Universität zu Köln

Thoenes, Michaela, Zimmermann, Ulrike, Ebermann, Inga, Ptok, Martin, Lewis, Morag A., Thiele, Holger, Morlot, Susanne, Hess, Markus M., Gal, Andreas, Eisenberger, Tobias, Bergmann, Carsten, Nuernberg, Gudrun, Nuernberg, Peter, Steel, Karen P., Knipper, Marlies and Bolz, Hanno Joern (2015). OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67). Orphanet J. Rare Dis., 10. LONDON: BMC. ISSN 1750-1172

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Thoenes, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED Zimmermann, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Ebermann, Inga UNSPECIFIED UNSPECIFIED UNSPECIFIED Ptok, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lewis, Morag A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Morlot, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Hess, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gal, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Eisenberger, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Bergmann, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Steel, Karen P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Knipper, Marlies UNSPECIFIED UNSPECIFIED UNSPECIFIED Bolz, Hanno Joern UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-407698
DOI:	10.1186/s13023-015-0238-5
Journal or Publication Title:	Orphanet J. Rare Dis.
Volume:	10
Date:	2015
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1750-1172
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MESSENGER-RNA; GENE; EXPRESSION; MUTATIONS; TOOL; IDENTIFICATION; PREDICTION; OTOFERLIN; PEDIGREES; MIR-96 Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40769