Vol.:(0123456789) 1 3 Human Genetics https://doi.org/10.1007/s00439-018-1885-0 ORIGINAL INVESTIGATION ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss Wu Li 1,6  · Jie Sun 2  · Jie Ling 3  · Jiada Li 4,5  · Chufeng He 1,6  · Yalan Liu 1,6  · Hongsheng Chen 1,6  · Meichao Men 7  · Zhijie Niu 1,6  · Yuyuan Deng 1,6  · Meng Li 1,6  · Taoxi Li 4,5  · Jie Wen 1,6  · Shushan Sang 1,6  · Haibo Li 8  · Zhengqing Wan 4,5  · Elodie M. Richard 9  · Prem Chapagain 10,11  · Denise Yan 12  · Xue Zhong Liu 1,12,13  · Lingyun Mei 1,6  · Yong Feng 1,6 Received: 20 December 2017 / Accepted: 16 April 2018 © Springer-Verlag GmbH Germany, part of Springer Nature 2018 Abstract Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identifed. The goal of this study was to determine the causative gene in a fve-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two afected indi- viduals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional efect of the identifed 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 identifed as a causative variant in this family afected 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 frst report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immu- nofuorescence 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 halfife 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 identifed for the frst time as responsible for ADNSHL. Introduction Deafness is recognized as a common human sensory dis- order, and approximately 60% of these cases are attributed to genetics (Petersen 2002). Hereditary deafness can be divided into syndromic and non-syndromic deafness. Non- syndromic deafness is not associated with other clinical manifestations. Over one hundred pathogenic genes have been associated with nonsyndromic hereditary hearing loss, with approximately 37 of them being linked to ADNSHL (http://hereditaryhearingloss.org). An ELMOD3 mutation responsible for autosomal recessive nonsyndromic hearing impairment in a Pakistani family, was reported for the frst time in 2013 (Jaworek et al. 2013). Here, we have identifed a variant (c.512A>G; p.His171Arg) in the ELMOD3 gene that segregates with the disease phenotype in an autosomal dominant fashion in the Chinese family HN-003. ELMOD3 encodes a member of the ELMO family. Based on the protein size and domain architecture, the human family of ELMO proteins have been divided as ELMO1-3 and ELMOD1-3. The ELMO and ELMOD proteins have a homologous sequence, the ELMO domain. ELMOD1 is essential for regulating the shape and maintenance of inner ear hair cell stereocilia in mouse with two spontaneous mutations in Elmod1 resulting in deafness (Johnson et al. Wu Li and Jie Sun contributed equally to this work. Lingyun Mei and Yong Feng are co-corresponding authors, they have equal contribution to this paper. The reported Nucleotide sequence data are available in the GenBank databases under the accession number SUB3343116. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-018-1885-0) contains supplementary material, which is available to authorized users. * Lingyun Mei entmly@163.com * Yong Feng fengyong_hn@hotmail.com Extended author information available on the last page of the article