Department of Otorhinolaryngology-Head and Neck Surgery, Bundang Hospital, College of Medicine, Seoul National University, Seongnam, Korea.
Department of Otorhinolaryngology-Head and Neck Surgery, East Avenue Medical Center, Metro Manila, Philippines.
Hum Mutat. 2020 Nov;41(11):1877-1883. doi: 10.1002/humu.24095. Epub 2020 Sep 9.
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.
LMX1A 编码 LIM 同源盒转录因子，对内耳发育至关重要。尽管之前有文献报道了三种与非综合征性听力损失（NSHL）相关的人类 LMX1A 变体，但这些变体的功能特征从未进行过研究。通过外显子组测序，在一名先天性重度至极重度耳聋患者中发现了一个位于 LMX1A 同源域的从头出现的、杂合的、错义变异（c.595A>G；p.Arg199Gly），受此启发，我们进行了荧光素酶检测，以评估文献中报道的所有 LMX1A 变体的转录活性，包括 p.Arg199Gly。结果表明，与中度降低的 p.Cys97Ser 和 p.Val241Leu 相关的活性（与渐进性 NSHL 相关的活性降低程度较轻）相比，表现出最严重 NSHL 的 p.Arg199Gly 显示出最大的转录活性降低，提示存在基因型-表型相关性。此外，我们的显性 LMX1A 变体通过杂合不足而不是显性负效应发挥致病作用。总之，我们提供了 LMX1A 变体的潜在基因型-表型相关性以及与 LMX1A 相关的 NSHL 的致病机制。
