PDF(Pubmed)
Abstract：
Purpose: To broaden the mutation and phenotype spectrum of the GJA8 and CHMP4B genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs). Methods: Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins. Results: Four heterozygous candidate variants in three different genes (CRYBB2, GJA8, and CHMP4B) were identified in affected individuals from the six families, including two novel missense variants (GJA8: c.64G > C/p. G22R, and CHMP4B: c.587C > G/p. S196C), one missense mutation (CRYBB2: c.562C > T/p. R188C), and one small deletion (GJA8: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the GJA8: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts. Conclusion: This study further expands the mutation spectrum and genotype-phenotype correlation of CRYBB2, GJA8, and CHMP4B underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.
摘要：
目的：扩大GJA8和CHMP4B基因的突变和表型谱，并揭示中国先天性白内障（CC）患者队列中的基因型-表型相关性。方法：本研究招募了六个具有常染色体显性遗传（AD）模式的CC的中国汉族家庭。所有患者均接受全面眼部检查。从所有可用患者及其未受影响的家庭成员收集的外周血白细胞中提取基因组DNA。对所有先证者及其至少一个父母进行全外显子组测序(WES)。通过Sanger测序进一步确认候选变体。使用若干计算预测程序进行生物信息学分析以评估候选变体对蛋白质的结构和功能的影响。结果：在来自六个家庭的受影响个体中鉴定出三个不同基因（CRYBB2，GJA8和CHMP4B）中的四个杂合候选变体，包括两个新颖的错义变体（GJA8：c.64G>C/p。G22R,和CHMP4B：c.587C>G/p。S196C),一个错义突变（CRYBB2：c.562C>T/p。R188C),和一个小的删除（GJA8：c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL）。在所有四个计算预测程序中,预测三个错义突变是有害的。在同源模型中，GJA8:p.143_147delLEGTL突变显示在Cx50蛋白的细胞质环上有5个氨基酸的序列缺失,靠近第三个跨膜结构域。携带同一基因突变的患者在年轻时表现出相似的白内障表型，包括白内障,Y-缝合胎儿核性白内障，和包膜下白内障。结论：本研究进一步扩展了CRYBB2、GJA8和CHMP4B基础CC的突变谱和基因型-表型相关性。这项研究揭示了比较同一年龄段患者先天性白内障表型的重要性。它为CC的发病机理提供了线索，并允许对携带这些遗传变异的家庭进行早期产前诊断。
