Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in the Eye
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Abstract
Abstract
Upwards of 90% of individuals with Bardet-Biedl syndrome (BBS) display rod-cone dystrophy with early macular involvement. BBS is an autosomal recessive, genetically heterogeneous, pleiotropic ciliopathy for which 21 causative genes have been discovered to date. In addition to retinal degeneration, the cardinal features of BBS include obesity, cognitive impairment, renal anomalies, polydactyly, and hypogonadism. Here, we review the genes, proteins, and protein complexes involved in BBS and the BBS model organisms available for the study of retinal degeneration. We include comprehensive lists for all known BBS genes, their known phenotypes, and the model organisms available. We also review the molecular mechanisms believed to lead to retinal degeneration. We provide an overview of the mode of inheritance and describe the relationships between BBS genes and Joubert syndrome, Leber Congenital Amaurosis, Senior-Løken syndrome, and non-syndromic retinitis pigmentosa. Finally, we propose ways that new advances in technology will allow us to better understand the role of different BBS genes in retinal formation and function.Article Details
How to Cite
WEIHBRECHT, Katie et al.
Keeping an Eye on Bardet-Biedl Syndrome: A Comprehensive Review of the Role of Bardet-Biedl Syndrome Genes in the Eye.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1526>. Date accessed: 16 apr. 2024.
Keywords
Bardet-Biedl syndrome, eye, retinal degeneration, ciliopathy, blindness, BBSome, photoreceptor, nyctalopia, Joubert syndrome, Leber Congenital Amaurosis, Senior-Løken syndrome
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Sheffield VC, Carmi R, Kwitek-Black A, Rokhlina T, Nishimura D, Duyk GM, et al. Identification of a Bardet-Biedl syndrome locus on chromosome 3 and evaluation of an efficient approach to homozygosity mapping. Hum Mol Genet. 1994;3(8):1331-5.
2. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437-46.
3. Sheffield V, Zhang Q, Heon E, Drack AV, Stone EM, Carmi R. The Bardet-Biedl Syndrome. In: Erickson RP, Wynshaw-Boris AJ, editors. Epstein's inborn errors of development : the molecular basis of clinical disorders of morphogenesis. Third edition. ed. p. xlvii, 1498 pages.
4. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003;425(6958):628-33.
5. Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet. 2003;72(3):650-8.
6. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004;117(4):541-52.
7. Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet. 2001;28(2):188-91.
8. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet. 2002;31(4):435-8.
9. Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, et al. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet. 2001;10(8):865-74.
10. Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet. 2005;77(6):1021-33.
11. Scheidecker S, Etard C, Pierce NW, Geoffroy V, Schaefer E, Muller J, et al. Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet. 2014;51(2):132-6.
12. Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, et al. The Conserved Bardet-Biedl Syndrome Proteins Assemble a Coat that Traffics Membrane Proteins to Cilia. Cell. 2010;141(7):1208-19.
13. Zhang Q, Yu D, Seo S, Stone EM, Sheffield VC. Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome. The Journal of biological chemistry. 2012;287(24):20625-35.
14. Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, et al. Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet. 2000;26(1):15-6.
15. Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet. 2007;80(1):1-11.
16. Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proceedings of the National Academy of Sciences. 2010;107(4):1488-93.
17. Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet. 2004;36(9):989-93.
18. Marion V, Stutzmann F, Gerard M, De Melo C, Schaefer E, Claussmann A, et al. Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet--Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet. 2012;49(5):317-21.
19. Seo S, Zhang Q, Bugge K, Breslow DK, Searby CC, Nachury MV, et al. A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS genetics. 2011;7(11):e1002358.
20. Stowe TR, Wilkinson CJ, Iqbal A, Stearns T. The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium. Mol Biol Cell. 2012;23(17):3322-35.
21. Barbelanne M, Hossain D, Chan DP, Peranen J, Tsang WY. Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. Hum Mol Genet. 2015;24(8):2185-200.
22. Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A. 2006;103(16):6287-92.
23. Xing D-J, Zhang H-X, Huang N, Wu K-C, Huang X-F, Huang F, et al. Comprehensive Molecular Diagnosis of Bardet-Biedl Syndrome by High-Throughput Targeted Exome Sequencing. PLOS ONE. 2014;9(3):e90599.
24. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008;40(4):443-8.
25. Kim SK, Shindo A, Park TJ, Oh EC, Ghosh S, Gray RS, et al. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science (New York, NY). 2010;329(5997):1337-40.
26. Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, et al. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet. 2010;42(10):840-50.
27. Aldahmesh MA, Li Y, Alhashem A, Anazi S, Alkuraya H, Hashem M, et al. IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. Hum Mol Genet. 2014;23(12):3307-15.
28. Lindstrand A, Frangakis S, Carvalho CM, Richardson EB, McFadden KA, Willer JR, et al. Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. Am J Hum Genet. 2016;99(2):318-36.
29. Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, et al. Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet. 2016;25(11):2283-94.
30. Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, et al. A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc Natl Acad Sci U S A. 2007;104(49):19422-7.
31. Datta P, Allamargot C, Hudson JS, Andersen EK, Bhattarai S, Drack AV, et al. Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A. 2015;112(32):E4400-9.
32. Sharif AS, Zhou J, Chen Q, Zhang W, Loertscher S, Nguyen K, et al., editors. C8orf37 knockout mice display abnormal photoreceptor outer segment morphogenesis and progressive photoreceptor degeneration. The Association for Research in Vision and Ophthalmology; 2016 May; Seattle, WA2016.
