Human Genetics

, Volume 116, Issue 4, pp 292–299 | Cite as

Characterization of Usher syndrome type I gene mutations in an Usher syndrome patient population

  • Xiao Mei Ouyang
  • Denise Yan
  • Li Lin Du
  • J. Fielding. Hejtmancik
  • Samuel G. Jacobson
  • Walter E. Nance
  • An Ren Li
  • Simon Angeli
  • Muriel Kaiser
  • Valerie Newton
  • Steve D. M. Brown
  • Thomas Balkany
  • Xue Zhong Liu
Original Investigation

Abstract

Usher syndrome type I (USH1), the most severe form of this syndrome, is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. At least seven USH1 loci, USH1A-G, have been mapped to the chromosome regions 14q32, 11q13.5, 11p15, 10q21-q22, 21q21, 10q21-q22, and 17q24-25, respectively. Mutations in five genes, including MYO7A, USH1C, CDH23, PCDH15 and SANS, have been shown to be the cause of Usher syndrome type 1B, type 1C, type 1D, type 1F and type 1G, respectively. In the present study, we carried out a systematic mutation screening of these genes in USH1 patients from USA and from UK. We identified a total of 27 different mutations; of these, 19 are novel, including nine missense, two nonsense, four deletions, one insertion and three splicing defects. Approximatelly 35–39% of the observed mutations involved the USH1B and USH1D genes, followed by 11% for USH1F and 7% for USH1C in non-Acadian alleles and 7% for USH1G. Two of the 12 MYO7A mutations, R666X and IVS40-1G>T accounted for 38% of the mutations at that locus. A 193delC mutation accounted for 26% of CDH23 (USH1D) mutations, confirming its high frequency. The most common PCDH15 (USH1F) mutation in this study, 5601-5603delAAC, accounts for 33% of mutant alleles. Interestingly, a novel SANS mutation, W38X, was observed only in the USA cohort. The present study suggests that mutations in MYO7A and CDH23 are the two major components of causes for USH1, while PCDH15, USH1C, and SANS are less frequent causes.

Notes

Acknowledgements

We thank the families for their participation in this study, which was supported in part by grants from the Foundation Fighting Blindness, NIH DC05575 (to X.Z.L.) and NIH EY-13385 (to S.G.J.). We thank Ms. S.B. Schwartz and Ms. E.E. Smilko for clinical coordination.

