJ Grayson C Spackman LA Willison KR Cheetham ME Mutations in the N-terminus of the X-linked retinitis pigmentosa protein RP2 interfere with the normal targeting of the protein to the plasma membraneHum Mol Genet2000 919191926

    Not in our library10.1093/hmg/9.13.1919

  144. 144.

    Evans RJ Schwarz N Nagel-Wolfrum K Wolfrum U Hardcastle AJ Cheetham ME The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary ciliumHum Mol Genet2010 1913581367

    Not in our library10.1093/hmg/ddq012

  145. 145.

    Hurd T Zhou W Jenkins P Liu CJ Swaroop A Khanna H Martens J Hildebrandt F Margolis B The retinitis pigmentosa protein RP2 interacts with polycystin 2 and regulates cilia-mediated vertebrate developmentHum Mol Genet2010 1943304344

    Not in our library10.1093/hmg/ddq355

  146. 146.

    Won J Gifford E Smith RS Yi H Ferreira PA Hicks WL Li T Naggert JK Nishina PM RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesisHum Mol Genet2009 1843294339

    Not in our library10.1093/hmg/ddp385

  147. 147.

    Pawlyk BS Bulgakov OV Liu X Xu X Adamian M Sun X Khani SC Berson EL Sandberg MA Li T Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosisHum Gene Ther2010 219931004

    Not in our library10.1089/hum.2009.218

  148. 148.

    Garcia-Gonzalo FR Corbit KC Sirerol-Piquer MS Ramaswami G Otto EA Noriega TR Seol AD Robinson JF Bennett CL Josifova DJ Garcia-Verdugo JM Katsanis N Hildebrandt F Reiter JF A transition zone complex regulates mammalian ciliogenesis and ciliary membrane compositionNat Genet2011 43776784

    Not in our library10.1038/ng.891

  149. 149.

    Thompson DA Khan NW Othman MI Chang B Jia L Grahek G Wu Z Hiriyanna S Nellissery J Li T Khanna H Colosi P Swaroop A Heckenlively JR Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15PloS One2012 7e35865

    Not in our library10.1371/journal.pone.0035865

  150. 150.

    Huang WC Wright AF Roman AJ Cideciyan AV Manson FD Gewaily DY Schwartz SB Sadigh S Limberis MP Bell P Wilson JM Swaroop A Jacobson SG RPGR-associated retinal degeneration in human X-linked RP and a murine modelInvest Ophthalmol Vis Sci2012 5355945608Print 2012 Sep

    Not in our library10.1167/iovs.12-10070

  151. 151.

    Jagger D Collin G Kelly J Towers E Nevill G Longo-Guess C Benson J Halsey K Dolan D Marshall J Naggert J Forge A Alstrom syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarityHum Mol Genet2011 20466481

    Not in our library10.1093/hmg/ddq493

  152. 152.

    Huang-Doran I Semple RK Knockdown of the Alstrom syndrome-associated gene Alms1 in 3 T3-L1 preadipocytes impairs adipogenesis but has no effect on cell-autonomous insulin actionInt J Obesity2010 3415541558

    Not in our library10.1038/ijo.2010.92

  153. 153.

    Arsov T Silva DG O'Bryan MK Sainsbury A Lee NJ Kennedy C Manji SS Nelms K Liu C Vinuesa CG de Kretser DM Goodnow CC Petrovsky N Fat aussie – a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesisMol Endocrinol2006 2016101622

    Not in our library10.1210/me.2005-0494

  154. 154.

    Collin GB Cyr E Bronson R Marshall JD Gifford EJ Hicks W Murray SA Zheng QY Smith RS Nishina PM Naggert JK Alms1-disrupted mice recapitulate human Alstrom syndromeHum Mol Genet2005 1423232333

    Not in our library10.1093/hmg/ddi235

  155. 155.

    Zhang Q Nishimura D Seo S Vogel T Morgan DA Searby C Bugge K Stone EM Rahmouni K Sheffield VC Bardet–Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypesProc Natl Acad Sci U S A2011 1082067820683Epub 2011 Dec 2

    Not in our library10.1073/pnas.1113220108

  156. 156.