33. Forsythe E, Beales PL. Bardet-Biedl Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
34. Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21(1):8-13.
35. Mockel A, Perdomo Y, Stutzmann F, Letsch J, Marion V, Dollfus H. Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog Retin Eye Res. 2011;30(4):258-74.
36. Stoler JM, Herrin JT, Holmes LB. Genital abnormalities in females with Bardet-Biedl syndrome. Am J Med Genet. 1995;55(3):276-8.
37. Klein D, Ammann F. The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neurol Sci. 1969;9(3):479-513.
38. Imhoff O, Marion V, Stoetzel C, Durand M, Holder M, Sigaudy S, et al. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clin J Am Soc Nephrol. 2011;6(1):22-9.
39. Sheffield VC. The blind leading the obese: the molecular pathophysiology of a human obesity syndrome. Trans Am Clin Climatol Assoc. 2010;121:172-81; discussion 81-2.
40. Guo DF, Rahmouni K. Molecular basis of the obesity associated with Bardet-Biedl syndrome. Trends Endocrinol Metab. 2011;22(7):286-93.
41. Putoux A, Attie-Bitach T, Martinovic J, Gubler MC. Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. Pediatr Nephrol. 2012;27(1):7-15.
42. Zaghloul NA, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest. 2009;119(3):428-37.
43. Novas R, Cardenas-Rodriguez M, Irigoin F, Badano JL. Bardet-Biedl syndrome: Is it only cilia dysfunction? FEBS Lett. 2015;589(22):3479-91.
44. Farag TI, Teebi AS. High incidence of Bardet Biedl syndrome among the Bedouin. Clinical Genetics. 1989;36(6):463-4.
45. M'Hamdi O, Ouertani I, Maazoul F, Chaabouni-Bouhamed H. Prevalence of Bardet-Biedl syndrome in Tunisia. Journal of community genetics. 2011;2(2):97-9.
46. Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017.
47. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science (New York, NY). 2001;293(5538):2256-9.
48. Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet. 2003;72(5):1187-99.
49. Hichri H, Stoetzel C, Laurier V, Caron S, Sigaudy S, Sarda P, et al. Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort. Eur J Hum Genet. 2005;13(5):607-16.
50. Nakane T, Biesecker LG. No evidence for triallelic inheritance of MKKS/BBS loci in Amish Mckusick-Kaufman syndrome. American journal of medical genetics Part A. 2005;138(1):32-4.
51. Abu-Safieh L, Al-Anazi S, Al-Abdi L, Hashem M, Alkuraya H, Alamr M, et al. In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet. 2012;20(4):420-7.
52. Zhang Q, Nishimura D, Seo S, Vogel T, Morgan DA, Searby C, et al. Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proc Natl Acad Sci U S A. 2011;108(51):20678-83.
53. Zhang Q, Nishimura D, Vogel T, Shao J, Swiderski R, Yin T, et al. BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking. Journal of Cell Science. 2013;126(11):2372-80.
54. Nishimura DY, Fath M, Mullins RF, Searby C, Andrews M, Davis R, et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(47):16588-93.
55. Airik R, Slaats GG, Guo Z, Weiss AC, Khan N, Ghosh A, et al. Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. Journal of the American Society of Nephrology : JASN. 2014;25(11):2573-83.
56. Insolera R, Shao W, Airik R, Hildebrandt F, Shi SH. SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron. 2014;83(4):805-22.
57. Cognard N, Scerbo MJ, Obringer C, Yu X, Costa F, Haser E, et al. Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice. Cilia. 2015;4(1):10.
58. Mykytyn K, Mullins RF, Andrews M, Chiang AP, Swiderski RE, Yang B, et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(23):8664-9.
59. Badano JL, Kim JC, Hoskins BE, Lewis RA, Ansley SJ, Cutler DJ, et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet. 2003;12(14):1651-9.
60. Zhang Y, Seo S, Bhattarai S, Bugge K, Searby CC, Zhang Q, et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet. 2014;23(1):40-51.
61. 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(7):E737-46.
62. Estrada-Cuzcano A, Roepman R, Cremers FP, den Hollander AI, Mans DA. Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Hum Mol Genet. 2012;21(R1):R111-24.
63. Denniston AK, Beales PL, Tomlins PJ, Good P, Langford M, Foggensteiner L, et al. Evaluation of visual function and needs in adult patients with bardet-biedl syndrome. Retina (Philadelphia, Pa). 2014;34(11):2282-9.
64. Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet. 2007;28(3):113-25.
65. Berezovsky A, Rocha DM, Sacai PY, Watanabe SS, Cavascan NN, Salomao SR. Visual acuity and retinal function in patients with Bardet-Biedl syndrome. Clinics (Sao Paulo, Brazil). 2012;67(2):145-9.
66. Fulton AB, Hansen RM, Glynn RJ. Natural course of visual functions in the Bardet-Biedl syndrome. Arch Ophthalmol. 1993;111(11):1500-6.
67. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7.
68. Azari AA, Aleman TS, Cideciyan AV, Schwartz SB, Windsor EA, Sumaroka A, et al. Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Invest Ophthalmol Vis Sci. 2006;47(11):5004-10.
69. 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 targeting. Proc Natl Acad Sci U S A. 2011;108(25):10320-5.
