ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss
| Autor: | Jia-Da Li, Xue Zhong Liu, Meng Li, Denise Yan, Prem P. Chapagain, Zhengqing Wan, Hongsheng Chen, Jie Sun, Chufeng He, Yong Feng, Elodie Richard, Haibo Li, Jie Ling, Zhijie Niu, Yalan Liu, Jie Wen, Wu Li, Lingyun Mei, Yuyuan Deng, Shushan Sang, Taoxi Li, Meichao Men |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine China Hearing loss Hearing Loss Sensorineural Biology medicine.disease_cause 03 medical and health sciences Exon symbols.namesake 0302 clinical medicine Cell Movement Genetics medicine Humans Missense mutation Exome Amino Acid Sequence Gene Genetics (clinical) Sanger sequencing Mutation Genetic heterogeneity GTPase-Activating Proteins Phenotype Pedigree 030104 developmental biology symbols Female medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Human Genetics. 137:329-342 |
| ISSN: | 1432-1203 0340-6717 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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