Confirmatory insights into ELMOD3-associated autosomal dominant non-syndromic hearing loss

Abstract

Sensorineural hearing loss (SNHL) is one of the most common sensory disorders, predominantly driven by monogenic causes with a higher Mendelian contribution. Although ELMOD3 variants have been implicated in both autosomal dominant (DFNA81) and autosomal recessive (DFNB88) hereditary deafness, only a single DFNA81 family has been reported, leaving the pathogenic role of the dominant allele largely unexplored. Through targeted panel sequencing, we herein identified a novel heterozygous ELMOD3 variant (c.640G>A; p.Gly214Ser) that co-segregates with autosomal dominant hearing loss in a Korean family. Molecular modeling and structure analysis indicates that replacing glycine at residue 214 with serine introduces spatial clashes with adjacent Ala160 and Cys162, thereby disrupting intermolecular interactions and compromising protein stability. Consistent with this, stability assays revealed a rapid degradation rate for the mutant protein. Furthermore, the ability to localize with F-actin in mutant protein was disrupted compared to the wild-type protein. Based on functional assays, the p.Gly214Ser variant demonstrated the functional pathogenicity and was classified as likely pathogenic according to the ACMG guideline for hearing loss. Collectively, these findings provide confirmatory insights into ELMOD3-associated DFNA81, potentially through a dominant-negative mechanism.