TBC1D24 Mutation Causes Autosomal‐Dominant Nonsyndromic Hearing Loss

Hela Azaiez; Kevin T Booth; Fengxiao Bu; Patrick Huygen; Seiji B Shibata; A. Eliot Shearer; Diana Kolbe; Nicole Meyer; E. Ann Black‐Ziegelbein; Richard J.H Smith

doi:10.1002/humu.22557

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TBC1D24 Mutation Causes Autosomal‐Dominant Nonsyndromic Hearing Loss

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TBC1D24 Mutation Causes Autosomal‐Dominant Nonsyndromic Hearing Loss

Hela Azaiez, Kevin T Booth, Fengxiao Bu, Patrick Huygen, Seiji B Shibata, A. Eliot Shearer, Diana Kolbe, Nicole Meyer, E. Ann Black‐Ziegelbein and Richard J.H Smith

Human mutation, Vol.35(7), pp.819-823

07/2014

DOI: 10.1002/humu.22557

PMCID: PMC4267685

PMID: 24729539

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Abstract

ABSTRACT Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal‐dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole‐exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase‐activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders. After excluding mutations in all genes implicated in non‐syndromic hearing loss, we completed segregation mapping and whole exome sequencing on 7 and 3 persons, respectively. WES data were hard filtered to identify 46 variants shared by the 3 affecteds, only one of which mapped to a segregating genomic interval. The Ser178Leu variant in TBC1D24 is highly conserved across species. The transcribed gene is expressed in inner and outer hair cells in the P2 mouse cochlea (green; actin, red; DAPI, blue).

OtoSCOPE

nonsyndromic

TBC1D24

hearing impairment

hearing loss

autosomal dominant

pleiotropy

Details

Title: Subtitle: TBC1D24 Mutation Causes Autosomal‐Dominant Nonsyndromic Hearing Loss
Creators: Hela Azaiez - University of Iowa Hospitals and Clinics
Kevin T Booth - University of Iowa Hospitals and Clinics
Fengxiao Bu - University of Iowa Hospitals and Clinics
Patrick Huygen - Radbound University Nijmegen Medical Centre
Seiji B Shibata - University of Iowa Hospitals and Clinics
A. Eliot Shearer - University of Iowa Carver College of Medicine
Diana Kolbe - University of Iowa Hospitals and Clinics
Nicole Meyer - University of Iowa Hospitals and Clinics
E. Ann Black‐Ziegelbein - University of Iowa Hospitals and Clinics
Richard J.H Smith - University of Iowa Carver College of Medicine
Resource Type: Journal article
Publication Details: Human mutation, Vol.35(7), pp.819-823
DOI: 10.1002/humu.22557
PMID: 24729539
PMCID: PMC4267685
NLM abbreviation: Hum Mutat
ISSN: 1059-7794
eISSN: 1098-1004
Number of pages: 5
Grant note: NIDCD RO1s (DC003544; DC012049)
Language: English
Date published: 07/2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984006466702771

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