Advertisement

neurogenetics

, Volume 17, Issue 2, pp 115–123 | Cite as

Recessive mutations of TMC1 associated with moderate to severe hearing loss

  • Ayesha Imtiaz
  • Azra Maqsood
  • Atteeq U. Rehman
  • Robert J. Morell
  • Jeffrey R. Holt
  • Thomas B. Friedman
  • Sadaf Naz
Original Article

Abstract

TMC1 encodes a protein required for the normal function of mechanically activated channels that enable sensory transduction in auditory and vestibular hair cells. TMC1 protein is localized at the tips of the hair cell stereocilia, the site of conventional mechanotransduction. In many populations, loss-of-function recessive mutations of TMC1 are associated with profound deafness across all frequencies tested. In six families reported here, variable moderate-to-severe or moderate-to-profound hearing loss co-segregated with STR (short tandem repeats) markers at the TMC1 locus DFNB7/11. Massively parallel and Sanger sequencing of genomic DNA revealed each family co-segregating hearing loss with a homozygous TMC1 mutation: two reported mutations (p.R34X and p.R389Q) and three novel mutations (p.S596R, p.N199I, and c.1404 + 1G > T). TMC1 cDNA sequence from affected subjects homozygous for the donor splice site transversion c.1404 + 1G > T revealed skipping of exon 16, deleting 60 amino acids from the TMC1 protein. Since the mutations in our study cause less than profound hearing loss, we speculate that there is hypo-functional TMC1 mechanotransduction channel activity and that other even less damaging variants of TMC1 may be associated with more common mild-to-severe sensorineural hearing loss.

