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Identification of 28 novel mutations in the Bardet–Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease

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Abstract

Bardet–Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

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References

  • 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 (2003) Basal body dysfunction is a likely cause of pleiotropic Bardet–Biedl syndrome. Nature 425:628–633

    Article  CAS  PubMed  Google Scholar 

  • Badano JL, Ansley SJ, Leitch CC, Lewis RA, Lupski JR, Katsanis N (2003) Identification of a novel Bardet–Biedl syndrome protein, BBS7, that shares structural features with BBS1 and BBS2. Am J Hum Genet 72:650–658

    Article  CAS  PubMed  Google Scholar 

  • Badano JL, Mitsuma N, Beales PL, Katsanis N (2006) The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet 7:125–148

    Article  CAS  PubMed  Google Scholar 

  • Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA (1999) New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet 36:437–446

    CAS  PubMed  Google Scholar 

  • Chiang AP, Nishimura D, Searby C, Elbedour K, Carmi R, Ferguson AL, Secrist J, Braun T, Casavant T, Stone EM, Sheffield VC (2004) Comparative genomic analysis identifies an ADP-ribosylation factor-like gene as the cause of Bardet–Biedl syndrome (BBS3). Am J Hum Genet 75:475–484

    Article  CAS  PubMed  Google Scholar 

  • Chiang AP, Beck JS, Yen HJ, Tayeh MK, Scheetz TE, Swiderski RE, Nishimura DY, Braun TA, Kim KY, Huang J, Elbedour K, Carmi R, Slusarski DC, Casavant TL, Stone EM, Sheffield VC (2006) Homozygosity mapping with SNP arrays identifies TRIM32, an E3 ubiquitin ligase, as a Bardet–Biedl syndrome gene (BBS11). Proc Natl Acad Sci USA 103:6287–6292

    Article  CAS  PubMed  Google Scholar 

  • Cossee M, Lagier-Tourenne C, Seguela C, Mohr M, Leturcq F, Gundesli H, Chelly J, Tranchant C, Koenig M, Mandel JL (2009) Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H. Neuromuscul Disord 19:255–260

    Article  PubMed  Google Scholar 

  • den Hollander AI, Roepman R, Koenekoop RK, Cremers FP (2008) Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res 27:391–419

    Article  Google Scholar 

  • Fan Y, Esmail MA, Ansley SJ, Blacque OE, Boroevich K, Ross AJ, Moore SJ, Badano JL, May-Simera H, Compton DS, Green JS, Lewis RA, van Haelst MM, Parfrey PS, Baillie DL, Beales PL, Katsanis N, Davidson WS, Leroux MR (2004) Mutations in a member of the Ras superfamily of small GTP-binding proteins causes Bardet–Biedl syndrome. Nat Genet 36:989–993

    Article  CAS  PubMed  Google Scholar 

  • Flicek P, Aken BL, Beal K, Ballester B, Caccamo M, Chen Y, Clarke L, Coates G, Cunningham F, Cutts T, Down T, Dyer SC, Eyre T, Fitzgerald S, Fernandez-Banet J, Graf S, Haider S, Hammond M, Holland R, Howe KL, Howe K, Johnson N, Jenkinson A, Kahari A, Keefe D, Kokocinski F, Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin B, Parker A, Pritchard B, Prlic A, Rice S, Rios D, Schuster M, Sealy I, Slater G, Smedley D, Spudich G, Trevanion S, Vilella AJ, Vogel J, White S, Wood M, Birney E, Cox T, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Hubbard TJ, Kasprzyk A, Proctor G, Smith J, Ureta-Vidal A, Searle S (2008) Ensembl 2008. Nucleic Acids Res 36:D707–D714

    Article  CAS  PubMed  Google Scholar 

  • Harville HM, Held S, Diaz-Font A, Davis EE, Diplas BH, Lewis RA, Borochowitz ZU, Zhou W, Chaki M, Macdonald J, Kayserili H, Beales PL, Katsanis N, Otto E, Hildebrandt F (2009) Identification of 11 novel mutations in 8 BBS genes by high-resolution homozygosity mapping. J Med Genet. doi:10.1136/jmg.2009.071365

  • Hichri H, Stoetzel C, Laurier V, Caron S, Sigaudy S, Sarda P, Hamel C, Martin-Coignard D, Gilles M, Leheup B, Holder M, Kaplan J, Bitoun P, Lacombe D, Verloes A, Bonneau D, Perrin-Schmitt F, Brandt C, Besancon AF, Mandel JL, Cossee M, Dollfus H (2005) Testing for triallelism: analysis of six BBS genes in a Bardet–Biedl syndrome family cohort. Eur J Hum Genet 13:607–616

