title: Truncating mutation of the DFNB59 gene causes cochlear hearing impairment and central vestibular dysfunction.
abstract: We have identified a consanguineous family from Morocco segregating autosomal recessive congenital progressive hearing loss (ARNSHL) and retinal degeneration. Detailed clinical investigation of the six siblings revealed combined severe cone-rod dystrophy (CORD) and severe/profound hearing impairment in two of them, while there is isolated CORD in three and nonsyndromic profound hearing loss in one. We therefore assumed a partial overlap of two nonsyndromic autosomal recessive conditions instead of a monogenic syndrome and performed genomewide linkage analysis. The disease loci were mapped to chromosome 2q31.1-2q32.1 for ARNSHL and to 2q13-2q14.1 for CORD, respectively. The retinal phenotype was shown to be due to homozygosity for a novel splice site mutation, c.2189+1G>T, in the retinitis pigmentosa gene MERTK. The ARNSHL interval comprised the DFNB59 locus. The DFNB59 gene has been identified recently, and two missense mutations (p.R183W and p.T54I) have been shown to cause auditory neuropathy in both humans and transgenic mice. Mutation screening in the DFNB59 gene in our family revealed homozygosity for a 1-bp insertion in exon 2 (c.113_114insT), predicting a truncated protein of 47 amino acids, in all three hearing impaired subjects. This is the first description of biallelic putative loss-of-function of the DFNB59 gene. Detailed audiological investigation clearly indicated hair cell dysfunction and, in contrast to cases reported previously, excluded auditory neuropathy. We show that besides otoferlin (OTOF), DFNB59 is the second known gene in which mutations can result in these two distinct forms of hearing impairment. Moreover, all patients in our family with homozygosity for the DFNB59 mutation display central vestibular dysfunction.
authors.affiliation: Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Ebermann
authors.forename: Martin
authors.initials: M
authors.lastname: Walger
authors.forename: Hendrik P N
authors.initials: HP
authors.lastname: Scholl
authors.forename: Peter
authors.initials: P
authors.lastname: Charbel Issa
authors.forename: Christoph
authors.initials: C
authors.lastname: Lüke
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Ruth
authors.initials: R
authors.lastname: Lang-Roth
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D001299:Audiometry; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006198:Hair Cells, Auditory / Q000503:physiopathology; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009018:Morocco; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012160:Retina / Q000473:pathology; D012162:Retinal Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D017384:Sequence Deletion; D035781:Siblings; D015837:Vestibular Diseases / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D000076202:c-Mer Tyrosine Kinase; D000094524:Gasdermins
chemical_list: D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D022821:RNA Splice Sites; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase; C519847:PJVK protein, human; D000094524:Gasdermins; C097072:MERTK protein, human