Keywords

TMC1 Mechanosensory transduction DFNB7/11 Moderate or severe hearing loss 

Abbreviations

STR

Short tandem repeats

CI

Confidence interval

dB

Decibels

HL

Hearing loss

PTA

Pure tune averages

ISO

International standards organization

cDNA

Complementary DNA

ExAC

Exome aggregation consortium

HGMD

Human gene mutation database

Mb

Megabase

QTL

Quantitative trait locus

Notes

Acknowledgments

We thank the participants in this study and the Special Education Schools, Punjab, for their help. We are grateful to Drs. C. Brewer and A.J. Griffith for review of this manuscript. The help of Dr. A.J. Griffith is also acknowledged for providing many of the primers to amplify and sequence TMC1. This work was supported by grant R01DC01352103 to Jeffery R Holt from the National Institute of Deafness and Other Communication Disorders, National Institute of Health, USA, and intramural funds DC000039-19 to Thomas B Friedman from the National Institute of Deafness and Other Communication Disorders, National Institutes of Health, USA, and grant R01TW007608 to Sadaf Naz from the Fogarty International Center, NIH and National Institute on Deafness and Other Communication Disorders, NIH. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov), and also the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Kitajiri SI, McNamara R, Makishima T, Husnain T, Zafar AU, Kittles RA, Ahmed ZM, Friedman TB, Riazuddin S, Griffith AJ (2007) Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan. Clin Genet 72:546–550CrossRefPubMedGoogle Scholar
  2. 2.
    Kurima K, Peters LM, Yang Y, Riazuddin S, Ahmed ZM, Naz S, Arnaud D, Drury S, Mo J, Makishima T, Ghosh M, Menon PS, Deshmukh D, Oddoux C, Ostrer H, Khan S, Riazuddin S, Deininger PL, Hampton LL, Sullivan SL, Battey JF Jr, Keats BJ, Wilcox ER, Friedman TB, Griffith AJ (2002) Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat Genet 30:277–284CrossRefPubMedGoogle Scholar
  3. 3.
    Makishima T, Kurima K, Brewer CC, Griffith AJ (2004) Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss. Otol Neurotol 25:714–719CrossRefPubMedGoogle Scholar
  4. 4.
    Vreugde S, Erven A, Kros CJ, Marcotti W, Fuchs H, Kurima K, Wilcox ER, Friedman TB, Griffith AJ, Balling R, Hrabé De Angelis M, Avraham KB, Steel KP (2002) Beethoven, a mouse model for dominant, progressive hearing loss DFNA36. Nat Genet 30:257–258CrossRefPubMedGoogle Scholar
  5. 5.
    Keats BJ, Nouri N, Huang JM, Money M, Webster DB, Berlin CI (1995) The deafness locus (dn) maps to mouse chromosome 19. Mamm Genome 6(1):8–10CrossRefPubMedGoogle Scholar
  6. 6.
    Labay V, Weichert RM, Makishima T, Griffith AJ (2010) Topology of transmembrane channel-like gene 1 protein. Biochemistry 49:8592–8598CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kawashima Y, Kurima K, Pan B, Griffith AJ, Holt JR (2015) Transmembrane channel-like (TMC) genes are required for auditory and vestibular mechanosensation. Pflugers Arch - Eur J Physiol 467:85–94CrossRefGoogle Scholar
  8. 8.
    Kurima K, Ebrahim S, Pan B, Sedlacek M, Sengupta P, Millis BA, Cui R, Nakanishi H, Fujikawa T, Kawashima Y, Choi BY, Monahan K, Holt JR, Griffith AJ, Kachar B (2015) TMC1 and TMC2 localize at the site of mechanotransduction in mammalian inner ear hair cell stereocilia. Cell Rep 12:1606–1617CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pan B, Holt JR (2015) The molecules that mediate sensory transduction in the mammalian inner ear. Curr Opin Neurobiol 34:165–171CrossRefPubMedGoogle Scholar
  10. 10.
    Maeda R, Kindt KS, Mo W, Morgan CP, Erickson T, Zhao H, Clemens-Grisham R, Barr-Gillespie PG, Nicolson T (2014) Tip-link protein protocadherin 15 interacts with transmembrane channel-like proteins TMC1 and TMC2. Proc Natl Acad Sci U S A 111:12907–12912CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Pan B, Géléoc GS, Asai Y, Horwitz GC, Kurima K, Ishikawa K, Kawashima Y, Griffith AJ, Holt JR (2013) TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79:504–515CrossRefPubMedGoogle Scholar
  12. 12.
    Riazuddin S, Belyantseva IA, Giese AP, Lee K, Indzhykulian AA, Nandamuri SP, Yousaf R, Sinha GP, Lee S, Terrell D, Hegde RS, Ali RA, Anwar S, Andrade-Elizondo PB, Sirmaci A, Parise LV, Basit S, Wali A, Ayub M, Ansar M, Ahmad W, Khan SN, Akram J, Tekin M, Riazuddin S, Cook T, Buschbeck EK, Frolenkov GI, Leal SM, Friedman TB, Ahmed ZM (2012) Alterations of the CIB2 calcium-and integrin-binding protein cause usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat Genet 44:1265–1271CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bademci G, Foster J 2nd, Mahdieh N, Bonyadi M, Duman D, Cengiz FB, Menendez I, Diaz-Horta O, Shirkavand A, Zeinali S, Subasioglu A, Tokgoz-Yilmaz S, Huesca-Hernandez F, de la Luz A-SM, Dominguez-Aburto J, Hernandez-Zamora E, Montenegro P, Paredes R, Moreta G, Vinueza R, Villegas F, Mendoza-Benitez S, Guo S, Bozan N, Tos T, Incesulu A, Sennaroglu G, Blanton SH, Ozturkmen-Akay H, Yildirim-Baylan M, Tekin M (2015) Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort. Genet Med. doi: 10.1038/gim.2015.89 PubMedGoogle Scholar