70. Veleri S, Bishop K, Dalle Nogare DE, English MA, Foskett TJ, Chitnis A, et al. Knockdown of Bardet-Biedl Syndrome Gene BBS9/PTHB1 Leads to Cilia Defects. PLOS ONE. 2012;7(3):e34389.
71. Marion V, Mockel A, De Melo C, Obringer C, Claussmann A, Simon A, et al. BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response. Cell Metabolism. 2012;16(3):363-77.
72. Fath MA, Mullins RF, Searby C, Nishimura DY, Wei J, Rahmouni K, et al. Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum Mol Genet. 2005;14(9):1109-18.
73. Abd-El-Barr MM, Sykoudis K, Andrabi S, Eichers ER, Pennesi ME, Tan PL, et al. Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome. Vision Research. 2007;47(27):3394-407.
74. Mokrzan EM, Lewis JS, Mykytyn K. Differences in renal tubule primary cilia length in a mouse model of Bardet-Biedl syndrome. Nephron Exp Nephrol. 2007;106(3):e88-96.
75. Eichers ER, Abd-El-Barr MM, Paylor R, Lewis RA, Bi W, Lin X, et al. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet. 2006;120(2):211-26.
76. Jiang J, Promchan K, Jiang H, Awasthi P, Marshall H, Harned A, et al. Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice. Journal of Genetics and Genomics. 2016;43(6):381-91.
77. Pretorius PR, Baye LM, Nishimura DY, Searby CC, Bugge K, Yang B, et al. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS genetics. 2010;6(3):e1000884.
78. Kudryashova E, Wu J, Havton LA, Spencer MJ. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Human Molecular Genetics. 2009;18(7):1353-67.
79. Wheway G, Abdelhamed Z, Natarajan S, Toomes C, Inglehearn C, Johnson CA. Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel–Gruber syndrome. Developmental Biology. 2013;377(1):55-66.
80. Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, et al. 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 mouse. Hum Mol Genet. 2006;15(11):1847-57.
81. Cui C, Chatterjee B, Lozito TP, Zhang Z, Francis RJ, Yagi H, et al. Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton. PLOS Biology. 2013;11(11):e1001720.
82. Swiderski RE, Nishimura DY, Mullins RF, Olvera MA, Ross JL, Huang J, et al. Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage. Invest Ophthalmol Vis Sci. 2007;48(7):3329-40.
83. Horst CJ, Johnson LV, Besharse JC. Transmembrane assemblage of the photoreceptor connecting cilium and motile cilium transition zone contain a common immunologic epitope. Cell Motil Cytoskeleton. 1990;17(4):329-44.
84. Yen HJ, Tayeh MK, Mullins RF, Stone EM, Sheffield VC, Slusarski DC. Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. Hum Mol Genet. 2006;15(5):667-77.
85. Wei Q, Zhang Y, Li Y, Zhang Q, Ling K, Hu J. The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol. 2012;14(9):950-7.
86. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-31.
87. Starks RD, Beyer AM, Guo DF, Boland L, Zhang Q, Sheffield VC, et al. Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. PLoS genetics. 2015;11(6):e1005311.
88. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A. 2008;105(11):4242-6.
89. Loktev AV, Jackson PK. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep. 2013;5(5):1316-29.
90. Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, et al. BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors. Sci Rep. 2015;5:11855.
91. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56:615-49.
92. Bolch SN, Dugger DR, Chong T, McDowell JH, Smith WC. A Splice Variant of Bardet-Biedl Syndrome 5 (BBS5) Protein that Is Selectively Expressed in Retina. PLoS One. 2016;11(2):e0148773.
93. Riazuddin SA, Iqbal M, Wang Y, Masuda T, Chen Y, Bowne S, et al. A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. Am J Hum Genet. 2010;86(5):805-12.
94. Farkas MH, Grant GR, White JA, Sousa ME, Consugar MB, Pierce EA. Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes. BMC Genomics. 2013;14(1):486.
95. Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009;13(6):587-92.
96. Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber's congenital amaurosis. Age-related findings in 35 patients. Ophthalmology. 1992;99(2):241-5.
97. Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004;49(4):379-98.
98. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26(7):1039-56.
99. Weleber RG, Francis PJ, Trzupek KM, Beattie C. Leber Congenital Amaurosis. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
100. Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol. 1999;14(9):583-90; discussion 90-1.
101. Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology. 1969;19(9):813-25.
102. Parisi M, Glass I. Joubert Syndrome and Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
103. Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol. 2009;16(3):143-54.
104. Hildebrandt F, Nothwang HG, Vossmerbaumer U, Springer C, Strahm B, Hoppe B, et al. Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B. APN Study Group. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Pediatr Nephrol. 1998;12(1):16-9.
105. Tusa RJ, Hove MT. Ocular and oculomotor signs in Joubert syndrome. J Child Neurol. 1999;14(10):621-7.
106. van Dorp DB, Palan A, Kwee ML, Barth PG, van der Harten JJ. Joubert syndrome: a clinical and pathological description of an affected male and a female fetus from the same sibship. Am J Med Genet. 1991;40(1):100-4.
107. Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet. 1992;43(4):726-31.
108. Chatterjee S, Lufkin T. The Sound of Silence: Mouse Models for Hearing Loss. Genetics Research International. 2011;2011:9.
109. Parisi M, Glass I. Joubert Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
110. Loken AC, Hanssen O, Halvorsen S, Jolster NJ. Hereditary renal dysplasia and blindness. Acta Paediatr. 1961;50:177-84.
