A systems-biology approach to understanding the ciliopathy disorders
© BioMed Central Ltd. 2011
Published: 26 September 2011
'Ciliopathies' are an emerging class of genetic multisystemic human disorders that are caused by a multitude of largely unrelated genes that affect ciliary structure/function. They are unified by shared clinical features, such as mental retardation, cystic kidney, retinal defects and polydactyly, and by the common localization of the protein products of these genes at or near the primary cilium of cells. With the realization that many previously disparate conditions are a part of this spectrum of disorders, there has been tremendous interest in the function of cilia in developmental signaling and homeostasis. Ciliopathies are mostly inherited as simple recessive traits, but phenotypic expressivity is under the control of numerous genetic modifiers, putting these conditions at the interface of simple and complex genetics. In this review, we discuss the ever-expanding ciliopathy field, which has three interrelated goals: developing a comprehensive understanding of genes mutated in the ciliopathies and required for ciliogenesis; understanding how the encoded proteins work together in complexes and networks to modulate activity and structure-function relationships; and uncovering signaling pathways and modifier relationships.
Cilia maintain separate cytoplasmic and membrane compartments, but are completely lacking vesicles. Instead cilia rely on specialized modes of transportation called intraflagellar transport (IFT) to deliver cargo proteins and lipids along the axoneme. IFT can operate in the anterograde direction (towards the ciliary tip) using complex B factors, or in the retrograde direction (towards the ciliary base) using complex A factors; together these factors regulate the transport speed and net cargo flux. An important, recently emerged aspect of cilia is the gatekeeper role of the septin family of proteins, regulating initial entry and exit of ciliary factors at the base of the cilium . The transition zone, where the gatekeeper functions, is an adjacent structure at the base of the cilium, forming the linkers between microtubule and ciliary membrane; it is probably required for unloading ciliary-directed cargo and sorting ciliary-based signaling mechanisms  so that the cell can interpret their context.
Emerging genetics of the ciliopathies
Ciliopathies, genes and subcellular functions of the proteins
Putative protein functions
Primary ciliary dyskinesia (PCD)/Kartagener syndrome (KS)
Chronic sinusitis, bronchiectasis and infertility with situs inversus (KS only) and occasional hydrocephalus (PCD)
Dynein arm preassembly, Cilia motility
Leber congenital amaurosis (LCA)
Retinal dystrophy, blindness or severe visual impairment such as sensory nystagmus, amaurotic pupils and absent electroretinogram signal
RPGR complex, trafficking
RPGR complex, trafficking
Polycystic kidney disease (PKD): dominant (ADPKD), recessive (ARPKD)
Hepatic cysts, pancreatic cysts (10%), cysts in the nephron (ADPKD only) and hepatic fibrosis, cysts in collecting ducts (ARPKD only)
Autosomal dominant, Autosomal recessive
Mechanosensation, cell-cell or cell-matrix interactions
Probable calcium channel protein
Probable receptor protein, PC2 modulation
Jeune asphyxiating thoracic dystrophy (JATD)
Postaxial polydactyly, short limbs, short and slender ribs, small ilia, irregular acetabulum and cystic kidney
Role in Shh signaling
Ellis-van Creveld syndrome (EVC)
Polydactyly, short ribs, dysplastic fingernails/teeth and cardiac defects
Oral-facial-digital syndrome type I (OFD1)
Craniofacial malformations, postaxial polydactyly, central nervous system defects and cystic kidney (~15%)
Ciliogenesis, Wnt/PCP signaling, association with LCA5 and SDCCAG8
Triad of tubular basement membrane disruption, tubulointerstitial nephropathy, corticomedullary cysts. Pancreatic/hepatic fibrosis, situs inversus, retinitis pigmentosa, cerebellar vermis hypoplasia, oculomotor apraxia and mental retardation (~10%)
Cilia structure, cell-cell adhesion
Wnt/PCP, cell cycle control
Cilia structure, IFT
RPGR complex, trafficking
Transcription factor, Wnt
Modulation of PC1 and PC2
Association with OFD1
Joubert syndrome (JBTS)/JBTS-related disorder (JSRD)
Hypotonia, ataxia, psychomotor delay, oculomotor apraxia, retinal degeneration and mental retardation. Occipital encephalocele, polymicrogyria, cystic kidney, hepatic fibrosis and polydactyly (JSRD)