    Davis RE Swiderski RE Rahmouni K Nishimura DY Mullins RF Agassandian K Philp AR Searby CC Andrews MP Thompson S Berry CJ Thedens DR Yang B Weiss RM Cassell MD Stone EM Sheffield VC A knockin mouse model of the Bardet–Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesityProc Natl Acad Sci U S A2007 1041942219427

    Not in our library10.1073/pnas.0708571104

  157. 157.

    Nishimura DY Fath M Mullins RF Searby C Andrews M Davis R Andorf JL Mykytyn K Swiderski RE Yang B Carmi R Stone EM Sheffield VC Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsinProc Natl Acad Sci U S A2004 1011658816593

    Not in our library10.1073/pnas.0405496101

  158. 158.

    Rahmouni K Fath MA Seo S Thedens DR Berry CJ Weiss R Nishimura DY Sheffield VC Leptin resistance contributes to obesity and hypertension in mouse models of Bardet–Biedl syndromeJ Clin Invest2008 11814581467

    Not in our library10.1172/jci32357

  159. 159.

    Abd-El-Barr MM Sykoudis K Andrabi S Eichers ER Pennesi ME Tan PL Wilson JH Katsanis N Lupski JR Wu SM Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndromeVis Res2007 4733943407

    Not in our library10.1016/j.visres.2007.09.016

  160. 160.

    Mykytyn K Mullins RF Andrews M Chiang AP Swiderski RE Yang B Braun T Casavant T Stone EM Sheffield VC Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assemblyProc Natl Acad Sci U S A2004 10186648669

    Not in our library10.1073/pnas.0402354101

  161. 161.

    Simons DL Boye SL Hauswirth WW Wu SM Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet–Biedl syndrome mouse modelProc Natl Acad Sci U S A2011 10862766281

    Not in our library10.1073/pnas.1019222108

  162. 162.

    Tadenev AL Kulaga HM May-Simera HL Kelley MW Katsanis N Reed RR Loss of Bardet–Biedl syndrome protein-8 (BBS8) perturbs olfactory function, protein localization, and axon targetingProc Natl Acad Sci U S A2011 1081032010325

    Not in our library10.1073/pnas.1016531108

  163. 163.

    Fath MA Mullins RF Searby C Nishimura DY Wei J Rahmouni K Davis RE Tayeh MK Andrews M Yang B Sigmund CD Stone EM Sheffield VC Mkks-null mice have a phenotype resembling Bardet–Biedl syndromeHum Mol Genet2005 1411091118

    Not in our library10.1093/hmg/ddi123

  164. 164.

    Sato T Mushiake S Kato Y Sato K Sato M Takeda N Ozono K Miki K Kubo Y Tsuji A Harada R Harada A The Rab8 GTPase regulates apical protein localization in intestinal cellsNature2007 448366369

    Not in our library10.1038/nature05929

  165. 165.

    Kudryashova E Wu J Havton LA Spencer MJ Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic componentHum Mol Genet2009 1813531367

    Not in our library10.1093/hmg/ddp036

  166. 166.

    Brancati F Barrano G Silhavy JL Marsh SE Travaglini L Bielas SL Amorini M Zablocka D Kayserili H Al-Gazali L Bertini E Boltshauser E D'Hooghe M Fazzi E Fenerci EY Hennekam RC Kiss A Lees MM Marco E Phadke SR Rigoli L Romano S Salpietro CD Sherr EH Signorini S Stromme P Stuart B Sztriha L Viskochil DH Yuksel A CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disordersAm J Hum Genet2007 81104113

    Not in our library10.1086/519026

  167. 167.

    Valente EM Silhavy JL Brancati F Barrano G Krishnaswami SR Castori M Lancaster MA Boltshauser E Boccone L Al-Gazali L Fazzi E Signorini S Louie CM Bellacchio E Bertini E Dallapiccola B Gleeson JG Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndromeNat Genet2006 38623625

    Not in our library10.1038/ng1805

  168. 168.

