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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Acknowledgements
The authors would like to thank the family members for their invaluable cooperation and participation. The study was supported by a grant from the National Natural Science Foundation of China (Grants no. 81470705, 81771023, 81771024, 81500803), the Major State Basic Research Development Program of China (973 Program) (Grants no. 2014CB541702, 2014CB943003), National Institutes of Health/National Institute on Deafness and Other Communication Disorders (Grants no. R01 DC012115, R01 DC01246, R01 DC05575) and in part by the China Postdoctoral Science Foundation (Grants no. 2017M620359).
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The reported Nucleotide sequence data are available in the GenBank databases under the accession number SUB3343116.
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Li, W., Sun, J., Ling, J. et al. ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss. Hum Genet 137, 329–342 (2018). https://doi.org/10.1007/s00439-018-1885-0
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DOI: https://doi.org/10.1007/s00439-018-1885-0