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

Orphanet J Rare Dis. 2015 Feb 10;10:15. doi: 10.1186/s13023-015-0238-5.

Michaela Thoenes ¹, Ulrike Zimmermann ², Inga Ebermann ³, Martin Ptok ⁴, Morag A Lewis ⁵, Holger Thiele ⁶, Susanne Morlot ⁷, Markus M Hess ⁸, Andreas Gal ⁹, Tobias Eisenberger ¹⁰, Carsten Bergmann ¹¹ ¹², Gudrun Nürnberg ¹³, Peter Nürnberg ¹⁴ ¹⁵, Karen P Steel ¹⁶, Marlies Knipper ¹⁷, Hanno Jörn Bolz ¹⁸ ¹⁹

Affiliations

1 Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. [email protected].
2 Molecular Physiology of Hearing, Hearing Research Centre Tübingen (THRC), Department of Otolaryngology, University of Tübingen, Tübingen, Germany. [email protected].
3 Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. [email protected].
4 Department of Phoniatrics and Pediatric Audiology, Hannover Medical School, Hannover, Germany. [email protected].
5 Wolfson Centre for Age-Related Diseases, King's College London, London, UK. [email protected].
6 Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [email protected].
7 Institute for Human Genetics, Hannover Medical School, Hannover, Germany. [email protected].
8 Department of Voice, Speech and Hearing Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
9 Department of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected].
10 Center for Human Genetics, Bioscientia, Ingelheim, Germany. [email protected].
11 Center for Human Genetics, Bioscientia, Ingelheim, Germany. [email protected].
12 Renal Division, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany. [email protected].
13 Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [email protected].
14 Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [email protected].
15 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. [email protected].
16 Wolfson Centre for Age-Related Diseases, King's College London, London, UK. [email protected].
17 Molecular Physiology of Hearing, Hearing Research Centre Tübingen (THRC), Department of Otolaryngology, University of Tübingen, Tübingen, Germany. [email protected].
18 Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. [email protected].
19 Center for Human Genetics, Bioscientia, Ingelheim, Germany. [email protected].

PMID: 25759012 DOI: 10.1186/s13023-015-0238-5

Abstract

Background: 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. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family.

Methods: A 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.

Results: Onset 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.

Conclusion: The 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.

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