Cilia stability, phosphatidylinositol signaling
Ciliogenesis, centrosomal docking, PCP signaling
Cilia structure, cell-cell adhesion
RPGR complex, trafficking
Cilia structure, IFT
Association with CEP290
Ciliogenesis, Wnt/PCP, association with LCA5 and SDCCAG8
Shh signaling, microtubule dynamics
Transition zone complex regulation
Bardet-Biedl syndrome (BBS)
Obesity, diabetes, polydactyly, mental retardation, cystic kidney, retinitis pigmentosa, hypogenitalism and situs inversus
BBSome, Wnt/PCP, IFT/trafficking
BBSome, IFT/trafficking, microtubule anchoring, cell cycle control
BBSome, IFT/trafficking, ciliogenesis
IFT/trafficking, Wnt/PCP, cytokinesis, chaperonin
Ciliogenesis, Wnt, chaperonin
E3 ubiquitin-protein ligase
Ciliogenesis, Wnt, chaperonin
Alström syndrome (ALMS)
Cone-rod retinal dystrophy, hearing defects, cardiomyopathy, early-onset obesity, renal failure and hepatic dysfunction
Meckel-Gruber syndrome (MKS)
Renal cysts, hepatic fibrosis, central nervous system malformations, polydactyly, liver malformations, laterality defects, cardiac defects
Ciliogenesis, centrosomal docking, PCP signaling
RPGR complex, trafficking
Association with CEP290
Although the disease-specific function of any single mutated gene in a particular ciliopathy has not yet been understood, the identification of several causative genes has contributed to a better understanding of the pathogenesis of the disorders and the biological functions of cilia over the past two decades. In the attempt to identify candidate genes, diverse high-throughput techniques have been applied, such as in silico comparative genomics, transcriptome analysis including analysis of X-box promoters, which are involved in the regulation of ciliary genes in Caenorhabditis elegans, and proteomics. These complementary approaches led to the identification of several new disease-causative ciliary genes and also propelled the ciliary biology field from basic science into the biomedical realm.
Here, we summarize the clinical and genetic features of each ciliopathy disorder and outline the expanding range of a systems-biology approach applied to the study of ciliopathies. We also discuss advantages of the new genomic approaches and future strategies that will assist the transfer of research achievements into clinical practice.
Genes required for ciliary-mediated signaling and ciliary function
Genes required for ciliary structure or motility
Formation of ciliary axonemal structures, such as the dynein arms, radial spokes, central pair of microtubules and central sheath, is necessary for regulating motility and beating of the cilia (Figure 1). Patients with primary ciliary dyskinesia or Kartagener syndrome (PCD/KS) can show ultrastructural axonemal defects in motile cilia . In addition, it is not surprising that many genes, such as DNAH5, DNAI1, DNAI2, DNAH1, KTU, RSPH9, RSPH4A and LRRC50, encoding proteins associated with ciliary axonemal architecture or entry of these factors into cilia, have been found to be mutated in PCD/KS [7–11].
Interestingly, a few genes mutated in the non-motile ciliopathies also seem to be linked with structural formation of the axoneme. For example, mutations of ARL13B in mouse Joubert syndrome (JBTS) and NPHP4 in C. elegans nephronophthisis (NPHP) give rise to ultra-structural defects of the ciliary axoneme, although the defects are relatively subtle [12, 13]. Patients with BBS have defects in the axoneme of spermatozoon flagella, which are closely related to cilia, and correspondingly Bbs2 knockout mice have abnormal spermatozoon flagellum formation . The connection between ciliary structure and function remains a central focus of the field.
Advanced high-throughput strategies in the study of ciliopathies
Using traditional approaches of human genetics, such as positional cloning, meiotic mapping, physical mapping and candidate-gene sequencing , PKD1 in PKD  and NPHP1 in NPHP  were identified as initial causative genes of ciliopathies in the late 1990s. Further diverse approaches, including promoter analysis, comparative genomics, transcriptome analysis and proteomics, have resulted in the identification of numerous ciliary-related genes and causative disease genes underlying ciliopathies [18, 19]. These new technologies gave new insights into understanding pathogenesis of the disorders and ciliary biology.
