title: Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6.
abstract: Hereditary hearing loss is the most common human sensorineural disorder. Genetic causes are highly heterogeneous, with mutations detected in >40 genes associated with nonsyndromic hearing loss, to date. Whereas autosomal recessive and autosomal dominant inheritance is prevalent, X-linked forms of nonsyndromic hearing impairment are extremely rare. Here, we present a Hungarian three-generation family with X-linked nonsyndromic congenital hearing loss and the underlying genetic defect. Next-generation sequencing and subsequent segregation analysis detected a missense mutation (c.1771G>A, p.Gly591Ser) in the type IV collagen gene COL4A6 in all affected family members. Bioinformatic analysis and expression studies support this substitution as being causative. COL4A6 encodes the alpha-6 chain of type IV collagen of basal membranes, which forms a heterotrimer with two alpha-5 chains encoded by COL4A5. Whereas mutations in COL4A5 and contiguous X-chromosomal deletions involving COL4A5 and COL4A6 are associated with X-linked Alport syndrome, a nephropathy associated with deafness and cataract, mutations in COL4A6 alone have not been related to any hereditary disease so far. Moreover, our index patient and other affected family members show normal renal and ocular function, which is not consistent with Alport syndrome, but with a nonsyndromic type of hearing loss. In situ hybridization and immunostaining demonstrated expression of the COL4A6 homologs in the otic vesicle of the zebrafish and in the murine inner ear, supporting its role in normal ear development and function. In conclusion, our results suggest COL4A6 as being the fourth gene associated with X-linked nonsyndromic hearing loss.
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Rost
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bach
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Cordula
authors.initials: C
authors.lastname: Neuner
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Department of Neuromuscular Research, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Dysek
authors.affiliation: Department of Neuromuscular Research, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.affiliation: DNA Analytics Core Facility and Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Keller
authors.affiliation: Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Comprehensive Hearing Center, University of Würzburg, Würzburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Mlynski
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Clemens R
authors.initials: CR
authors.lastname: Müller
authors.affiliation: Department of Human Genetics, University of Würzburg, Würzburg, Germany.
authors.forename: Erdmute
authors.initials: E
authors.lastname: Kunstmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002675:Child, Preschool; D003051:Cochlea / Q000002:abnormalities*; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D022821:RNA Splice Sites; D015027:Zebrafish
chemical_list: C559044:COL4A6 protein, human; D024141:Collagen Type IV; D022821:RNA Splice Sites