References

  1. Adato A, Weil D, Kalinski H, Pel-Or Y, Ayadi H, Petit C, Korostishevsky M, Bonne-Tamir B (1997) Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis in Usher 1B families from diverse origins. Am J Hum Genet 61:813–821Google Scholar
  2. Ahmed ZM, Riazuddin S, Bernstein SL, Ahmed Z, Khan S, Griffith AJ, Morell RJ, Friedman TB, Riazuddin S, Wilcox ER (2001) Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am J Hum Genet 69:25–34CrossRefPubMedGoogle Scholar
  3. Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari, Menon PSN, Deshmukh D, Griffith AJ, Riazuddin S, Friedman TB, Wilcox ER (2002) Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum Genet 110:527–531CrossRefPubMedGoogle Scholar
  4. Ahmed ZM, Riazuddin S, Riazuddin S, Wilcox ER (2003a) The molecular genetics of Usher syndrome. Clin Genet 63:431–444CrossRefPubMedGoogle Scholar
  5. Ahmed ZM, Riazuddin S, Ahmad J, Bernstein SL, Guo Y, Sabar MF, Sieving P, Riazuddin S, Griffith AJ, Friedman TB, Belyantseva IA, Wilcox ER (2003b) PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum Mol Genet 12:3215–3223CrossRefPubMedGoogle Scholar
  6. Alagramam KM, Yuan H, Huehn MH, Murcia CL, Wayne S, Srisailpathy CR, Lowry RB, Knaus R, Van Laer L, Bernier FP, Schwartz S, Lee C, Morton CC, Mullins RF, Ramesh A, Van Camp G, Hageman GS, Woychik RP, Smith RJ, Hagemen GS (2001) Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum Mol Genet 10:1709–1718CrossRefGoogle Scholar
  7. Astuto LM, Weston MD, Carney CA, Hoover DM, Cremers CW, Wagenaar M, Moller C, Smith RJ, Pieke-Dahl S, Greenberg J, Ramesar R, Jacobson SG, Ayuso C, Heckenlively JR, Tamayo M, Gorin MB, Reardon W, Kimberling WJ (2000) Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I. Am J Hum Genet 67:1569–1574CrossRefGoogle Scholar
  8. Astuto LM, Bork JM, Weston MD, Askew JW, Fields RR, Orten DJ, Ohliger SJ, Riazuddin S, Morell RJ, Khan S, Riazuddin S, Kremer H, van Hauwe P, Moller CG, Cremers CW, Ayuso C, Heckenlively JR, Rohrschneider K, Spandau U, Greenberg J, Ramesar R, Reardon W, Bitoun P, Millan J, Legge R, Friedman TB, Kimberling WJ (2002) CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet 71:262–275CrossRefGoogle Scholar
  9. Bharadwaj AK, Kasztejna JP, Huq S, Berson EL, Dryja TP (2000) Evaluation of the myosin VIIA gene and visual function in patients with Usher syndrome type I. Exp Eye Res 12:173–181CrossRefGoogle Scholar
  10. Bitner-Glindzicz M, Lindley KJ, Rurland P, Blaydon D, Smith VV, Milla PJ, Hussain K, Furth-Lavi J, Cosgrove KE, Shepherd RM, Barnes PD, O’Brien RE, Farndon PA, Sowden J, Liu XZ, Scanlan MJ, Malcolm S, Dunne MJ, Aynsley-Green A, Glaser B (2000) A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet 260:56–60CrossRefGoogle Scholar
  11. Blaydon DC, Mueller RF, Hutchin TP, Leroy BP, Bhattacharya SS, Bird AC, Malcolm S, Bitner-Glindzicz M (2003) The contribution of USH1C mutations to syndromic and non-syndromic deafness in the UK. Clin Genet 63: 303–307Google Scholar
  12. Bolz H, von Brederlow, Ramirez A, Bryda EC, Kutsche K, Nothwang HG, Seeliger M, del C-Salcedo Cabrera M, Vila MC, Molina OP, Gal A, Kubisch C (2001) Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet 27:108–112Google Scholar
  13. Bork JM, Peters LM, Riazuddin S, Bernstein SL, Ahmed ZM, Ness SL, Polomeno R, Ramesh A, Schloss M, Srisailpathy CR, Wayne S, Bellman S, Desmukh D, Ahmed Z, Khan SN, Kaloustian VM, Li XC, Lalwani A, Riazuddin S, Bitner-Glindzicz M, Nance WE, Liu XZ, Wistow G, Smith RJ, Griffith AJ, Wilcox ER, Friedman TB, Morell RJ (2001) Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet 68:26–37CrossRefPubMedGoogle Scholar
  14. Boughman JA, Vernon M, Shaver KA (1983) Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis 36:595–603CrossRefGoogle Scholar
  15. Janecke AR, Meins M, Sadeghi M, Grundmann K, Apfelstedt-Sylla E, Zrenner E, Rosenberg T, Gal A (1999) Twelve novel myosin VIIA mutations in 34 patients with Usher syndrome type I: confirmation of genetic heterogeneity. Hum Mutat 13:133–140Google Scholar
  16. Kay BK, Williamson MP, Sudol M (2000) The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains. FASEB J 14:231–241PubMedGoogle Scholar
  17. Keats BJ, Corey DP (1999) The Usher syndromes. Am J Med Genet 89:58–66Google Scholar
  18. Kimberling WJ, Möller C (1995) Clinical and molecular genetics of Usher syndrome. J Am Acad Audiol 6:63–72Google Scholar
  19. Larget-Piet D, Gerber S, Bonneau D, Rozet JM, Marc S, Ghazi I, Dufier JL, David A, Bitoun P, Weissenbach J, Munnich A, Kaplan J (1994) Genetic heterogeneity of Usher syndrome type 1 in French families. Genomics 21:138–143CrossRefGoogle Scholar
