ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss

Hum Genet. 2018 Apr;137(4):329-342. doi: 10.1007/s00439-018-1885-0.

Wu Li ¹ ², Jie Sun ³, Jie Ling ⁴, Jiada Li ⁵ ⁶, Chufeng He ¹ ², Yalan Liu ¹ ², Hongsheng Chen ¹ ², Meichao Men ⁷, Zhijie Niu ¹ ², Yuyuan Deng ¹ ², Meng Li ¹ ², Taoxi Li ⁵ ⁶, Jie Wen ¹ ², Shushan Sang ¹ ², Haibo Li ⁸, Zhengqing Wan ⁵ ⁶, Elodie M Richard ⁹, Prem Chapagain ¹⁰ ¹¹, Denise Yan ¹², Xue Zhong Liu ¹ ¹² ¹³, Lingyun Mei ¹⁴ ¹⁵, Yong Feng ¹⁶ ¹⁷

Affiliations

1 Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
2 Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, Hunan, China.
3 Department of Otolaryngology, The Eight Affiliated Hospital, Sun Yat-sen University, 3025 Shennan Middle Road, Shenzhen, Guangdong, China.
4 Institute of Precision Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
5 Center for Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan, China.
6 School of Life Sciences, Central South University of China, 110 Xiangya Road, Changsha, Hunan, China.
7 Health Management Center, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
8 Department of Ophthalmology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China.
9 Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
10 Department of Physics, Florida International University, Miami, Florida, USA.
11 Biomolecular Sciences Institute, Florida International University, Miami, FL, USA.
12 Department of Otolaryngology, University of Miami Miller School of Medicine, Miami, USA.
13 Dr. John T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
14 Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China. [email protected].
15 Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, Hunan, China. [email protected].
16 Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, China. [email protected].
17 Province Key Laboratory of Otolaryngology Critical Diseases, Changsha, Hunan, China. [email protected].

PMID: 29713870 DOI: 10.1007/s00439-018-1885-0

Abstract

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.

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