111. Senior B, Friedmann AI, Braudo JL. Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy. Am J Ophthalmol. 1961;52:625-33.
112. Mongeau JG, Worthen HG. Nephronophthisis and medullary cystic disease. Am J Med. 1967;43(3):345-55.
113. Strauss MB, Sommers SC. Medullary cystic disease and familial juvenile nephronophthisis. N Engl J Med. 1967;277(16):863-4.
114. Dekaban AS. Familial occurrence of congenital retinal blindness and developmental renal lesions. J Genet Hum. 1969;17(3):289-96.
115. Schimke RN. Hereditary renal-retinal dysplasia. Ann Intern Med. 1969;70(4):735-44.
116. Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005;37(3):282-8.
117. Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2007;28(4):416.
118. Medhioub M, Cherif D, Benessy F, Silbermann F, Gubler MC, Le Paslier D, et al. Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity. Genomics. 1994;22(2):296-301.
119. Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9(3).
120. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006;38(6):674-81.
121. Coussa RG, Otto EA, Gee HY, Arthurs P, Ren H, Lopez I, et al. WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome. Clin Genet. 2013;84(2):150-9.
122. Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013;132(8):865-84.
123. Bizet AA, Becker-Heck A, Ryan R, Weber K, Filhol E, Krug P, et al. Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nat Commun. 2015;6:8666.
124. Estrada-Cuzcano A, Koenekoop RK, Senechal A, De Baere EB, de Ravel T, Banfi S, et al. BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome. Arch Ophthalmol. 2012;130(11):1425-32.
125. Shevach E, Ali M, Mizrahi-Meissonnier L, McKibbin M, El-Asrag M, Watson CM, et al. Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. JAMA Ophthalmol. 2015;133(3):312-8.
126. Aldahmesh MA, Safieh LA, Alkuraya H, Al-Rajhi A, Shamseldin H, Hashem M, et al. Molecular characterization of retinitis pigmentosa in Saudi Arabia. Mol Vis. 2009;15:2464-9.
127. Estrada-Cuzcano A, Neveling K, Kohl S, Banin E, Rotenstreich Y, Sharon D, et al. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. Am J Hum Genet. 2012;90(1):102-9.
128. Fenn TD, Schnieders MJ, Brunger AT, Pande VS. Polarizable atomic multipole x-ray refinement: hydration geometry and application to macromolecules. Biophys J. 2010;98(12):2984-92.
129. Wiley LA, Burnight ER, DeLuca AP, Anfinson KR, Cranston CM, Kaalberg EE, et al. cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Sci Rep. 2016;6:30742.
130. Seo S, Mullins RF, Dumitrescu AV, Bhattarai S, Gratie D, Wang K, et al. Subretinal Gene Therapy of Mice With Bardet-Biedl Syndrome Type 1Subretinal Gene Therapy of Mice With BBS1. Investigative Ophthalmology & Visual Science. 2013;54(9):6118-32.
131. Tucker BA, Mullins RF, Stone EM. Stem cells for investigation and treatment of inherited retinal disease. Hum Mol Genet. 2014;23(R1):R9-R16.
2. Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437-46.
3. Sheffield V, Zhang Q, Heon E, Drack AV, Stone EM, Carmi R. The Bardet-Biedl Syndrome. In: Erickson RP, Wynshaw-Boris AJ, editors. Epstein's inborn errors of development : the molecular basis of clinical disorders of morphogenesis. Third edition. ed. p. xlvii, 1498 pages.
4. Ansley SJ, Badano JL, Blacque OE, Hill J, Hoskins BE, Leitch CC, et al. Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome. Nature. 2003;425(6958):628-33.
5. Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N. Identification of a novel Bardet-Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet. 2003;72(3):650-8.
6. Li JB, Gerdes JM, Haycraft CJ, Fan Y, Teslovich TM, May-Simera H, et al. Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell. 2004;117(4):541-52.
7. Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, et al. Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet. 2001;28(2):188-91.
8. Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, et al. Identification of the gene (BBS1) most commonly involved in Bardet-Biedl syndrome, a complex human obesity syndrome. Nat Genet. 2002;31(4):435-8.
9. Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, et al. Positional cloning of a novel gene on chromosome 16q causing Bardet-Biedl syndrome (BBS2). Hum Mol Genet. 2001;10(8):865-74.
10. Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, et al. Comparative genomics and gene expression analysis identifies BBS9, a new Bardet-Biedl syndrome gene. Am J Hum Genet. 2005;77(6):1021-33.
11. Scheidecker S, Etard C, Pierce NW, Geoffroy V, Schaefer E, Muller J, et al. Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18). J Med Genet. 2014;51(2):132-6.
12. Jin H, White SR, Shida T, Schulz S, Aguiar M, Gygi SP, et al. The Conserved Bardet-Biedl Syndrome Proteins Assemble a Coat that Traffics Membrane Proteins to Cilia. Cell. 2010;141(7):1208-19.
13. Zhang Q, Yu D, Seo S, Stone EM, Sheffield VC. Intrinsic protein-protein interaction-mediated and chaperonin-assisted sequential assembly of stable bardet-biedl syndrome protein complex, the BBSome. The Journal of biological chemistry. 2012;287(24):20625-35.
14. Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, et al. Mutations in MKKS cause Bardet-Biedl syndrome. Nat Genet. 2000;26(1):15-6.
15. Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, et al. Identification of a novel BBS gene (BBS12) highlights the major role of a vertebrate-specific branch of chaperonin-related proteins in Bardet-Biedl syndrome. Am J Hum Genet. 2007;80(1):1-11.
16. Seo S, Baye LM, Schulz NP, Beck JS, Zhang Q, Slusarski DC, et al. BBS6, BBS10, and BBS12 form a complex with CCT/TRiC family chaperonins and mediate BBSome assembly. Proceedings of the National Academy of Sciences. 2010;107(4):1488-93.
17. Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, et al. Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet-Biedl syndrome. Nat Genet. 2004;36(9):989-93.
18. Marion V, Stutzmann F, Gerard M, De Melo C, Schaefer E, Claussmann A, et al. Exome sequencing identifies mutations in LZTFL1, a BBSome and smoothened trafficking regulator, in a family with Bardet--Biedl syndrome with situs inversus and insertional polydactyly. J Med Genet. 2012;49(5):317-21.
19. Seo S, Zhang Q, Bugge K, Breslow DK, Searby CC, Nachury MV, et al. A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened. PLoS genetics. 2011;7(11):e1002358.
20. Stowe TR, Wilkinson CJ, Iqbal A, Stearns T. The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium. Mol Biol Cell. 2012;23(17):3322-35.
21. Barbelanne M, Hossain D, Chan DP, Peranen J, Tsang WY. Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. Hum Mol Genet. 2015;24(8):2185-200.
22. Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, et al. Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet-Biedl syndrome gene (BBS11). Proc Natl Acad Sci U S A. 2006;103(16):6287-92.
23. Xing D-J, Zhang H-X, Huang N, Wu K-C, Huang X-F, Huang F, et al. Comprehensive Molecular Diagnosis of Bardet-Biedl Syndrome by High-Throughput Targeted Exome Sequencing. PLOS ONE. 2014;9(3):e90599.
24. Leitch CC, Zaghloul NA, Davis EE, Stoetzel C, Diaz-Font A, Rix S, et al. Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet-Biedl syndrome. Nat Genet. 2008;40(4):443-8.
25. Kim SK, Shindo A, Park TJ, Oh EC, Ghosh S, Gray RS, et al. Planar cell polarity acts through septins to control collective cell movement and ciliogenesis. Science (New York, NY). 2010;329(5997):1337-40.
26. Otto EA, Hurd TW, Airik R, Chaki M, Zhou W, Stoetzel C, et al. Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nat Genet. 2010;42(10):840-50.
27. Aldahmesh MA, Li Y, Alhashem A, Anazi S, Alkuraya H, Hashem M, et al. IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. Hum Mol Genet. 2014;23(12):3307-15.
28. Lindstrand A, Frangakis S, Carvalho CM, Richardson EB, McFadden KA, Willer JR, et al. Copy-Number Variation Contributes to the Mutational Load of Bardet-Biedl Syndrome. Am J Hum Genet. 2016;99(2):318-36.
29. Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, et al. Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet. 2016;25(11):2283-94.
30. Davis RE, Swiderski RE, Rahmouni K, Nishimura DY, Mullins RF, Agassandian K, et al. A knockin mouse model of the Bardet-Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity. Proc Natl Acad Sci U S A. 2007;104(49):19422-7.
31. Datta P, Allamargot C, Hudson JS, Andersen EK, Bhattarai S, Drack AV, et al. Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome. Proc Natl Acad Sci U S A. 2015;112(32):E4400-9.
32. Sharif AS, Zhou J, Chen Q, Zhang W, Loertscher S, Nguyen K, et al., editors. C8orf37 knockout mice display abnormal photoreceptor outer segment morphogenesis and progressive photoreceptor degeneration. The Association for Research in Vision and Ophthalmology; 2016 May; Seattle, WA2016.
33. Forsythe E, Beales PL. Bardet-Biedl Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
34. Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21(1):8-13.
35. Mockel A, Perdomo Y, Stutzmann F, Letsch J, Marion V, Dollfus H. Retinal dystrophy in Bardet-Biedl syndrome and related syndromic ciliopathies. Prog Retin Eye Res. 2011;30(4):258-74.
36. Stoler JM, Herrin JT, Holmes LB. Genital abnormalities in females with Bardet-Biedl syndrome. Am J Med Genet. 1995;55(3):276-8.
37. Klein D, Ammann F. The syndrome of Laurence-Moon-Bardet-Biedl and allied diseases in Switzerland. Clinical, genetic and epidemiological studies. J Neurol Sci. 1969;9(3):479-513.
38. Imhoff O, Marion V, Stoetzel C, Durand M, Holder M, Sigaudy S, et al. Bardet-Biedl syndrome: a study of the renal and cardiovascular phenotypes in a French cohort. Clin J Am Soc Nephrol. 2011;6(1):22-9.
39. Sheffield VC. The blind leading the obese: the molecular pathophysiology of a human obesity syndrome. Trans Am Clin Climatol Assoc. 2010;121:172-81; discussion 81-2.
40. Guo DF, Rahmouni K. Molecular basis of the obesity associated with Bardet-Biedl syndrome. Trends Endocrinol Metab. 2011;22(7):286-93.
41. Putoux A, Attie-Bitach T, Martinovic J, Gubler MC. Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. Pediatr Nephrol. 2012;27(1):7-15.