Following the identification of many causative genes underlying specific classes of ciliopathies, it was observed that the proteins from a given class of ciliopathies tend to assemble with reproducible stoichiometry. This was first demonstrated for the complex of proteins encoded by genes mutated in BBS (called the BBSome), and has since extended to proteins from other ciliopathies, including those in the NPHP-JBTS-MKS complex [20, 21]. The core of each complex is made up of the proteins identified from humans with similar disease. For example, the BBSome is constituted by tight interactions between 7 of 12 BBS proteins. The NPHP-JBTS-MKS complex contains non-overlapping components, mostly proteins previously implicated in NPHP, JBTS and MKS, but also some unexpected proteins such as ATXN10 and TCTN2, both of which were subsequently found to be mutated in NPHP and JBTS, suggesting the likely relevance of the complex.
The BBSome and the NPHP-JBTS-MKS complex are present in the ciliary region in the absence of ciliary disease. However, the function of these complexes in ciliary biology (and ciliary disease) is still not clear, although evidence suggests that the BBSome functions as a vesicular coat that transports membrane proteins to the cilia . There is mounting evidence that the NPHP-JBTS-MKS complex, with an estimated molecular weight between 0.7 and 2 MDa, functions at or near the transition zone of the primary cilia and regulates ciliary entry/localization of many proteins . It remains to be determined whether other multigenic ciliopathy disorders similarly display non-overlapping components and how such complexes function at or near the cilium.
Thus, it is informative to consider these as disease-specific protein complexes, constituted by a host of non-redundant factors, each of which serves a still poorly defined function. Work in C. elegans suggests that the MKS and NPHP proteins establish basal body/transition zone membrane attachments coincident with IFT-dependent axoneme extension. In this light, it is perhaps not surprising that genetic evidence obtained by crossing mutants in C. elegans demonstrates more severe synthetic phenotypes (functional interactions) only when mutations occur in two different disease modules . For instance, the B9 domain proteins of the MKS module functionally interact with the NPHP module  but not with most other proteins in the MKS module. We can conclude that each protein complex probably forms an intricate modular network, as evidenced by specificity in the protein complexes and by functional redundancy.
Application of next-generation sequencing
The ciliary biology field has greatly benefited from the tremendous gains in proteomics and genomics through the definition of the concept of the 'ciliome'. The ciliome consists almost completely of genes implicated in ciliary function, on the basis of a compilation of results from various studies involving human genetics, functional genetics and proteomics, and it is currently made up of more than 2,500 human orthologs. As expected, many of the genes subsequently identified as mutated in ciliopathies were already part of this compiled list, which has led to more efficient workflow by focusing on these genes. By applying next-generation sequencing (NGS) with a focus on the ciliome, new human disease genes have recently been identified in a relatively short time  and much larger groups of patients can be screened for existing genes, greatly aiding future genotype-phenotype correlations [26, 27]. The phenotypic variability often shown among ciliopathy patients carrying the same combinations of mutations has suggested the presence of modifier genes and/or the involvement of tri-allelic inheritance [28–32]. NGS potentially allows sequencing of an entire human genome in a few days and outputs thousands of new variants in candidate genes. In addition, a recent study, combining a massive number of in vivo experiments , has tested the possibility that new deleterious variants of known causative genes may function as modifiers in ciliopathies.
NGS approaches are greatly broadening the sophistication and types of today's experiments in the ciliopathy field, as is occurring in other fields, using genome-wide approaches. By targeting human families with key ciliopathy features, and applying either homozygosity mapping or whole exome sequencing approaches to identify causative genes, several diseases that were previously not considered as ciliopathies, such as Jeune syndrome , acrocallosal syndrome  and cranioectodermal dysplasia [35–37], are now considered to be in the extended ciliopathy spectrum. Interestingly, not all genes encoding centrosomal or pericentrosomal proteins cause ciliopathies, as the recent examples involving Seckel syndrome (primordial dwarfism) have shown [38, 39]. We thus conclude that there must be specificity of function in these centrosomal proteins, some functioning in cell cycle regulation or DNA repair and others in ciliary regulation, even if these functions are not as well delineated in non-human species .
