Yang Yan, Xiong YuanPing, Lai Hua, Feng Chuanxin, Chen ZhongFa, Huang YaJuan, Guo Zhen, Li XinYu, Luo Laipeng, Zhao Feng, Wu Ping, Luo Haiyan, Liu Yanqiu, Liu Yuhe, Zou Yongyi
Jiangxi Key Laboratory of Birth Defect Prevention and Control, Jiangxi Maternal and Child Health Hospital, No. 318, Bayi AvenueDonghu District, Nanchang, Jiangxi Province 330006, China.
Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 17 Yongwaizheng Street, Donghu District, Nanchang, Jiangxi Province 330006, China.
Hum Mol Genet. 2025 Jun 30. doi: 10.1093/hmg/ddaf109.
The TECTA gene encodes α-tectorin, the major non-collagenous glycoprotein of the tectorial membrane, and plays a critical role in intracochlear sound transmission. Unsurprisingly, mutations in TECTA underlie hearing loss in both mice and humans. Two forms of hearing loss are linked to TECTA mutations: DFNA8/12 (autosomal dominant) and DFNB21 (autosomal recessive). Using a combination of clinical examination, pedigree analysis, exome sequencing, and functional studies, we identified a novel aberrant splicing variant, c.5999G > A (p.Gly2000Glu), in TECTA as the cause of autosomal dominant hearing loss in five-generation kindred of Chinese descent and provided prenatal diagnosis for the family. To investigate whether the variant acts via a a dominant-negative effect, consistent with pathogenesis observed in mouse models, we performed in vivo RNA analysis. Our data demonstrated that the variant altered RNA splicing, specifically causing aberrant splicing of exon 20 and resulting in two in-frame deletions. Quantitative real-time polymerase chain reaction revealed no significant reduction in mRNA levels in lymphoblasts derived from individuals harboring the TECTA c.5999G > A (p.Gly2000Glu) variant or the TECTA c.5383 + 6 T > A splicing variant, previously shown to result in exon 16 skipping. This study confirms the involvement of an aberrant splicing mutation in TECTA in autosomal dominant nonsyndromic hearing loss, expands the mutational landscape of DFNA8/12 to include coding variants that alter RNA splicing, and underscores the importance of investigating splicing effects of coding variants.
TECTA基因编码α - 肌动蛋白，它是盖膜的主要非胶原蛋白糖蛋白，在耳蜗内声音传导中起关键作用。毫不奇怪，TECTA基因的突变是小鼠和人类听力损失的基础。两种听力损失形式与TECTA突变有关：DFNA8/12（常染色体显性）和DFNB21（常染色体隐性）。通过临床检查、系谱分析、外显子组测序和功能研究相结合的方法，我们在中国汉族五代家系中鉴定出TECTA基因的一种新的异常剪接变体c.5999G>A（p.Gly2000Glu），它是常染色体显性听力损失的病因，并为该家族提供了产前诊断。为了研究该变体是否通过显性负效应起作用，这与在小鼠模型中观察到的发病机制一致，我们进行了体内RNA分析。我们的数据表明，该变体改变了RNA剪接，具体导致外显子20的异常剪接，并导致两个框内缺失。定量实时聚合酶链反应显示，携带TECTA c.5999G>A（p.Gly2000Glu）变体或TECTA c.5383+6 T>A剪接变体（先前已证明会导致外显子16跳跃）的个体来源的淋巴母细胞中，mRNA水平没有显著降低。本研究证实了TECTA基因的异常剪接突变与常染色体显性非综合征性听力损失有关，将DFNA8/12的突变谱扩展到包括改变RNA剪接的编码变体，并强调了研究编码变体剪接效应的重要性。
