CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis.
CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis.
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CFTR 创始人突变导致中国囊性纤维化患者出现蛋白质运输缺陷。
DOI：
10.1002/mgg3.258
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发表时间：
2017-01
影响因子：
2
通讯作者：
Lee SL
中科院分区：
文献类型：
--
作者：
Leung GK;Ying D;Mak CC;Chen XY;Xu W;Yeung KS;Wong WL;Chu YW;Mok GT;Chau CS;McLuskey J;Ong WP;Leong HY;Chan KY;Yang W;Chen JH;Li AM;Sham PC;Lau YL;Chung BH;Lee SL
囊性纤维化（CF）在亚洲人中是一种罕见的疾病。自1985年以来，只有大约30例中国患者被报道得到分子确认。使用我们内部的下一代测序（NGS）管道用于儿童支气管扩张，我们在香港的CF患者中鉴定了致病CFTR突变。在多名患者中鉴定p.I1023R后，使用全基因组微阵列进行单倍型分析，以确定这是创始突变的可能性。我们还通过Western杂交和膜片钳试验评估了突变蛋白的加工和门控活性。在4名患者中确认了分子诊断，其中3名患者共享错义突变：CFTR：c.3068T>G：p.I1023R。结果提示，p.I1023R是中国南方汉族人群中的一个奠基突变。此外，通过凝胶电泳和膜片钳试验评估突变蛋白的加工和门控活性。突变蛋白表现出运输缺陷，表明功能障碍是由完全糖基化蛋白的细胞表面表达减少引起的。与其他先前报道的突变一起，本文提出的特定创始者突变表明中国南方人群中存在独特的CFTR突变谱，这一发现对改善中国CF患者的分子检测和突变特异性治疗具有重要意义。
Cystic fibrosis (CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation. Using our in‐house next‐generation sequencing (NGS) pipeline for childhood bronchiectasis, we identified disease‐causing CFTR mutations in CF patients in Hong Kong. After identifying p.I1023R in multiple patients, haplotype analysis was performed with genome‐wide microarray to ascertain the likelihood of this being a founder mutation. We also assessed the processing and gating activity of the mutant protein by Western hybridization and patch‐clamp test. Molecular diagnoses were confirmed in four patients, three of whom shared a missense mutation: CFTR:c.3068T>G:p.I1023R. The results suggested that p.I1023R is a founder mutation in southern Han Chinese. In addition, the processing and gating activity of the mutant protein was assessed by gel electrophoresis and a patch‐clamp test. The mutant protein exhibited trafficking defects, suggesting that the dysfunction is caused by reduced cell surface expression of the fully glycosylated proteins. Together with other previously reported mutations, the specific founder mutation presented herein suggests a unique CFTR mutation spectrum in the southern Chinese populations, and this finding has vital implications for improving molecular testing and mutation‐specific treatments for Chinese patients with CF.