  14. 14.
    Ganapathy A, Pandey N, Srisailapathy CR, Jalvi R, Malhotra V, Venkatappa M, Chatterjee A, Sharma M, Santhanam R, Chadha S, Ramesh A, Agarwal AK, Rangasayee RR, Anand A (2014) Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE. PLoS One 9(1):e84773. doi: 10.1371/journal.pone.0084773, eCollection 2014CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yang T, Wei X, Chai Y, Li L, Wu H (2013) Genetic etiology study of the non-syndromic deafness in Chinese Hans by targeted next-generation sequencing. Orphanet J Rare Dis 8:Q110KCrossRefGoogle Scholar
  16. 16.
    Kalay E, Karaguzel A, Caylan R, Heister A, Cremers FP, Cremers CW, Brunner HG, de Brouwer AP, Kremer H (2005) Four novel TMC1 (DFNB7/DFNB11) mutations in Turkish patients with congenital autosomal recessive nonsyndromic hearing loss. Hum Mutat 26:591–591CrossRefPubMedGoogle Scholar
  17. 17.
    Schrauwen I, Sommen M, Corneveaux JJ, Reiman RA, Hackett NJ, Claes C, Claes K, Bitner-Glindzicz M, Coucke P, Van Camp G, Huentelman MJ (2013) A sensitive and specific diagnostic test for hearing loss using a microdroplet PCR‐based approach and next generation sequencing. Am J Med Genet A 161:145–152CrossRefGoogle Scholar
  18. 18.
    Tlili A, Rebeh IB, Aifa-Hmani M, Dhouib H, Moalla J, Tlili-Chouchène J, Said MB, Lahmar I, Benzina Z, Charfedine I, Driss N, Ghorbel A, Ayadi H, Masmoudi S (2007) TMC1 but not TMC2 is responsible for autosomal recessive nonsyndromic hearing impairment in Tunisian families. Audiol Neuro-Otol 13:213–218CrossRefGoogle Scholar
  19. 19.
    Mazzoli M, van Camp G, Newton V, Giarbini N, Declau FAP (2003) Recommendations for the description of genetic and audiological data for families with nonsyndromic hereditary hearing impairment. Audiol Med 1:148–150CrossRefGoogle Scholar
  20. 20.
    Grimberg J, Nawoschik S, Belluscio L, Mckee R, Turck A, Eisenberget A (1989) A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acids Res 17:83–90Google Scholar
  21. 21.
    Salman M, Bashir R, Imtiaz A, Maqsood A, Mujtaba G, Iqbal M, Naz S (2015) Mutations of GJB2 encoding connexin 26 contribute to non-syndromic moderate and severe hearing loss in Pakistan. Eur Arch Otorhinolaryngol. doi: 10.1007/s00405-015-3523-y PubMedGoogle Scholar
  22. 22.
    Zein WM, Falsini B, Tsilou ET, Turriff AE, Schultz JM, Friedman TB, Brewer CC, Zalewski CK, King KA, Muskett JA, Rehman AU, Morell RJ, Griffith AJ, Sieving PA (2014) Cone responses in usher syndrome types 1 and 2 by microvolt electroretinography. Invest Ophthalmol Vis Sci 56:107–14CrossRefPubMedGoogle Scholar
  23. 23.
    Ye S, Dhillon S, Ke X, Collins AR, Day IN (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Res 29:e88–e88CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Hildebrand MS, Kahrizi K, Bromhead CJ, Shearer AE, Webster JA, Khodaei H, Abtahi R, Bazazzadegan N, Babanejad M, Nikzat N, Kimberling WJ, Stephan D, Huygen PL, Bahlo M, Smith RJ, Najmabadi H (2010) Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population. Ann Otol Rhinol Laryngol 119:830–835CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gao X, Su Y, Guan LP, Yuan YY, Huang SS, Lu Y, Wang GJ, Han MY, Yu F, Song YS, Zhu QY, Wu J, Dai P (2013) Novel compound heterozygous TMC1 mutations associated with autosomal recessive hearing loss in a Chinese family. PLoS One 8:e63026CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Hilgert N, Alasti F, Dieltjens N, Pawlik B, Wollnik B, Uyguner O, Delmaghani S, Weil D, Petit C, Danis E, Yang T, Pandelia E, Petersen MB, Goossens D, Favero JD, Sanati MH, Smith RJ, Van Camp G (2008) Mutation analysis of TMC1 identifies four new mutations and suggests an additional deafness gene at loci DFNA36 and DFNB7/11. Clin Genet 74:223–232CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    de Heer AM, Collin RW, Huygen PL, Schraders M, Oostrik J, Rouwette M, Kunst HP, Kremer H, Cremers CW (2011) Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1. Audiol Neurootol 16:93–105CrossRefPubMedGoogle Scholar
  28. 28.
    Delmaghani S, Aghaie A, Michalski N, Bonnet C, Weil D, Petit C (2012) Defect in the gene encoding the EAR/EPTP domain-containing protein TSPEAR causes DFNB98 profound deafness. Hum Mol Genet 21:3835–3844CrossRefPubMedGoogle Scholar
