A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.
A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.
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CRYAB终止密码子（p.X176Y）的一个新的杂合突变可能导致中国家庭先天性后极白内障。
DOI：
10.1080/13816810.2020.1855665
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Ke Yao
中科院分区：
文献类型：
--
作者：
Yinhui Yu;Jingjie Xu;Yue Qiao;Jinyu Li;Ke Yao
摘要背景：本研究旨在确定一个常染色体显性遗传性先天性白内障（ADCC）家系的潜在遗传缺陷。方法：详细记录家族史和临床资料。对54个已知的白内障相关基因进行靶向外显子组测序，结合高通量下一代测序，然后进行桑格测序和生物信息学分析，以确定该家族的致病基因病变。结果：一个四代同堂的后极型白内障家系。目的基因的富集发现α B-晶状体蛋白（αB-crystallin，αB-crystallin AB）基因终止密码子处存在一个新的杂合突变p.X176Yfs19*，该突变导致终止密码子丢失，突变蛋白延长19个氨基酸残基。桑格测序显示与疾病完全共分离。预测延长的突变蛋白通过在二级结构中形成新的α-螺旋和无规卷曲以及在三级结构中产生延伸链而具有致病性，可能导致疏水性增加和蛋白质稳定性降低。结论：我们的报告在先天性白内障的谱系中增加了一个新的突变。结果表明，α B-晶状体蛋白羧基端X176残基对α B-晶状体蛋白的功能具有重要作用，这对进一步研究先天性白内障的发病机制具有重要意义。缩略语：你好，α B-晶状体蛋白;脱氧核糖核酸：脱氧核糖核酸; PCR：聚合酶链反应;工商业污水附加费：靶向外显子组测序; ACD：α B-晶体蛋白结构域。
ABSTRACT Background: The present study aims to identify the underlying genetic defects in a Chinese family with autosomal dominant congenital cataracts (ADCC). Methods: Detailed family histories and clinical data were recorded. Targeted exome sequencing of 54 known cataract-associated genes combined with high-throughput next-generation sequencing was conducted followed by Sanger sequencing and bioinformatic analysis to identify the causative gene lesion for the family. Results: A four-generation Chinese family with posterior pole type cataract were enrolled. Enrichment of targeted genes revealed a new heterozygous p.X176Y mutation in the stop codon of αB-crystallin (CRYAB) gene, which resulted in the loss of the stop codon and prolongation of the mutant protein by 19 amino acid residues (p.X176Yfs19*). Sanger sequencing showed complete co-segregation with the disease. The elongated mutant protein was predicted to be pathogenic by forming new α-helix and random-coil in the secondary structure as well as producing an extended strand in the tertiary structure, potentially leading to increased hydrophobicity and reduced protein stability. Conclusions: Our report added a new mutation in the spectrum of congenital cataracts. The data suggested that X176 residue in the COOH-terminal is of crucial importance for the αB-crystallin protein function which was valuable for further study of the pathogenesis of congenital cataracts. Abbreviations: CRYAB: αB-crystallin; DNA: deoxyribonucleic acid; PCR: polymerase chain reaction; TES: targeted exome sequencing; ACD: αB-crystallin domain.
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