Article

European Journal of Human Genetics (2014) 22, 208–215; doi:10.1038/ejhg.2013.108; published online 29 May 2013

Novel form of X-linked nonsyndromic hearing loss with cochlear malformation caused by a mutation in the type IV collagen gene COL4A6

Simone Rost1, Elisa Bach1, Cordula Neuner1, Indrajit Nanda1, Sandra Dysek2, Reginald E Bittner2, Alexander Keller3, Oliver Bartsch4, Robert Mlynski5, Thomas Haaf1, Clemens R Müller1 and Erdmute Kunstmann1

  1. 1Department of Human Genetics, University of Würzburg, Würzburg, Germany
  2. 2Department of Neuromuscular Research, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
  3. 3DNA Analytics Core Facility and Department of Animal Ecology and Tropical Biology, University of Würzburg, Würzburg, Germany
  4. 4Institute of Human Genetics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
  5. 5Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery, Comprehensive Hearing Center, University of Würzburg, Würzburg, Germany

Correspondence: Dr S Rost or Professor Dr T Haaf, Department of Human Genetics, University of Würzburg, Biocenter, Am Hubland, Würzburg 97074, Germany. Tel: +49 931 31 84095 or +49 931 31 88738; Fax: +49 931 31 84069; E-mail: simone.rost@biozentrum.uni-wuerzburg.de or thomas.haaf@uni-wuerzburg.de

Received 30 October 2012; Revised 8 April 2013; Accepted 19 April 2013
Advance online publication 29 May 2013

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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.

Keywords:

next-generation sequencing; X-linked nonsyndromic hearing loss; type IV collagen; COL4A6