title: OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67).
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. michaela.thoenes@uk-koeln.de.
authors.forename: Michaela
authors.initials: M
authors.lastname: Thoenes
authors.affiliation: Molecular Physiology of Hearing, Hearing Research Centre Tübingen (THRC), Department of Otolaryngology, University of Tübingen, Tübingen, Germany. ulrike.zimmermann@uni-tuebingen.de.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zimmermann
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. ingaebermann@yahoo.de.
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.affiliation: Department of Phoniatrics and Pediatric Audiology, Hannover Medical School, Hannover, Germany. Ptok.Martin@mh-hannover.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Ptok
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK. morag.lewis@kcl.ac.uk.
authors.forename: Morag A
authors.initials: MA
authors.lastname: Lewis
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. holger.thiele@uni-koeln.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute for Human Genetics, Hannover Medical School, Hannover, Germany. Morlot.Susanne@mh-hannover.de.
authors.forename: Susanne
authors.initials: S
authors.lastname: Morlot
authors.affiliation: Department of Voice, Speech and Hearing Disorders, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. hess@uke.de.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Hess
authors.affiliation: Department of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. gal@uke.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gal
authors.affiliation: Center for Human Genetics, Bioscientia, Ingelheim, Germany. tobias.eisenberger@bioscientia.de.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberger
authors.affiliation: Center for Human Genetics, Bioscientia, Ingelheim, Germany. carsten.bergmann@bioscientia.de.|Renal Division, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany. carsten.bergmann@bioscientia.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. nuernberg@uni-koeln.de.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.affiliation: Cologne Center for Genomics (CCG) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. gudrun.nuernberg@uni-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. gudrun.nuernberg@uni-koeln.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Wolfson Centre for Age-Related Diseases, King's College London, London, UK. karen.steel@kcl.ac.uk.
authors.forename: Karen P
authors.initials: KP
authors.lastname: Steel
authors.affiliation: Molecular Physiology of Hearing, Hearing Research Centre Tübingen (THRC), Department of Otolaryngology, University of Tübingen, Tübingen, Germany. marlies.knipper@uni-tuebingen.de.
authors.forename: Marlies
authors.initials: M
authors.lastname: Knipper
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany. hanno.bolz@bioscientia.de.|Center for Human Genetics, Bioscientia, Ingelheim, Germany. hanno.bolz@bioscientia.de.
authors.forename: Hanno Jörn
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002675:Child, Preschool; D003638:Deafness / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D006198:Hair Cells, Auditory / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D059547:Stereocilia / Q000378:metabolism*; D055815:Young Adult; D000098825:Oxysterol Binding Proteins
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D011987:Receptors, Steroid; C541554:Mirn96 microRNA, mouse; C461064:OSBPL2 protein, human; D000098825:Oxysterol Binding Proteins