42. Zaghloul NA, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest. 2009;119(3):428-37.
43. Novas R, Cardenas-Rodriguez M, Irigoin F, Badano JL. Bardet-Biedl syndrome: Is it only cilia dysfunction? FEBS Lett. 2015;589(22):3479-91.
44. Farag TI, Teebi AS. High incidence of Bardet Biedl syndrome among the Bedouin. Clinical Genetics. 1989;36(6):463-4.
45. M'Hamdi O, Ouertani I, Maazoul F, Chaabouni-Bouhamed H. Prevalence of Bardet-Biedl syndrome in Tunisia. Journal of community genetics. 2011;2(2):97-9.
46. Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017.
47. Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, et al. Triallelic inheritance in Bardet-Biedl syndrome, a Mendelian recessive disorder. Science (New York, NY). 2001;293(5538):2256-9.
48. Beales PL, Badano JL, Ross AJ, Ansley SJ, Hoskins BE, Kirsten B, et al. Genetic interaction of BBS1 mutations with alleles at other BBS loci can result in non-Mendelian Bardet-Biedl syndrome. Am J Hum Genet. 2003;72(5):1187-99.
49. Hichri H, Stoetzel C, Laurier V, Caron S, Sigaudy S, Sarda P, et al. Testing for triallelism: analysis of six BBS genes in a Bardet-Biedl syndrome family cohort. Eur J Hum Genet. 2005;13(5):607-16.
50. Nakane T, Biesecker LG. No evidence for triallelic inheritance of MKKS/BBS loci in Amish Mckusick-Kaufman syndrome. American journal of medical genetics Part A. 2005;138(1):32-4.
51. Abu-Safieh L, Al-Anazi S, Al-Abdi L, Hashem M, Alkuraya H, Alamr M, et al. In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet. 2012;20(4):420-7.
52. Zhang Q, Nishimura D, Seo S, Vogel T, Morgan DA, Searby C, et al. Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes. Proc Natl Acad Sci U S A. 2011;108(51):20678-83.
53. Zhang Q, Nishimura D, Vogel T, Shao J, Swiderski R, Yin T, et al. BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking. Journal of Cell Science. 2013;126(11):2372-80.
54. Nishimura DY, Fath M, Mullins RF, Searby C, Andrews M, Davis R, et al. Bbs2-null mice have neurosensory deficits, a defect in social dominance, and retinopathy associated with mislocalization of rhodopsin. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(47):16588-93.
55. Airik R, Slaats GG, Guo Z, Weiss AC, Khan N, Ghosh A, et al. Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. Journal of the American Society of Nephrology : JASN. 2014;25(11):2573-83.
56. Insolera R, Shao W, Airik R, Hildebrandt F, Shi SH. SDCCAG8 regulates pericentriolar material recruitment and neuronal migration in the developing cortex. Neuron. 2014;83(4):805-22.
57. Cognard N, Scerbo MJ, Obringer C, Yu X, Costa F, Haser E, et al. Comparing the Bbs10 complete knockout phenotype with a specific renal epithelial knockout one highlights the link between renal defects and systemic inactivation in mice. Cilia. 2015;4(1):10.
58. Mykytyn K, Mullins RF, Andrews M, Chiang AP, Swiderski RE, Yang B, et al. Bardet–Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(23):8664-9.
59. Badano JL, Kim JC, Hoskins BE, Lewis RA, Ansley SJ, Cutler DJ, et al. Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus. Hum Mol Genet. 2003;12(14):1651-9.
60. Zhang Y, Seo S, Bhattarai S, Bugge K, Searby CC, Zhang Q, et al. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum Mol Genet. 2014;23(1):40-51.
61. 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(7):E737-46.
62. Estrada-Cuzcano A, Roepman R, Cremers FP, den Hollander AI, Mans DA. Non-syndromic retinal ciliopathies: translating gene discovery into therapy. Hum Mol Genet. 2012;21(R1):R111-24.
63. Denniston AK, Beales PL, Tomlins PJ, Good P, Langford M, Foggensteiner L, et al. Evaluation of visual function and needs in adult patients with bardet-biedl syndrome. Retina (Philadelphia, Pa). 2014;34(11):2282-9.
64. Adams NA, Awadein A, Toma HS. The retinal ciliopathies. Ophthalmic Genet. 2007;28(3):113-25.
65. Berezovsky A, Rocha DM, Sacai PY, Watanabe SS, Cavascan NN, Salomao SR. Visual acuity and retinal function in patients with Bardet-Biedl syndrome. Clinics (Sao Paulo, Brazil). 2012;67(2):145-9.
66. Fulton AB, Hansen RM, Glynn RJ. Natural course of visual functions in the Bardet-Biedl syndrome. Arch Ophthalmol. 1993;111(11):1500-6.
67. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007;2:7.
68. Azari AA, Aleman TS, Cideciyan AV, Schwartz SB, Windsor EA, Sumaroka A, et al. Retinal disease expression in Bardet-Biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Invest Ophthalmol Vis Sci. 2006;47(11):5004-10.
69. 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 targeting. Proc Natl Acad Sci U S A. 2011;108(25):10320-5.
70. Veleri S, Bishop K, Dalle Nogare DE, English MA, Foskett TJ, Chitnis A, et al. Knockdown of Bardet-Biedl Syndrome Gene BBS9/PTHB1 Leads to Cilia Defects. PLOS ONE. 2012;7(3):e34389.
