Journal article
Mutations of KCNJ10 Together with Mutations of SLC26A4 Cause Digenic Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct Syndrome
American journal of human genetics, Vol.84(5), pp.651-657
05/15/2009
DOI: 10.1016/j.ajhg.2009.04.014
PMCID: PMC2681005
PMID: 19426954
Abstract
Mutations in SLC26A4 cause nonsyndromic hearing loss associated with an enlarged vestibular aqueduct (EVA, also known as DFNB4) and Pendred syndrome (PS), the most common type of autosomal-recessive syndromic deafness. In many patients with an EVA/PS phenotype, mutation screening of SLC26A4 fails to identify two disease-causing allele variants. That a sizable fraction of patients carry only one SLC26A4 mutation suggests that EVA/PS is a complex disease involving other genetic factors. Here, we show that mutations in the inwardly rectifying K+ channel gene KCNJ10 are associated with nonsyndromic hearing loss in carriers of SLC26A4 mutations with an EVA/PS phenotype. In probands from two families, we identified double heterozygosity in affected individuals. These persons carried single mutations in both SLC26A4 and KCNJ10. The identified SLC26A4 mutations have been previously implicated in EVA/PS, and the KCNJ10 mutations reduce K+ conductance activity, which is critical for generating and maintaining the endocochlear potential. In addition, we show that haploinsufficiency of Slc26a4 in the Slc26a4+/− mouse mutant results in reduced protein expression of Kcnj10 in the stria vascularis of the inner ear. Our results link KCNJ10 mutations with EVA/PS and provide further support for the model of EVA/PS as a multigenic complex disease.
Details
- Title: Subtitle
- Mutations of KCNJ10 Together with Mutations of SLC26A4 Cause Digenic Nonsyndromic Hearing Loss Associated with Enlarged Vestibular Aqueduct Syndrome
- Creators
- Tao Yang - Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. ChinaJose G Gurrola - Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA52242, USAHao Wu - Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, P.R. ChinaSui M Chiu - Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec H3H 1P3, CanadaPhiline Wangemann - Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USAPeter M Snyder - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA52242, USARichard J.H Smith - Department of Otolaryngology-Head and Neck Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA52242, USA
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.84(5), pp.651-657
- DOI
- 10.1016/j.ajhg.2009.04.014
- PMID
- 19426954
- PMCID
- PMC2681005
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 05/15/2009
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Cardiovascular Medicine; Medicine Administration; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007299502771
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