  20. Levy G, Levi-Acobas F, Blanchard S, Gerber S, Larget-Piet D, Chenal V, Liu XZ, Newton V, Steel KP, Brown SD, Munnich A, Kaplan J, Petit C, Weil D (1997) Myosin VIIA gene: heterogeneity of the mutations responsible for Usher syndrome type IB. Hum Mol Genet 6:111–116CrossRefPubMedGoogle Scholar
  21. Liu XZ, Walsh J, Mburu P, Kendrick-Jones J, Cope MJ, Steel KP, Brown SD (1997) Mutations in the myosin VII a gene cause nonsyndromic recessive deafness. Nat Genet 16:188–190CrossRefGoogle Scholar
  22. Liu XZ, Hope C, Walsh J, Newton V, Ke XM, Liang CY, Xu LR, Zhou JM, Trump D, Steel K, Bundey S, Brown SDM (1998) Mutations in the myosin VIIA gene Causing a wide phenotypic spectrum including atyical Usher syndrome. Am J Hum Genet 63:909–912CrossRefGoogle Scholar
  23. Ouyang XM, Hejtmancik JF, Jacobson SG, Xia XJ, Li A, Du LL, Newton V, Kaiser M, Balkany T, Nance WE, Liu XZ (2003) USH1C: a rare cause of USH1 in a non-Acadian population and a founder effect of the Acadian allele. Clin Genet 63:150–153Google Scholar
  24. Siemens J, Kazmierczak P, Reynolds A, Sticker M, Littlewood-Evans A, Muller U (2002) The Usher syndrome proteins cadherin 23 and harmonin form a complex by means of PDZ-domain interactions. Proc Natl Acad Sci USA 99:14946–14951CrossRefGoogle Scholar
  25. Smith RJH, Berlin CI, Hejtmancik JF, Keats BJ, Kimberling WJ, Lewis RA, Moller CG, Pelias MZ, Tranebjaerg L (1994) Clinical diagnosis of the Usher syndromes. Usher syndrome consortium. Am J Med Genet 50:32–38Google Scholar
  26. Suzuki ST (2000) Recent progress in protocadherin research. Exp Cell Res 26:13–18CrossRefGoogle Scholar
  27. Titus MA (1997) Unconventional myosins: new frontiers in actin-based motors. Trends Cell Biol 7:119–123CrossRefGoogle Scholar
  28. Vernon M (1969) Usher’s syndrome-deafness and progressive blindness. Clinical cases, prevention, theory and literature survey. J Chronic Dis 22:133–151Google Scholar
  29. Verpy E, Leibovivici M, Zwaenepoel I, Liu XZ, Gal A, Salem N, Mansour A, Blanchard S, Kobayashi I, Keats BJ, Slim R, Petit C (2000) A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet 26:51–55Google Scholar
  30. von Brederlow B, Bolz H, Janecke A, La O, Cabrera A, Rudolph G, Lorenz B, Schwinger E, Gal A (2002) Identification and in vitro expression of novel CDH23 mutations of patients with Usher syndrome type 1D. Hum Mutat 19:268–273CrossRefGoogle Scholar
  31. Weil D, Blanchard S, Kaplan J, Guilford P, Gibson F et al (1995) Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374:60–61CrossRefPubMedGoogle Scholar
  32. Weil D, Levy G, Sahly I, Levi-Acobas F, Blanchard S, El-Amraoui A, Crozet F, Philippe H, Abitbol M, Petit C (1996) Human myosin VIIA responsible for the Usher 1B syndrome: a predicted membrane-associated motor protein expressed in developing sensory epithelia. Proc Natl Acad Sci USA 93:3232–3237Google Scholar
  33. Weil D, El-Amraoui A, Masmoudi S, Mustapha M, KikkawaY, Laine S, Delmaghani S, Adato A, Nadifi S, Ben Zina Z, Hamel C, Gal A, Ayadi H, Yonekawa H, Petit C (2003) Usher syndrome type IG (USH1G) is caused by mutation in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin. Hum Mol Genet 12:463–471CrossRefGoogle Scholar
  34. Weston MD, Kelley PM, Overbeck LD, Wagenaar M, Orten DJ, Hasson T, Chen ZY, Corey D, Mooseker M, Sumegi J, Cremers C, Moller C, Jacobson SG, Gorin MB, KimberlingWJ (1996) Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. Am J Hum Genet 59:1074–1083PubMedGoogle Scholar
  35. Zwaenepoel I, Verpy E, Blanchard S, Meins M, Apfelstedt-Sylla E, Gal A, Petit C (2001) Identification of three novel mutations in the USH1C gene and detection of thirty-one polymorphisms used for haplotype analysis. Hum Mutat 17:34–41Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Xiao Mei Ouyang
    • 1
  • Denise Yan
    • 1
  • Li Lin Du
    • 1
  • J. Fielding. Hejtmancik
    • 2
  • Samuel G. Jacobson
    • 3
  • Walter E. Nance
    • 4
  • An Ren Li
    • 2
  • Simon Angeli
    • 1
  • Muriel Kaiser
    • 2
  • Valerie Newton
    • 5
  • Steve D. M. Brown
    • 6
  • Thomas Balkany
    • 1
  • Xue Zhong Liu
    • 1
  1. 1.Department of Otolaryngology (D-48)University of MiamiMiamiUSA
  2. 2.National Eye Institute/NIHBethesdaUSA
  3. 3.Scheie Eye InstituteUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Department of Human GeneticsVirginia Commonwealth UniversityRichmondUSA
  5. 5.Center for AudiologyUniversity of ManchesterManchesterEngland
  6. 6.MRC Mouse Genome Centre and MRC Mammalian Genetics UnitEngland

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