  29. 29.
    Shabbir MI, Ahmed ZM, Khan SY, Riazuddin S, Waryah AM, Khan SN, Camps RD, Ghosh M, Kabra M, Belyantseva IA, Friedman TB, Riazuddin S (2006) Mutations of human TMHS cause recessively inherited non-syndromic hearing loss. J Med Genet 43:634–640CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Schraders M, Ruiz-Palmero L, Kalay E, Oostrik J, del Castillo FJ, Sezgin O, Beynon AJ, Strom TM, Pennings RJ, Seco CZ, Oonk AM, Kunst HP, Domínguez-Ruiz M, García-Arumi AM, del Campo M, Villamar M, Hoefsloot LH, Moreno F, Admiraal RJ, del Castillo I, Kremer H (2012) Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment. Am J Hum Genet 91:883–9CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yariz KO, Duman D, Seco CZ, Dallman J, Huang M, Peters TA, Sirmaci A, Lu N, Schraders M, Skromne I, Oostrik J, Diaz-Horta O, Young JI, Tokgoz-Yilmaz S, Konukseven O, Shahin H, Hetterschijt L, Kanaan M, Oonk AM, Edwards YJ, Li H, Atalay S, Blanton S, Desmidt AA, Liu XZ, Pennings RJ, Lu Z, Chen ZY, Kremer H, Tekin M (2012) Mutations in OTOGL, encoding the inner ear protein otogelin-like, cause moderate sensorineural hearing loss. Am J Hum Genet 91:872–882CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Seco CZ, Oonk AM, Domínguez-Ruiz M, Draaisma JM, Gandía M, Oostrik J, Neveling K, Kunst HP, Hoefsloot LH, del Castillo I, Pennings RJ, Kremer H, Admiraal RJ, Schraders M (2014) Progressive hearing loss and vestibular dysfunction caused by a homozygous nonsense mutation in CLIC5. Eur J Hum Genet 23:189–94CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Jenkinson EM, Rehman AU, Walsh T, Clayton-Smith J, Lee K, Morell RJ, Drummond MC, Khan SN, Naeem MA, Rauf B, Billington N, Schultz JM, Urquhart JE, Lee MK, Berry A, Hanley NA, Mehta S, Cilliers D, Clayton PE, Kingston H, Smith MJ, Warner TT, University of Washington Center for Mendelian Genomics, Black GC, Trump D, Davis JR, Ahmad W, Leal SM, Riazuddin S, King MC, Friedman TB, Newman WG (2013) Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 92:605–613CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ahmed ZM, Goodyear R, Riazuddin S, Lagziel A, Legan PK, Behra M, Burgess SM, Lilley KS, Wilcox ER, Riazuddin S, Griffith AJ, Frolenkov GI, Belyantseva IA, Richardson GP, Friedman TB (2006) The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J Neurosci 26:7022–34CrossRefPubMedGoogle Scholar
  35. 35.
    Yang T, Kahrizi K, Bazazzadeghan N, Meyer N, Najmabadi H, Smith RJ (2010) A novel mutation adjacent to the Bth mouse mutation in the TMC1 gene makes this mouse an excellent model of human deafness at the DFNA36 locus. Clin Genet 77:395–8CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhao Y, Wang D, Zong L, Zhao F, Guan L, Zhang P, Shi W, Lan L, Wang H, Li Q, Han B, Yang L, Jin X, Wang J, Wang J, Wang Q (2014) A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family. PLoS One 9:e97064CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ben Saïd M, Hmani-Aifa M, Amar I, Baig SM, Mustapha M, Delmaghani S, Tlili A, Ghorbel A, Ayadi H, Van Camp G, Smith RJ, Tekin M, Masmoudi S (2010) High frequency of the p. R34X mutation in the TMC1 gene associated with nonsyndromic hearing loss is due to founder effects. Genet Test Mol Biomark 14:307–311CrossRefGoogle Scholar
  38. 38.
    Johnson KR, Longo-Guess CM, Gagnon LH (2015) A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice. Mamm Genome 26:338–347CrossRefPubMedGoogle Scholar
  39. 39.
    Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ (2011) Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest 121:4796–809CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Jain PK, Fukushima K, Deshmukh D, Ramesh A, Thomas E, Lalwani AK, Kumar S, Plopis B, Skarka H, Srisailapathy CR, Wayne S, Zbar RIS, Verma IC, Smith RJH, Wilcox ER (1995) A human recessive neurosensory nonsyndromic hearing impairment locus is potential homologue of murine deafness (dn) locus. Hum Mol Genet 4:2391–4CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ayesha Imtiaz
    • 1
    • 2
  • Azra Maqsood
    • 1
  • Atteeq U. Rehman
    • 2
  • Robert J. Morell
    • 2
  • Jeffrey R. Holt
    • 3
  • Thomas B. Friedman
    • 2
  • Sadaf Naz
    • 1
  1. 1.School of Biological SciencesUniversity of the PunjabLahorePakistan
  2. 2.National Institute on Deafness and Other Communication DisordersNational Institutes of HealthBethesdaUSA
  3. 3.Department of Otolaryngology, F. M. Kirby Neurobiology CenterBoston Children’s Hospital, Harvard Medical SchoolBostonUSA

Personalised recommendations