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

ABSTRACT: BACKGROUND:Auditory 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. METHODS:We performed whole-exome sequencing on DNA samples from the AUNX1 family and another small phenotypically similar but unrelated ANSD family. RESULTS:We 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. CONCLUSIONS:Variants 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.

SUBMITTER: Zong L

PROVIDER: S-EPMC4518735 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Zong Liang L Guan Jing J Ealy Megan M Zhang Qiujing Q Wang Dayong D Wang Hongyang H Zhao Yali Y Shen Zhirong Z Campbell Colleen A CA Wang Fengchao F Yang Ju J Sun Wei W Lan Lan L Ding Dalian D Xie Linyi L Qi Yue Y Lou Xin X Huang Xusheng X Shi Qiang Q Chang Suhua S Xiong Wenping W Yin Zifang Z Yu Ning N Zhao Hui H Wang Jun J Wang Jing J Salvi Richard J RJ Petit Christine C Smith Richard J H RJ Wang Qiuju Q

Journal of medical genetics 20150518 8

<h4>Background</h4>Auditory 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 ...[more]

PMID: 25986071

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Project description:BackgroundMany hearing-loss diseases are demonstrated to have Mendelian inheritance caused by mutations in single gene. However, many deaf individuals have diseases that remain genetically unexplained. Auditory neuropathy is a sensorineural deafness in which sounds are able to be transferred into the inner ear normally but the transmission of the signals from inner ear to auditory nerve and brain is injured, also known as auditory neuropathy spectrum disorder (ANSD). The pathogenic mutations of the genes responsible for the Chinese ANSD population remain poorly understood.MethodsA total of 127 patients with non-syndromic hearing loss (NSHL) were enrolled in Guangxi Zhuang Autonomous Region. A hereditary deafness gene mutation screening was performed to identify the mutation sites in four deafness-related genes (GJB2, GJB3, 12S rRNA, and SLC26A4). In addition, whole-exome sequencing (WES) was applied to explore unappreciated mutation sites in the cases with the singularity of its phenotype.ResultsWell-characterized mutations were found in only 8.7% (11/127) of the patients. Interestingly, two mutations in the OTOF gene were identified in two affected siblings with ANSD from a Chinese family, including one nonsense mutation c.1273C > T (p.R425X) and one missense mutation c.4994 T > C (p.L1665P). Furthermore, we employed Sanger sequencing to confirm the mutations in each subject. Two compound heterozygous mutations in the OTOF gene were observed in the two affected siblings, whereas the two parents and unaffected sister were heterozygous carriers of c.1273C > T (father and sister) and c.4994 T > C (mother). The nonsense mutation p.R425X, contributes to a premature stop codon, may result in a truncated polypeptide, which strongly suggests its pathogenicity for ANSD. The missense mutation p.L1665P results in a single amino acid substitution in a highly conserved region.ConclusionsTwo mutations in the OTOF gene in the Chinese deaf population were recognized for the first time. These findings not only extend the OTOF gene mutation spectrum for ANSD but also indicate that whole-exome sequencing is an effective approach to clarify the genetic characteristics in non-syndromic ANSD patients.

Dataset Information

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

Publications

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

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