    Article  CAS  PubMed  Google Scholar 

  • Karolchik D, Kuhn RM, Baertsch R, Barber GP, Clawson H, Diekhans M, Giardine B, Harte RA, Hinrichs AS, Hsu F, Kober KM, Miller W, Pedersen JS, Pohl A, Raney BJ, Rhead B, Rosenbloom KR, Smith KE, Stanke M, Thakkapallayil A, Trumbower H, Wang T, Zweig AS, Haussler D, Kent WJ (2008) The UCSC genome browser database: 2008 update. Nucleic Acids Res 36:D773–D779

    Article  CAS  PubMed  Google Scholar 

  • Katsanis N (2004) The oligogenic properties of Bardet–Biedl syndrome. Hum Mol Genet 13(Spec No 1):R65–R71

    Article  CAS  PubMed  Google Scholar 

  • Katsanis N, Beales PL, Woods MO, Lewis RA, Green JS, Parfrey PS, Ansley SJ, Davidson WS, Lupski JR (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nat Genet 26:67–70

    Article  CAS  PubMed  Google Scholar 

  • Katsanis N, Ansley SJ, Badano JL, Eichers ER, Lewis RA, Hoskins BE, Scambler PJ, Davidson WS, Beales PL, Lupski JR (2001) Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science 293:2256–2259

    Article  CAS  PubMed  Google Scholar 

  • Kim JC, Ou YY, Badano JL, Esmail MA, Leitch CC, Fiedrich E, Beales PL, Archibald JM, Katsanis N, Rattner JB, Leroux MR (2005) MKKS/BBS6, a divergent chaperonin-like protein linked to the obesity disorder Bardet–Biedl syndrome, is a novel centrosomal component required for cytokinesis. J Cell Sci 118:1007–1020

    Article  CAS  PubMed  Google Scholar 

  • Laurier V, Stoetzel C, Muller J, Thibault C, Corbani S, Jalkh N, Salem N, Chouery E, Poch O, Licaire S, Danse JM, Amati-Bonneau P, Bonneau D, Megarbane A, Mandel JL, Dollfus H (2006) Pitfalls of homozygosity mapping: an extended consanguineous Bardet–Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism. Eur J Hum Genet 14:1195–1203

    Article  CAS  PubMed  Google Scholar 

  • 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 (2008) Hypomorphic mutations in syndromic encephalocele genes are associated with Bardet–Biedl syndrome. Nat Genet 40:443–448

    Article  CAS  PubMed  Google 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 (2004) Comparative genomics identifies a flagellar and basal body proteome that includes the BBS5 human disease gene. Cell 117:541–552

    Article  CAS  PubMed  Google Scholar 

  • Mykytyn K, Braun T, Carmi R, Haider NB, Searby CC, Shastri M, Beck G, Wright AF, Iannaccone A, Elbedour K, Riise R, Baldi A, Raas-Rothschild A, Gorman SW, Duhl DM, Jacobson SG, Casavant T, Stone EM, Sheffield VC (2001) Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat Genet 28:188–191

    Article  CAS  PubMed  Google Scholar 

  • Mykytyn K, Nishimura DY, Searby CC, Shastri M, Yen HJ, Beck JS, Braun T, Streb LM, Cornier AS, Cox GF, Fulton AB, Carmi R, Luleci G, Chandrasekharappa SC, Collins FS, Jacobson SG, Heckenlively JR, Weleber RG, Stone EM, Sheffield VC (2002) Identification of the gene (BBS1) most commonly involved in Bardet–Biedl syndrome, a complex human obesity syndrome. Nat Genet 31:435–438

    CAS  PubMed  Google Scholar 

  • Mykytyn K, Nishimura DY, Searby CC, Beck G, Bugge K, Haines HL, Cornier AS, Cox GF, Fulton AB, Carmi R, Iannaccone A, Jacobson SG, Weleber RG, Wright AF, Riise R, Hennekam RC, Luleci G, Berker-Karauzum S, Biesecker LG, Stone EM, Sheffield VC (2003) Evaluation of complex inheritance involving the most common Bardet–Biedl syndrome locus (BBS1). Am J Hum Genet 72:429–437

    Article  CAS  PubMed  Google Scholar 

  • Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814

    Article  CAS  PubMed  Google Scholar 

  • Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE, Bamshad M, Nickerson DA, Shendure J (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461:272–276

    Article  CAS  PubMed  Google Scholar 

  • Nishimura DY, Searby CC, Carmi R, Elbedour K, Van Maldergem L, Fulton AB, Lam BL, Powell BR, Swiderski RE, Bugge KE, Haider NB, Kwitek-Black AE, Ying L, Duhl DM, Gorman SW, Heon E, Iannaccone A, Bonneau D, Biesecker LG, Jacobson SG, Stone EM, Sheffield VC (2001) Positional cloning of a novel gene on chromosome 16q causing Bardet–Biedl syndrome (BBS2). Hum Mol Genet 10:865–874

