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.

• Authors: Liang Zong, Jing Guan, Megan Ealy, Qiujing Zhang, Dayong Wang, Hongyang Wang, Yali Zhao, Zhirong Shen, Colleen A Campbell, Fengchao Wang, Ju Yang, Wei Sun, Lan Lan, Dalian Ding, Linyi Xie, Yue Qi, Xin Lou, Xusheng Huang, Qiang Shi, Suhua Chang, Wenping Xiong, Zifang Yin, Ning Yu, Hui Zhao, Jun Wang, Jing Wang, Richard J Salvi, Christine Petit, Richard J H Smith, Qiuju Wang
• Journal: Journal of medical genetics (J Med Genet) Vol. 52 Issue 8 Pg. 523-31 (Aug 2015) ISSN: 1468-6244 [Electronic] England
• PMID: 25986071 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Chemical References

• AIFM1 protein, human
• Apoptosis Inducing Factor

Topics

• Animals
• Apoptosis Inducing Factor (chemistry, genetics)
• Chromosome Mapping
• Cohort Studies
• DNA Mutational Analysis
• Exome (genetics)
• Female
• Genes, X-Linked
• Hearing Loss, Central (genetics, pathology)
• Humans
• Male
• Mice
• Mutation, Missense
• Pedigree
• Protein Structure, Tertiary