    Coppieters F Lefever S Leroy BP De Baere E CEP290, a gene with many faces: mutation overview and presentation of CEP290baseHum Mutat2010 3110971108

    Not in our library10.1002/humu.21337

  169. 169.
    Genetic screening of LCA in Belgium: predominance of CEP290 and identification of potential modifier alleles in AHI1 of CEP290-related phenotypes · 2010
    No notice
  170. 170.

    Morecroft I Doyle B Nilsen M Kolch W Mair K Maclean MR Mice lacking the Raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertensionBr J Pharmacol2011 163948963

    Not in our library10.1111/j.1476-5381.2011.01305.x

  171. 171.

    Iannaccone A Wang X Jablonski MM Kuo SF Baldi A Cosgrove D Morton CC Swaroop A Increasing evidence for syndromic phenotypes associated with RPGR mutationsAm J Ophthalmol2004 137785786author reply 786

    Not in our library10.1016/j.ajo.2003.11.050

  172. 172.

    Shu X Black GC Rice JM Hart-Holden N Jones A O'Grady A Ramsden S Wright AF RPGR mutation analysis and disease: an updateHum Mutat2007 28322328

    Not in our library10.1002/humu.20461

  173. 173.

    Zito I Downes SM Patel RJ Cheetham ME Ebenezer ND Jenkins SA Bhattacharya SS Webster AR Holder GE Bird AC Bamiou DE Hardcastle AJ RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infectionsJ Med Genet2003 40609615

    Not in our library10.1136/jmg.40.8.609

  174. 174.

    Schmid F Glaus E Cremers FP Kloeckener-Gruissem B Berger W Neidhardt J Mutation- and tissue-specific alterations of RPGR transcriptsInvest Ophthalmol Vis Sci2010 5116281635

    Not in our library10.1167/iovs.09-4031

  175. 175.

    Hong DH Li T Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing enhancersInvest Ophthalmol Vis Sci2002 4333733382

    Not in our library

  176. 176.

    He S Parapuram SK Hurd TW Behnam B Margolis B Swaroop A Khanna H Retinitis Pigmentosa GTPase Regulator (RPGR) protein isoforms in mammalian retina: insights into X-linked Retinitis Pigmentosa and associated ciliopathiesVision Res2008 48366376

    Not in our library10.1016/j.visres.2007.08.005

  177. 177.

    Meindl A Dry K Herrmann K Manson F Ciccodicola A Edgar A Carvalho MR Achatz H Hellebrand H Lennon A Migliaccio C Porter K Zrenner E Bird A Jay M Lorenz B Wittwer B D'Urso M Meitinger T Wright A A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3)Nat Genet1996 133542

    Not in our library10.1038/ng0596-35

  178. 178.

    Yan D Swain PK Breuer D Tucker RM Wu W Fujita R Rehemtulla A Burke D Swaroop A Biochemical characterization and subcellular localization of the mouse retinitis pigmentosa GTPase regulator (mRpgr)J Biol Chem1998 2731965619663

    Not in our library10.1074/jbc.273.31.19656

  179. 179.

    Iannaccone A Breuer DK Wang XF Kuo SF Normando EM Filippova E Baldi A Hiriyanna S MacDonald CB Baldi F Cosgrove D Morton CC Swaroop A Jablonski MM Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with recurrent infections and hearing loss in association with an RPGR mutationJ Med Genet2003 40e118

    Not in our library10.1136/jmg.40.11.e118

  180. 180.

    Sharon D Sandberg MA Rabe VW Stillberger M Dryja TP Berson EL RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosaAm J Hum Genet2003 7311311146

    Not in our library10.1086/379379

  181. 181.

    Ocbina PJ Eggenschwiler JT Moskowitz I Anderson KV Complex interactions between genes controlling trafficking in primary ciliaNat Genet2011 43547553

    Not in our library10.1038/ng.832

  182. 182.

    Friedman TB Schultz JM Ahmed ZM Tsilou ET Brewer CC Usher syndrome: hearing loss with vision lossAdv Otorhinolaryngol2011 705665

    Not in our library10.1159/000322473

  183. 183.