71. Marion V, Mockel A, De Melo C, Obringer C, Claussmann A, Simon A, et al. BBS-Induced Ciliary Defect Enhances Adipogenesis, Causing Paradoxical Higher-Insulin Sensitivity, Glucose Usage, and Decreased Inflammatory Response. Cell Metabolism. 2012;16(3):363-77.
72. Fath MA, Mullins RF, Searby C, Nishimura DY, Wei J, Rahmouni K, et al. Mkks-null mice have a phenotype resembling Bardet-Biedl syndrome. Hum Mol Genet. 2005;14(9):1109-18.
73. Abd-El-Barr MM, Sykoudis K, Andrabi S, Eichers ER, Pennesi ME, Tan PL, et al. Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet–Biedl syndrome. Vision Research. 2007;47(27):3394-407.
74. Mokrzan EM, Lewis JS, Mykytyn K. Differences in renal tubule primary cilia length in a mouse model of Bardet-Biedl syndrome. Nephron Exp Nephrol. 2007;106(3):e88-96.
75. Eichers ER, Abd-El-Barr MM, Paylor R, Lewis RA, Bi W, Lin X, et al. Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expressivity. Hum Genet. 2006;120(2):211-26.
76. Jiang J, Promchan K, Jiang H, Awasthi P, Marshall H, Harned A, et al. Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice. Journal of Genetics and Genomics. 2016;43(6):381-91.
77. Pretorius PR, Baye LM, Nishimura DY, Searby CC, Bugge K, Yang B, et al. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS genetics. 2010;6(3):e1000884.
78. Kudryashova E, Wu J, Havton LA, Spencer MJ. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Human Molecular Genetics. 2009;18(7):1353-67.
79. Wheway G, Abdelhamed Z, Natarajan S, Toomes C, Inglehearn C, Johnson CA. Aberrant Wnt signalling and cellular over-proliferation in a novel mouse model of Meckel–Gruber syndrome. Developmental Biology. 2013;377(1):55-66.
80. Chang B, Khanna H, Hawes N, Jimeno D, He S, Lillo C, et al. 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 mouse. Hum Mol Genet. 2006;15(11):1847-57.
81. Cui C, Chatterjee B, Lozito TP, Zhang Z, Francis RJ, Yagi H, et al. Wdpcp, a PCP Protein Required for Ciliogenesis, Regulates Directional Cell Migration and Cell Polarity by Direct Modulation of the Actin Cytoskeleton. PLOS Biology. 2013;11(11):e1001720.
82. Swiderski RE, Nishimura DY, Mullins RF, Olvera MA, Ross JL, Huang J, et al. Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage. Invest Ophthalmol Vis Sci. 2007;48(7):3329-40.
83. Horst CJ, Johnson LV, Besharse JC. Transmembrane assemblage of the photoreceptor connecting cilium and motile cilium transition zone contain a common immunologic epitope. Cell Motil Cytoskeleton. 1990;17(4):329-44.
84. Yen HJ, Tayeh MK, Mullins RF, Stone EM, Sheffield VC, Slusarski DC. Bardet-Biedl syndrome genes are important in retrograde intracellular trafficking and Kupffer's vesicle cilia function. Hum Mol Genet. 2006;15(5):667-77.
85. Wei Q, Zhang Y, Li Y, Zhang Q, Ling K, Hu J. The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol. 2012;14(9):950-7.
86. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-31.
87. Starks RD, Beyer AM, Guo DF, Boland L, Zhang Q, Sheffield VC, et al. Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins. PLoS genetics. 2015;11(6):e1005311.
88. Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc Natl Acad Sci U S A. 2008;105(11):4242-6.
89. Loktev AV, Jackson PK. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep. 2013;5(5):1316-29.
90. Xu Q, Zhang Y, Wei Q, Huang Y, Li Y, Ling K, et al. BBS4 and BBS5 show functional redundancy in the BBSome to regulate the degradative sorting of ciliary sensory receptors. Sci Rep. 2015;5:11855.
91. Gilman AG. G proteins: transducers of receptor-generated signals. Annu Rev Biochem. 1987;56:615-49.
92. Bolch SN, Dugger DR, Chong T, McDowell JH, Smith WC. A Splice Variant of Bardet-Biedl Syndrome 5 (BBS5) Protein that Is Selectively Expressed in Retina. PLoS One. 2016;11(2):e0148773.
93. Riazuddin SA, Iqbal M, Wang Y, Masuda T, Chen Y, Bowne S, et al. A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. Am J Hum Genet. 2010;86(5):805-12.
94. Farkas MH, Grant GR, White JA, Sousa ME, Consugar MB, Pierce EA. Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes. BMC Genomics. 2013;14(1):486.
95. Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009;13(6):587-92.
96. Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber's congenital amaurosis. Age-related findings in 35 patients. Ophthalmology. 1992;99(2):241-5.
97. Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004;49(4):379-98.
98. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26(7):1039-56.
99. Weleber RG, Francis PJ, Trzupek KM, Beattie C. Leber Congenital Amaurosis. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
100. Maria BL, Boltshauser E, Palmer SC, Tran TX. Clinical features and revised diagnostic criteria in Joubert syndrome. J Child Neurol. 1999;14(9):583-90; discussion 90-1.
101. Joubert M, Eisenring JJ, Robb JP, Andermann F. Familial agenesis of the cerebellar vermis. A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology. 1969;19(9):813-25.
