DOI: 10.6084/m9.figshare.27116728
title: <i>TECTA</i> c.5999G&gt;A (p.Gly2000Glu)

description: TECTA gene encodes α-tectorin, the major component of noncollagenous glycoprotein of the tectorial membrane, and has a role in intracochlear sound transmission. Unsurprisingly, mutations in TECTA underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in TECTA,which were DFNA8/12and DFNB21.Using a combination of clinical examination, pedigree analysis and exome sequencing and functional studies, we identified a novel aberrant splicing variant c.5999G&gt;A(p.G2000E) in TECTA as the cause of autosomal dominant hearing loss in a five-generation kindred of Chinese descent and provideprenatal disgnosis for them.To investigate whether the variant exert their effect via a consistent with the pathogenesis of haplodose insufficiency revealed in mouse models,we used in vivo RNA analysis. Our data demonstrated that the variant induced alterated RNA splicing, specifically leading to aberrant exon 20 splicing and resulting in two in-frame deletions. Quantitative real-time PCR analysis revealed no significant reduction in mRNA levels in lymphoblasts derived from individuals harboring the <i>TECTA</i> c.5999G&gt;A (p.Gly2000Glu) variant and the <i>TECTA</i> c.5383+6T&gt;A splicing variant, which was previously confirmed to result in exon 16 skipping.This study confirms the involvement of aberrant splicing mutation TECTA in autosomal dominant nonsyndromic hearing loss, expands the mutational landscape of DFNA8/12 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.TECTA gene encodes α-tectorin, the major component of noncollagenous glycoprotein of the tectorial membrane, and has a role in intracochlear sound transmission. Unsurprisingly, mutations in TECTA underly hearing loss in mice and humans. Two forms of hearing loss are linked to mutations in TECTA,which were DFNA8/12and DFNB21.Using a combination of clinical examination, pedigree analysis and exome sequencing and functional studies, we identified a novel aberrant splicing variant c.5999G&gt;A(p.G2000E) in TECTA as the cause of autosomal dominant hearing loss in a five-generation kindred of Chinese descent and provideprenatal disgnosis for them.To investigate whether the variant exert their effect via a consistent with the pathogenesis of haplodose insufficiency revealed in mouse models,we used in vivo RNA analysis. Our data demonstrated that the variant induced alterated RNA splicing, specifically leading to aberrant exon 20 splicing and resulting in two in-frame deletions. Quantitative real-time PCR analysis revealed no significant reduction in mRNA levels in lymphoblasts derived from individuals harboring the <i>TECTA</i> c.5999G&gt;A (p.Gly2000Glu) variant and the <i>TECTA</i> c.5383+6T&gt;A splicing variant, which was previously confirmed to result in exon 16 skipping.This study confirms the involvement of aberrant splicing mutation TECTA in autosomal dominant nonsyndromic hearing loss, expands the mutational landscape of DFNA8/12 to include coding variants that alter RNA splicing, and highlights the need to investigate the effect of coding variants on RNA splicing.