    Murga-Zamalloa CA Swaroop A Khanna H RPGR-containing protein complexes in syndromic and non-syndromic retinal degeneration due to ciliary dysfunctionJ Genet2009 88399407

    Not in our library10.1007/s12041-009-0061-7

  184. 184.

    Travaglini L Brancati F Attie-Bitach T Audollent S Bertini E Kaplan J Perrault I Iannicelli M Mancuso B Rigoli L Rozet JM Swistun D Tolentino J Dallapiccola B Gleeson JG Valente EM Zankl A Leventer R Grattan-Smith P Janecke A D'Hooghe M Sznajer Y Van Coster R Demerleir L Dias K Moco C Moreira A Kim CA Maegawa G Petkovic D Expanding CEP290 mutational spectrum in ciliopathiesAm J Med Genet A2009 149A21732180

    Not in our library10.1002/ajmg.a.33025

  185. 185.

    Chaki M Hoefele J Allen SJ Ramaswami G Janssen S Bergmann C Heckenlively JR Otto EA Hildebrandt F Genotype–phenotype correlation in 440 patients with NPHP-related ciliopathiesKidney Int2011 8012391245

    Not in our library10.1038/ki.2011.284

  186. 186.

    Zhang Q Seo S Bugge K Stone EM Sheffield VC BBS proteins interact genetically with the IFT pathway to influence SHH related phenotypesHum Mol Genet2012 2119451953Epub 2012 Jan 6

    Not in our library10.1093/hmg/dds004

  187. 187.

    Badano JL Kim JC Hoskins BE Lewis RA Ansley SJ Cutler DJ Castellan C Beales PL Leroux MR Katsanis N Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet–Biedl patients with two mutations at a second BBS locusHum Mol Genet2003 1216511659

    Not in our library10.1093/hmg/ddg188

  188. 188.

    Beales PL Badano JL Ross AJ Ansley SJ Hoskins BE Kirsten B Mein CA Froguel P Scambler PJ Lewis RA Lupski JR Katsanis N Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet–Biedl syndromeAm J Hum Genet2003 7211871199

    Not in our library10.1086/375178

  189. 189.

    Bin J Madhavan J Ferrini W Mok CA Billingsley G Heon E BBS7 and TTC8 (BBS8) mutations play a minor role in the mutational load of Bardet–Biedl syndrome in a multiethnic populationHum Mutat2009 30E737E746

    Not in our library10.1002/humu.21040

  190. 190.

    Katsanis N Eichers ER Ansley SJ Lewis RA Kayserili H Hoskins BE Scambler PJ Beales PL Lupski JR BBS4 is a minor contributor to Bardet–Biedl syndrome and may also participate in triallelic inheritanceAm J Hum Genet2002 712229

    Not in our library10.1086/341031

  191. 191.

    Takeda S Narita K Structure and function of vertebrate cilia, towards a new taxonomyDifferentiation2011 83S4S11Epub 2011 Nov 25

    Not in our library10.1016/j.diff.2011.11.002

  192. 192.

    Nachury MV Loktev AV Zhang Q Westlake CJ Peranen J Merdes A Slusarski DC Scheller RH Bazan JF Sheffield VC Jackson PK A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesisCell2007 12912011213

    Not in our library10.1016/j.cell.2007.03.053

  193. 193.

    Sang L Miller JJ Corbit KC Giles RH Brauer MJ Otto EA Baye LM Wen X Scales SJ Kwong M Huntzicker EG Sfakianos MK Sandoval W Bazan JF Kulkarni P Garcia-Gonzalo FR Seol AD O'Toole JF Held S Reutter HM Lane WS Rafiq MA Noor A Ansar M Devi AR Sheffield VC Slusarski DC Vincent JB Doherty DA Hildebrandt F Mapping the NPHP–JBTS–MKS protein network reveals ciliopathy disease genes and pathwaysCell2011 145513528

    Not in our library10.1016/j.cell.2011.04.019

  194. 194.

    van Reeuwijk J Arts HH Roepman R Scrutinizing ciliopathies by unraveling ciliary interaction networksHum Mol Genet2011 20R2R149R157

    Not in our library10.1093/hmg/ddr354

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