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

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.

Roles for ELMOD2 and Rootletin in ciliogenesis

“…Mutation of this single arginine is sufficient to eliminate in vitro GAP activity (Ivanova et al, 2014). ELMODs are also implicated in a number of pathologies, including deafness in mammals (ELMOD1, ELMOD3 (Johnson et al, 2012;Jaworek et al, 2013;Lahbib et al, 2018;Li et al, 2018;Li et al, 2019)), intellectual disability (ELMOD1, ELMOD3 (Miryounesi et al, 2019)), idiopathic pulmonary fibrosis, and antiviral response (ELMOD2 (Hodgson et al, 2006;Pulkkinen et al, 2010)). The mechanisms by which mutations or disruption of these proteins causes disease are unclear.…”

The ARF GAP ELMOD2 acts with different GTPases to regulate centrosomal microtubule nucleation and cytokinesis

“…, 2006 ]), deafness (ELMOD1 and ELMOD3 [ Johnson et al. , 2012 ; Li et al. , 2018 , 2019 ], intellectual disability (ELMOD1 and ELMOD3 [ Miryounesi et al.…”

“Roles for ELMOD2 and Rootletin in Ciliogenesis”

“…Mutation of this single arginine is sufficient to eliminate in vitro GAP activity (Ivanova et al, 2014). ELMODs are also implicated in a number of pathologies, including deafness in mammals (ELMOD1, ELMOD3 (Jaworek et al, 2013; Johnson et al, 2012; Lahbib et al, 2018; Li et al, 2019; Li et al, 2018)), intellectual disability (ELMOD1, ELMOD3 (Miryounesi et al, 2019)), idiopathic pulmonary fibrosis, and antiviral response (ELMOD2 (Hodgson et al, 2006; Pulkkinen et al, 2010)). The mechanisms by which mutations or disruption of these proteins causes disease are unclear.…”