OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67).

Michaela Thoenes,Hanno Jörn Bolz,Karen P Steel,Inga Ebermann,Marlies Knipper,Carsten Bergmann,Markus M Hess,Susanne Morlot,Holger Thiele,Martin Ptok,Andreas Gal,Peter Nürnberg,Ulrike Zimmermann,Tobias Eisenberger,Morag A Lewis,Gudrun Nürnberg

doi:10.1186/s13023-015-0238-5

Abstract

BackgroundEarly-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family.MethodsA panel of 66 known deafness genes was analyzed for mutations by next-generation sequencing (NGS) in the index patient. We then conducted genome-wide linkage analysis, and whole-exome sequencing was carried out with samples of two patients. Expression of Osbpl2 in the mouse cochlea was determined by immunohistochemistry. Because Osbpl2 has been proposed as a target of miR-96, we investigated homozygous Mir96 mutant mice for its upregulation.ResultsOnset of hearing loss in the investigated ADNSHL family is in childhood, initially affecting the high frequencies and progressing to profound deafness in adulthood. However, there is considerable intrafamilial variability. We mapped a novel ADNSHL locus, DFNA67, to chromosome 20q13.2-q13.33, and subsequently identified a co-segregating heterozygous frameshift mutation, c.141_142delTG (p.Arg50Alafs*103), in OSBPL2, encoding a protein known to interact with the DFNA1 protein, DIAPH1. In mice, Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells. We found no significant Osbpl2 upregulation at the mRNA level in homozygous Mir96 mutant mice.ConclusionThe function of OSBPL2 in the hearing process remains to be determined. Our study and the recent description of another frameshift mutation in a Chinese ADNSHL family identify OSBPL2 as a novel gene for progressive deafness.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0238-5) contains supplementary material, which is available to authorized users.

Highlights

Early-onset hearing loss is mostly of genetic origin
Clinical characterization of DFNA67 patients In most affected family members, bilateral sensorineural non-syndromic hearing loss was first noted in the early second decade of life and affected initially the high frequencies
No audiological data were available for IV:12, a 39-years old carrier of the OSBPL2 mutation, who does not use hearing aids but claims worse hearing in stressful situations

Summary

Introduction

Early-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. We aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family. Hearing impairment is the most common sensory disorder, affecting approximately 1/500 newborns. Most cases are of genetic origin, and there is extensive allelic and non-allelic heterogeneity. 20% of patients have autosomal dominantly-inherited forms (ADNSHL) and typically display postlingual progressive hearing impairment. Sixty-five ADNSHL loci have been officially designated, and 30 causative genes have been reported [1,2,3]. Because of the extensive genetic heterogeneity of hearing impairment, the identification of the causative mutation in single patients has been the exception until recently. With the advent of next-generation sequencing (NGS), deafness genes have become accessible to comprehensive genetic analysis and routine genetic testing by targeted NGS of “gene panels” [4]

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Conclusion