Application of high-throughput genomics
Cell-based screens using high-throughput functional analysis offer an exciting opportunity to identify key regulators of cellular structure and function. Application of genetic, chemical or even genome-wide small interfering RNA libraries to ciliated cells followed by assessment of signaling or ciliary structure provides an important complementary approach to understanding ciliary-specific genetic requirements [41–44]. These cellular analyses have uncovered many important signaling mechanisms, some of which are pharmacologically tractable and may serve as a basis for the development of future therapy, in particular because the assays can be targeted to bypass specific patient-related cellular defects. For instance, we found that positive regulators of actin polymerization functioned as negative regulators of ciliogenesis , and vice versa, prompting us to question whether actin destabilizers might promote ciliogenesis in cellular models of disease. We found that low dose application of the actin polymerization inhibitor cytochalasin D partially rescued cilum elongation defects caused by the hypomorphic mouse mutation Ift88 [41–44]. Further genomic screening focusing on a specific cellular process, such as ciliation linked to cell cycle regulation, post-translational modification of microtubules and regulation of ciliary transport and signaling, will lead to a greater understanding of ciliary structure/function relationships, their relevance to disease and potential treatments.
The broad range of clinical features observed in ciliopathies leads us to ask how defects caused in a small cellular organelle give rise to such diverse clinical features in multiple organs. Identification and functional investigation of causative genes have always been emphasized and the recent accessibility of high-throughput NGS has propelled the ciliary biology field from basic science into the biomedical realm. The main challenge of NGS, however, lies in interpreting the massive amount of resulting data. The thousands of novel mutations found in every exome must be sorted by thorough filtering of the variants to determine which one is causative. Careful selection of patients with highly similar clinical features increases the likelihood of finding many different mutations in the same genes and the ability to distinguish pathogenic from benign variants.
As ciliopathies are rare, complex, multi-symptom diseases, treatment to ameliorate the symptoms and provide better (prenatal) diagnosis will be more feasible than targeted therapies. For instance, kidney failure is the most widespread symptom among several ciliopathies. It therefore may be possible that candidate drugs used to treat kidney disease, such as polycystic kidney disease (PKD), can be used in ciliopathy patients to help alleviate kidney symptoms. With rapidly dropping costs of NGS and more sophisticated advances in bioinformatics, it may be possible to use genomics to stratify patients for optimal prescribing and/or treatment in the near future. Personalized medicine developed through comprehensive data obtained by complementary approaches may be the best hope for patients with ciliopathies.
Jeune asphyxiating thoracic dystrophy
planar cell polarity
platelet derived growth factor
polycystic kidney disease
primary ciliary dyskinesia
JEL would like to acknowledge funding support from American Heart Association (grant number 09POST2250641). JGG is an investigator with the Howard Hughes Medical Institute. The authors would like to thank Francis Lee for giving comments on the manuscript.
- Hu Q, Milenkovic L, Jin H, Scott MP, Nachury MV, Spiliotis ET, Nelson WJ: A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science. 2010, 329: 436-439. 10.1126/science.1191054.View ArticlePubMed CentralPubMedGoogle Scholar
- Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L, Bialas NJ, Stupay RM, Chen N, Blacque OE, Yoder BK, Leroux MR: MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol. 2011, 192: 1023-1041. 10.1083/jcb.201012116.View ArticlePubMed CentralPubMedGoogle Scholar
- Kim JC, Badano JL, Sibold S, Esmail MA, Hill J, Hoskins BE, Leitch CC, Venner K, Ansley SJ, Ross AJ, Leroux MR, Katsanis N, Beales PL: The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression. Nat Genet. 2004, 36: 462-470. 10.1038/ng1352.View ArticlePubMedGoogle Scholar
- 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 syndrome. Nature. 2003, 425: 628-633. 10.1038/nature02030.View ArticlePubMedGoogle Scholar
- Taulman PD, Haycraft CJ, Balkovetz DF, Yoder BK: Polaris, a protein involved in left-right axis patterning, localizes to basal bodies and cilia. Mol Biol Cell. 2001, 12: 589-599.View ArticlePubMed CentralPubMedGoogle Scholar
- Afzelius BA: A human syndrome caused by immotile cilia. Science. 1976, 193: 317-319. 10.1126/science.1084576.View ArticlePubMedGoogle Scholar
- Omran H, Haffner K, Volkel A, Kuehr J, Ketelsen UP, Ross UH, Konietzko N, Wienker T, Brandis M, Hildebrandt F: Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene. Am J Respir Cell Mol Biol. 2000, 23: 696-702.View ArticlePubMedGoogle Scholar
- Horvath J, Fliegauf M, Olbrich H, Kispert A, King SM, Mitchison H, Zariwala MA, Knowles MR, Sudbrak R, Fekete G, Neesen J, Reinhardt R, Omran H: Identification and analysis of axonemal dynein light chain 1 in primary ciliary dyskinesia patients. Am J Respir Cell Mol Biol. 2005, 33: 41-47. 10.1165/rcmb.2004-0335OC.View ArticlePubMedGoogle Scholar
- Loges NT, Olbrich H, Fenske L, Mussaffi H, Horvath J, Fliegauf M, Kuhl H, Baktai G, Peterffy E, Chodhari R, Chung EM, Rutman A, O'Callaghan C, Blau H, Tiszlavicz L, Voelkel K, Witt M, Zietkiewicz E, Neesen J, Reinhardt R, Mitchison HM, Omran H: DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. Am J Hum Genet. 2008, 83: 547-558. 10.1016/j.ajhg.2008.10.001.View ArticlePubMed CentralPubMedGoogle Scholar
- Castleman VH, Romio L, Chodhari R, Hirst RA, de Castro SC, Parker KA, Ybot-Gonzalez P, Emes RD, Wilson SW, Wallis C, Johnson CA, Herrera RJ, Rutman A, Dixon M, Shoemark A, Bush A, Hogg C, Gardiner RM, Reish O, Greene ND, O'Callaghan C, Purton S, Chung EM, Mitchison HM: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet. 2009, 84: 197-209. 10.1016/j.ajhg.2009.01.011.View ArticlePubMed CentralPubMedGoogle Scholar
- Loges NT, Olbrich H, Becker-Heck A, Häffner K, Heer A, Reinhard C, Schmidts M, Kispert A, Zariwala MA, Leigh MW, Knowles MR, Zentgraf H, Seithe H, Nürnberg G, Nürnberg P, Reinhardt R, Omran H: Deletions and point mutations of LRRC50 cause primary ciliary dyskinesia due to dynein arm defects. Am J Hum Genet. 2009, 85: 883-889. 10.1016/j.ajhg.2009.10.018.View ArticlePubMed CentralPubMedGoogle Scholar
- Caspary T, Larkins CE, Anderson KV: The graded response to Sonic Hedgehog depends on cilia architecture. Dev Cell. 2007, 12: 767-778. 10.1016/j.devcel.2007.03.004.View ArticlePubMedGoogle Scholar
- Jauregui AR, Nguyen KC, Hall DH, Barr MM: The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol. 2008, 180: 973-988. 10.1083/jcb.200707090.View ArticlePubMed CentralPubMedGoogle Scholar
- 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 rhodopsin. Proc Natl Acad Sci USA. 2004, 101: 16588-16593. 10.1073/pnas.0405496101.View ArticlePubMed CentralPubMedGoogle Scholar
- Collins FS: Positional cloning moves from perditional to traditional. Nat Genet. 1995, 9: 347-350. 10.1038/ng0495-347.View ArticlePubMedGoogle Scholar
- Peral B, Ong AC, San Millan JL, Gamble V, Rees L, Harris PC: A stable, nonsense mutation associated with a case of infantile onset polycystic kidney disease 1 (PKD1). Hum Mol Genet. 1996, 5: 539-542. 10.1093/hmg/5.4.539.View ArticlePubMedGoogle Scholar
- Hildebrandt F, Otto E, Rensing C, Nothwang HG, Vollmer M, Adolphs J, Hanusch H, Brandis M: A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet. 1997, 17: 149-153. 10.1038/ng1097-149.View ArticlePubMedGoogle Scholar
- Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, Li H, Blacque OE, Li L, Leitch CC, Lewis RA, Green JS, Parfrey PS, Leroux MR, Davidson WS, Beales PL, Guay-Woodford LM, Yoder BK, Stormo GD, Katsanis N, Dutcher SK: Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004, 117: 541-552. 10.1016/S0092-8674(04)00450-7.View ArticlePubMedGoogle Scholar
- Avidor-Reiss T, Maer AM, Koundakjian E, Polyanovsky A, Keil T, Subramaniam S, Zuker CS: Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell. 2004, 117: 527-539.View ArticlePubMedGoogle Scholar
- 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, et al: Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell. 2011, 145: 513-528. 10.1016/j.cell.2011.04.019.View ArticlePubMed CentralPubMedGoogle Scholar
- Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peränen 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 biogenesis. Cell. 2007, 129: 1201-1213. 10.1016/j.cell.2007.03.053.View ArticlePubMedGoogle Scholar
- Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, Bazan JF, Nachury MV: The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia. Cell. 2010, 141: 1208-1219. 10.1016/j.cell.2010.05.015.View ArticlePubMed CentralPubMedGoogle Scholar
- Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G, Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ, García-Verdugo JM, Katsanis N, Hildebrandt F, Reiter JF: A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet. 2011, 43: 776-784. 10.1038/ng.891.View ArticlePubMed CentralPubMedGoogle Scholar
- Williams CL, Winkelbauer ME, Schafer JC, Michaud EJ, Yoder BK: Functional redundancy of the B9 proteins and nephrocystins in Caenorhabditis elegans ciliogenesis. Mol Biol Cell. 2008, 19: 2154-2168. 10.1091/mbc.E07-10-1070.View ArticlePubMed CentralPubMedGoogle Scholar
- 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, et al: Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet. 2010, 42: 840-850. 10.1038/ng.662.View ArticlePubMed CentralPubMedGoogle Scholar
- Otto EA, Ramaswami G, Janssen S, Chaki M, Allen SJ, Zhou W, Airik R, Hurd TW, Ghosh AK, Wolf MT, Hoppe B, Neuhaus TJ, Bockenhauer D, Milford DV, Soliman NA, Antignac C, Saunier S, Johnson CA, Hildebrandt F: Mutation analysis of 18 nephronophthisis associated ciliopathy disease genes using a DNA pooling and next generation sequencing strategy. J Med Genet. 2011, 48: 105-116. 10.1136/jmg.2010.082552.View ArticlePubMed CentralPubMedGoogle Scholar
- Janssen S, Ramaswami G, Davis EE, Hurd T, Airik R, Kasanuki JM, Van Der Kraak L, Allen SJ, Beales PL, Katsanis N, Otto EA, Hildebrandt F: Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals. Hum Genet. 2011, 129: 79-90. 10.1007/s00439-010-0902-8.View ArticlePubMed CentralPubMedGoogle Scholar
- Louie CM, Caridi G, Lopes VS, Brancati F, Kispert A, Lancaster MA, Schlossman AM, Otto EA, Leitges M, Gröne 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 nephronophthisis. Nat Genet. 2010, 42: 175-180. 10.1038/ng.519.View ArticlePubMed CentralPubMedGoogle Scholar
- 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 disorder. Science. 2001, 293: 2256-2259. 10.1126/science.1063525.View ArticlePubMedGoogle Scholar
- 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 population. Hum Mutat. 2009, 30: E737-746. 10.1002/humu.21040.View ArticlePubMedGoogle Scholar
- 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, Attié-Bitach T, Johnson CA, Otto EA, Bhattacharya SS, Hildebrandt F, et al: A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat Genet. 2009, 41: 739-745. 10.1038/ng.366.View ArticlePubMed CentralPubMedGoogle Scholar
- Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV, Muzny DM, Young AC, Wheeler DA, Cruz P, Morgan M, Lewis LR, Cherukuri P, Maskeri B, Hansen NF, Mullikin JC, Blakesley RW, Bouffard GG, Gyapay G, Rieger S, Tönshoff B, Kern I, Soliman NA, Neuhaus TJ, Swoboda KJ, Kayserili H, et al: TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet. 2011, 43: 189-196. 10.1038/ng.756.View ArticlePubMed CentralPubMedGoogle Scholar
- Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J, Johnson C, Irving M, Elcioglu N, Winey M, Tada M, Scambler PJ: IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet. 2007, 39: 727-729. 10.1038/ng2038.View ArticlePubMedGoogle Scholar
- Putoux A, Thomas S, Coene KL, Davis EE, Alanay Y, Ogur G, Uz E, Buzas D, Gomes C, Patrier S, Bennett CL, Elkhartoufi N, Frison MH, Rigonnot L, Joyé N, Pruvost S, Utine GE, Boduroglu K, Nitschke P, Fertitta L, Thauvin-Robinet C, Munnich A, Cormier-Daire V, Hennekam R, Colin E, Akarsu NA, Bole-Feysot C, Cagnard N, Schmitt A, Goudin N, et al: KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet. 2011, 43: 601-606. 10.1038/ng.826.View ArticlePubMed CentralPubMedGoogle Scholar
- Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW: Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet. 2010, 86: 949-956. 10.1016/j.ajhg.2010.04.012.View ArticlePubMed CentralPubMedGoogle Scholar
- Gilissen C, Arts HH, Hoischen A, Spruijt L, Mans DA, Arts P, van Lier B, Steehouwer M, van Reeuwijk J, Kant SG, Roepman R, Knoers NV, Veltman JA, Brunner HG: Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am J Hum Genet. 2010, 87: 418-423. 10.1016/j.ajhg.2010.08.004.View ArticlePubMed CentralPubMedGoogle Scholar
- Arts HH, Bongers EM, Mans DA, van Beersum SE, Oud MM, Bolat E, Spruijt L, Cornelissen EA, Schuurs-Hoeijmakers JH, de Leeuw N, Cormier-Daire V, Brunner HG, Knoers NV, Roepman R: C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome. J Med Genet. 2011, 48: 390-395. 10.1136/jmg.2011.088864.View ArticlePubMedGoogle Scholar
- Kalay E, Yigit G, Aslan Y, Brown KE, Pohl E, Bicknell LS, Kayserili H, Li Y, Tüysüz B, Nürnberg G, Kiess W, Koegl M, Baessmann I, Buruk K, Toraman B, Kayipmaz S, Kul S, Ikbal M, Turner DJ, Taylor MS, Aerts J, Scott C, Milstein K, Dollfus H, Wieczorek D, Brunner HG, Hurles M, Jackson AP, Rauch A, Nürnberg P, et al: CEP152 is a genome maintenance protein disrupted in Seckel syndrome. Nat Genet. 2011, 43: 23-26. 10.1038/ng.725.View ArticlePubMed CentralPubMedGoogle Scholar
- Rauch A, Thiel CT, Schindler D, Wick U, Crow YJ, Ekici AB, van Essen AJ, Goecke TO, Al-Gazali L, Chrzanowska KH, Zweier C, Brunner HG, Becker K, Curry CJ, Dallapiccola B, Devriendt K, Dörfler A, Kinning E, Megarbane A, Meinecke P, Semple RK, Spranger S, Toutain A, Trembath RC, Voss E, Wilson L, Hennekam R, de Zegher F, Dörr HG, Reis A: Mutations in the pericentrin (PCNT) gene cause primordial dwarfism. Science. 2008, 319: 816-819. 10.1126/science.1151174.View ArticlePubMedGoogle Scholar
- Miyoshi K, Kasahara K, Miyazaki I, Shimizu S, Taniguchi M, Matsuzaki S, Tohyama M, Asanuma M: Pericentrin, a centrosomal protein related to microcephalic primordial dwarfism, is required for olfactory cilia assembly in mice. FASEB J. 2009, 23: 3289-3297. 10.1096/fj.08-124420.View ArticlePubMedGoogle Scholar
- Engel BD, Ishikawa H, Feldman JL, Wilson CW, Chuang PT, Snedecor J, Williams J, Sun Z, Marshall WF: A cell-based screen for inhibitors of flagella-driven motility in Chlamydomonas reveals a novel modulator of ciliary length and retrograde actin flow. Cytoskeleton (Hoboken). 2011, 68: 188-203.View ArticleGoogle Scholar
- Evangelista M, Lim TY, Lee J, Parker L, Ashique A, Peterson AS, Ye W, Davis DP, de Sauvage FJ: Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Sci Signal. 2008, 1: ra7-10.1126/scisignal.1162925.View ArticlePubMedGoogle Scholar
- Lai CK, Gupta N, Wen X, Rangell L, Chih B, Peterson AS, Bazan JF, Li L, Scales SJ: Functional characterization of putative cilia genes by high-content analysis. Mol Biol Cell. 2011, 22: 1104-1119. 10.1091/mbc.E10-07-0596.View ArticlePubMed CentralPubMedGoogle Scholar
- Kim J, Lee JE, Heynen-Genel S, Suyama E, Ono K, Lee K, Ideker T, Aza-Blanc P, Gleeson JG: Functional genomic screen for modulators of ciliogenesis and cilium length. Nature. 2010, 464: 1048-1051. 10.1038/nature08895.View ArticlePubMed CentralPubMedGoogle Scholar