102. Parisi M, Glass I. Joubert Syndrome and Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
103. Doherty D. Joubert syndrome: insights into brain development, cilium biology, and complex disease. Semin Pediatr Neurol. 2009;16(3):143-54.
104. Hildebrandt F, Nothwang HG, Vossmerbaumer U, Springer C, Strahm B, Hoppe B, et al. Lack of large, homozygous deletions of the nephronophthisis 1 region in Joubert syndrome type B. APN Study Group. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Pediatr Nephrol. 1998;12(1):16-9.
105. Tusa RJ, Hove MT. Ocular and oculomotor signs in Joubert syndrome. J Child Neurol. 1999;14(10):621-7.
106. van Dorp DB, Palan A, Kwee ML, Barth PG, van der Harten JJ. Joubert syndrome: a clinical and pathological description of an affected male and a female fetus from the same sibship. Am J Med Genet. 1991;40(1):100-4.
107. Saraiva JM, Baraitser M. Joubert syndrome: a review. Am J Med Genet. 1992;43(4):726-31.
108. Chatterjee S, Lufkin T. The Sound of Silence: Mouse Models for Hearing Loss. Genetics Research International. 2011;2011:9.
109. Parisi M, Glass I. Joubert Syndrome. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993.
110. Loken AC, Hanssen O, Halvorsen S, Jolster NJ. Hereditary renal dysplasia and blindness. Acta Paediatr. 1961;50:177-84.
111. Senior B, Friedmann AI, Braudo JL. Juvenile familial nephropathy with tapetoretinal degeneration. A new oculorenal dystrophy. Am J Ophthalmol. 1961;52:625-33.
112. Mongeau JG, Worthen HG. Nephronophthisis and medullary cystic disease. Am J Med. 1967;43(3):345-55.
113. Strauss MB, Sommers SC. Medullary cystic disease and familial juvenile nephronophthisis. N Engl J Med. 1967;277(16):863-4.
114. Dekaban AS. Familial occurrence of congenital retinal blindness and developmental renal lesions. J Genet Hum. 1969;17(3):289-96.
115. Schimke RN. Hereditary renal-retinal dysplasia. Ann Intern Med. 1969;70(4):735-44.
116. Otto EA, Loeys B, Khanna H, Hellemans J, Sudbrak R, Fan S, et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet. 2005;37(3):282-8.
117. Perrault I, Delphin N, Hanein S, Gerber S, Dufier JL, Roche O, et al. Spectrum of NPHP6/CEP290 mutations in Leber congenital amaurosis and delineation of the associated phenotype. Hum Mutat. 2007;28(4):416.
118. Medhioub M, Cherif D, Benessy F, Silbermann F, Gubler MC, Le Paslier D, et al. Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity. Genomics. 1994;22(2):296-301.
119. Braun DA, Hildebrandt F. Ciliopathies. Cold Spring Harb Perspect Biol. 2017;9(3).
120. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, et al. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Nat Genet. 2006;38(6):674-81.
121. Coussa RG, Otto EA, Gee HY, Arthurs P, Ren H, Lopez I, et al. WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome. Clin Genet. 2013;84(2):150-9.
122. Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, et al. Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet. 2013;132(8):865-84.
123. Bizet AA, Becker-Heck A, Ryan R, Weber K, Filhol E, Krug P, et al. Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nat Commun. 2015;6:8666.
124. Estrada-Cuzcano A, Koenekoop RK, Senechal A, De Baere EB, de Ravel T, Banfi S, et al. BBS1 mutations in a wide spectrum of phenotypes ranging from nonsyndromic retinitis pigmentosa to Bardet-Biedl syndrome. Arch Ophthalmol. 2012;130(11):1425-32.
125. Shevach E, Ali M, Mizrahi-Meissonnier L, McKibbin M, El-Asrag M, Watson CM, et al. Association between missense mutations in the BBS2 gene and nonsyndromic retinitis pigmentosa. JAMA Ophthalmol. 2015;133(3):312-8.
126. Aldahmesh MA, Safieh LA, Alkuraya H, Al-Rajhi A, Shamseldin H, Hashem M, et al. Molecular characterization of retinitis pigmentosa in Saudi Arabia. Mol Vis. 2009;15:2464-9.
127. Estrada-Cuzcano A, Neveling K, Kohl S, Banin E, Rotenstreich Y, Sharon D, et al. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement. Am J Hum Genet. 2012;90(1):102-9.
128. Fenn TD, Schnieders MJ, Brunger AT, Pande VS. Polarizable atomic multipole x-ray refinement: hydration geometry and application to macromolecules. Biophys J. 2010;98(12):2984-92.
129. Wiley LA, Burnight ER, DeLuca AP, Anfinson KR, Cranston CM, Kaalberg EE, et al. cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness. Sci Rep. 2016;6:30742.
130. Seo S, Mullins RF, Dumitrescu AV, Bhattarai S, Gratie D, Wang K, et al. Subretinal Gene Therapy of Mice With Bardet-Biedl Syndrome Type 1Subretinal Gene Therapy of Mice With BBS1. Investigative Ophthalmology & Visual Science. 2013;54(9):6118-32.
131. Tucker BA, Mullins RF, Stone EM. Stem cells for investigation and treatment of inherited retinal disease. Hum Mol Genet. 2014;23(R1):R9-R16.