, 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


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.


TMC1 Mechanosensory transduction DFNB7/11 Moderate or severe hearing loss 



Short tandem repeats


Confidence interval




Hearing loss


Pure tune averages


International standards organization


Complementary DNA


Exome aggregation consortium


Human gene mutation database




Quantitative trait locus



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 (, and also the computational resources of the NIH HPC Biowulf cluster (

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


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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

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