Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

Qiujing Zhang; Colleen A Campbell; Liang Zong; Jing Guan; Richard J H Smith; Ju Yang; Megan Ealy; Qiang Shi; Dayong Wang; Hongyang Wang; Yali Zhao; Zhirong Shen; Fengchao Wang; Wei Sun; Lan Lan; Dalian Ding; Linyi Xie; Yue Qi; Xin Lou; Xusheng Huang; Suhua Chang; Wenping Xiong; Zifang Yin; Ning Yu; Hui Zhao; Jun Wang; Jing Wang; Richard J Salvi; Christine Petit; Qiuju Wang

doi:10.1136/jmedgenet-2014-102961

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Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

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Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder

Qiujing Zhang, Colleen A Campbell, Liang Zong, Jing Guan, Richard J H Smith, Ju Yang, Megan Ealy, Qiang Shi, Dayong Wang, Hongyang Wang, …

Journal of medical genetics, Vol.52(8), pp.523-531

08/2015

DOI: 10.1136/jmedgenet-2014-102961

PMCID: PMC4518735

PMID: 25986071

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Abstract

BackgroundAuditory neuropathy spectrum disorder (ANSD) is a form of hearing loss in which auditory signal transmission from the inner ear to the auditory nerve and brain stem is distorted, giving rise to speech perception difficulties beyond that expected for the observed degree of hearing loss. For many cases of ANSD, the underlying molecular pathology and the site of lesion remain unclear. The X-linked form of the condition, AUNX1, has been mapped to Xq23-q27.3, although the causative gene has yet to be identified.MethodsWe performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family.ResultsWe identified two missense mutations in AIFM1 in these families: c.1352G>A (p.R451Q) in the AUNX1 family and c.1030C>T (p.L344F) in the second ANSD family. Mutation screening in a large cohort of 3 additional unrelated families and 93 sporadic cases with ANSD identified 9 more missense mutations in AIFM1. Bioinformatics analysis and expression studies support this gene as being causative of ANSD.ConclusionsVariants in AIFM1 gene are a common cause of familial and sporadic ANSD and provide insight into the expanded spectrum of AIFM1-associated diseases. The finding of cochlear nerve hypoplasia in some patients was AIFM1-related ANSD implies that MRI may be of value in localising the site of lesion and suggests that cochlea implantation in these patients may have limited success.

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Title: Subtitle: Mutations in apoptosis-inducing factor cause X-linked recessive auditory neuropathy spectrum disorder
Creators: Qiujing Zhang - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Colleen A Campbell - Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA
Liang Zong - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Jing Guan - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Richard J H Smith - Molecular Otolaryngology and Renal Research Laboratories and the Department of Otolaryngology-Head and Neck Surgery, University of Iowa, Iowa City, Iowa, USA
Ju Yang - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Megan Ealy - Department of Otolaryngology-Head & Neck Surgery, Stanford University School of Medicine, Stanford, California, USA
Qiang Shi - Department of Neurology, PLA General Hospital, Beijing, China
Dayong Wang - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Hongyang Wang - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Yali Zhao - Beijing Institute of Otorhinolaryngology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Zhirong Shen - National Institute of Biological Sciences, Beijing, China
Fengchao Wang - National Institute of Biological Sciences, Beijing, China
Wei Sun - Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA
Lan Lan - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Dalian Ding - Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA
Linyi Xie - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Yue Qi - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Xin Lou - Department of Radiology, PLA General Hospital, Beijing, China
Xusheng Huang - Department of Neurology, PLA General Hospital, Beijing, China
Suhua Chang - Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
Wenping Xiong - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Zifang Yin - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Ning Yu - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Hui Zhao - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Jun Wang - BGI-Shenzhen, Shenzhen, China
Jing Wang - Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
Richard J Salvi - Department of Communicative Disorders & Sciences, Center for Hearing and Deafness, University at Buffalo, Buffalo, New York, USA
Christine Petit - Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, Collège de France, Paris, France
Qiuju Wang - Department of Otolaryngology-Head and Neck Surgery, Institute of Otolaryngology, PLA General Hospital, Beijing, China
Resource Type: Journal article
Publication Details: Journal of medical genetics, Vol.52(8), pp.523-531
DOI: 10.1136/jmedgenet-2014-102961
PMID: 25986071
PMCID: PMC4518735
NLM abbreviation: J Med Genet
ISSN: 0022-2593
eISSN: 1468-6244
Language: English
Date published: 08/2015
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; Endocrinology and Metabolism; Otolaryngology; Internal Medicine
Record Identifier: 9984006361802771

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