Ophthalmologic Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Henan Provincial Eye Hospital, Zhengzhou, Henan, 450052, China.
Sci Rep. 2017 Dec 19;7(1):17848. doi: 10.1038/s41598-017-18222-z.
Congenital cataract (CC) is a clinical and genetically heterogeneous eye disease that primarily causes lens disorder and even amblyopic blindness in children. As the mechanism underlying CC is genetically inherited, identification of CC-associated gene mutations and their role in protein distribution are topics of both pharmacological and biological research. Through physical and ophthalmic examinations, two Chinese pedigrees with autosomal dominant congenital cataract (ADCC) were recruited for this study. Mutation analyses of CC candidate genes by next-generation sequencing (NGS) and Sanger sequencing revealed a novel missense mutation in CRYBB2 (p.V146L) and a deletion mutation in CRYAA (p.116_118del). Both mutations fully co-segregated were not observed in unaffected family members or in 100 unrelated healthy controls. The CRYBB2 missense mutation disrupts the distribution of CRYBB2 in human lens epithelial cells (HLEpiCs), and the CRYAA deletion mutation causes hyperdispersion of CRYAA. Furthermore, these two crystallin mutations result in aberrant expression of unfolded protein response (UPR) marker genes as well as apoptosis in HLEpiCs. Collectively, these findings broaden the genetic spectrum of ADCC.
先天性白内障（CC）是一种临床和遗传异质性眼部疾病，主要导致儿童晶状体紊乱，甚至弱视失明。由于 CC 的发病机制是遗传的，因此鉴定与 CC 相关的基因突变及其在蛋白质分布中的作用是药理学和生物学研究的主题。通过体格检查和眼科检查，本研究招募了两个常染色体显性遗传性先天性白内障（ADCC）的中国家系。下一代测序（NGS）和 Sanger 测序对 CC 候选基因的突变分析显示 CRYBB2 中的一个新错义突变（p.V146L）和 CRYAA 中的缺失突变（p.116_118del）。这两种突变均未在未受影响的家庭成员或 100 名无关健康对照中观察到完全共分离。CRYBB2 的错义突变破坏了 CRYBB2 在人晶状体上皮细胞（HLEpiCs）中的分布，CRYAA 的缺失突变导致 CRYAA 超分散。此外，这两种晶体蛋白突变导致未折叠蛋白反应（UPR）标记基因以及 HLEpiCs 中的细胞凋亡异常表达。总之，这些发现拓宽了 ADCC 的遗传谱。