    Article  CAS  PubMed  Google Scholar 

  • Nishimura DY, Swiderski RE, Searby CC, Berg EM, Ferguson AL, Hennekam R, Merin S, Weleber RG, Biesecker LG, Stone EM, Sheffield VC (2005) Comparative genomics and gene expression analysis identifies BBS9, a new Bardet–Biedl syndrome gene. Am J Hum Genet 77:1021–1033

    Article  CAS  PubMed  Google Scholar 

  • Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: server and survey. Nucleic Acids Res 30:3894–3900

    Article  CAS  PubMed  Google Scholar 

  • Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comput Biol 4:311–323

    Article  CAS  PubMed  Google Scholar 

  • Rogozin IB, Milanesi L (1997) Analysis of donor splice sites in different eukaryotic organisms. J Mol Evol 45:50–59

    Article  CAS  PubMed  Google Scholar 

  • Saihan Z, Webster AR, Luxon L, Bitner-Glindzicz M (2009) Update on Usher syndrome. Curr Opin Neurol 22:19–27

    Article  PubMed  Google Scholar 

  • Slavotinek AM, Stone EM, Mykytyn K, Heckenlively JR, Green JS, Heon E, Musarella MA, Parfrey PS, Sheffield VC, Biesecker LG (2000) Mutations in MKKS cause Bardet–Biedl syndrome. Nat Genet 26:15–16

    Article  CAS  PubMed  Google Scholar 

  • Slavotinek AM, Searby C, Al-Gazali L, Hennekam RC, Schrander-Stumpel C, Orcana-Losa M, Pardo-Reoyo S, Cantani A, Kumar D, Capellini Q, Neri G, Zackai E, Biesecker LG (2002) Mutation analysis of the MKKS gene in McKusick–Kaufman syndrome and selected Bardet–Biedl syndrome patients. Hum Genet 110:561–567

    Article  CAS  PubMed  Google Scholar 

  • Stoetzel C, Laurier V, Davis EE, Muller J, Rix S, Badano JL, Leitch CC, Salem N, Chouery E, Corbani S et al (2006a) BBS10 encodes a vertebrate-specific chaperonin-like protein and is a major BBS locus. Nat Genet 38(5):521–524

    Article  CAS  PubMed  Google Scholar 

  • Stoetzel C, Laurier V, Faivre L, Megarbane A, Perrin-Schmitt F, Verloes A, Bonneau D, Mandel JL, Cossee M, Dollfus H (2006b) BBS8 is rarely mutated in a cohort of 128 Bardet–Biedl syndrome families. J Hum Genet 51:81–84

    Article  PubMed  Google Scholar 

  • Stoetzel C, Muller J, Laurier V, Davis EE, Zaghloul NA, Vicaire S, Jacquelin C, Plewniak F, Leitch CC, Sarda P et al (2007) 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 80(1):1–11

    Article  CAS  PubMed  Google Scholar 

  • Thompson JD, Higgins DG, Gibson TJ (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    Article  CAS  PubMed  Google Scholar 

  • UniProt (2008) The universal protein resource (UniProt). Nucleic Acids Res 36: D190–D195

    Google Scholar 

  • Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25:1189–1191

    Article  CAS  PubMed  Google Scholar 

  • Wheeler DL, Barrett T, Benson DA, Bryant SH, Canese K, Chetvernin V, Church DM, Dicuccio M, Edgar R, Federhen S, Feolo M, Geer LY, Helmberg W, Kapustin Y, Khovayko O, Landsman D, Lipman DJ, Madden TL, Maglott DR, Miller V, Ostell J, Pruitt KD, Schuler GD, Shumway M, Sequeira E, Sherry ST, Sirotkin K, Souvorov A, Starchenko G, Tatusov RL, Tatusova TA, Wagner L, Yaschenko E (2008) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 36:D13–D21

    Article  CAS  PubMed  Google Scholar 

  • Yeo G, Hoon S, Venkatesh B, Burge CB (2004) Variation in sequence and organization of splicing regulatory elements in vertebrate genes. Proc Natl Acad Sci USA 101:15700–15705

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the BBS patients for their continued support and enthusiastic participation. We also thank the Centre National de Genotypage of Evry and the Affymetrix platform of IGBMC/Genopole de Strasbourg. We acknowledge the financial support to HD of PHRC national 2002, RETINA France, LION’s club du Kochersberg, Fédération des Maladies Orphelines, the PNRV INSERM program. This study was also funded with grants from the College de France (J.L.M.).

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Correspondence to Jean Muller.

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J. Muller and C. Stoetzel contributed equally to this work.

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Muller, J., Stoetzel, C., Vincent, M.C. et al. Identification of 28 novel mutations in the Bardet–Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease. Hum Genet 127, 583–593 (2010). https://doi.org/10.1007/s00439-010-0804-9

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