Novel genotype–phenotype correlation of functionally characterized LMX1A variants linked to sensorineural hearing loss

다국어 초록 (Multilingual Abstract)

LMX1A, encoding the LIM homeobox transcription factor, is essential for inner ear development. Despite previous reports of three human LMX1A variants with nonsyndromic hearing loss (NSHL) in the literature, functional characterization of these variants has never been performed. Encouraged by identification of a de novo, heterozygous, missense variant (c.595A > G; p.Arg199Gly) located in the homeodomain of LMX1A in a subject with congenital severe‐to‐profound deafness through Exome sequencing, we performed luciferase assay to evaluate transcriptional activity of all LMX1A variants reported in the literature including p.Arg199Gly. Resultantly, p.Arg199Gly manifesting the most severe NSHL showed the biggest reduction of transcriptional activity in contrast with moderately reduced activity of p.Cys97Ser and p.Val241Leu associated with less severe progressive NSHL, proposing a genotype–phenotype correlation. Further, our dominant LMX1A variant exerted pathogenic effects via haploinsufficiency rather than dominant‐negative effect. Collectively, we provide a potential genotype–phenotype correlation of LMX1A variants as well as the pathogenic mechanism of LMX1A‐related NSHL.