Leung Gordon K C, Ying Dingge, Mak Christopher C Y, Chen Xin-Ying, Xu Weiyi, Yeung Kit-San, Wong Wai-Lap, Chu Yoyo W Y, Mok Gary T K, Chau Christy S K, McLuskey Jenna, Ong Winnie P T, Leong Huey-Yin, Chan Kelvin Y K, Yang Wanling, Chen Jeng-Haur, Li Albert M, Sham Pak C, Lau Yu-Lung, Chung Brian H Y, Lee So-Lun
Department of Paediatrics and Adolescent Medicine LKS Faculty of Medicine The University of Hong Kong Hong Kong Hong Kong.
Department of Psychiatry LKS Faculty of Medicine The University of Hong Kong Hong Kong Hong Kong.
Mol Genet Genomic Med. 2016 Nov 13;5(1):40-49. doi: 10.1002/mgg3.258. eCollection 2017 Jan.
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 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: :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 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.
囊性纤维化（CF）在亚洲人中较为罕见。自1985年以来，仅有约30例经分子确认的中国患者报告。
利用我们内部用于儿童支气管扩张症的下一代测序（NGS）流程，我们在香港的CF患者中鉴定出致病突变。在多名患者中鉴定出p.I1023R后，使用全基因组微阵列进行单倍型分析，以确定其成为奠基者突变的可能性。我们还通过蛋白质印迹法和膜片钳试验评估突变蛋白的加工和门控活性。
4例患者得到分子诊断确认，其中3例共享一个错义突变：c.3068T>G:p.I1023R。结果表明p.I1023R是中国南方汉族人群中的一个奠基者突变。此外，通过凝胶电泳和膜片钳试验评估了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所致。
结合本文中报告的其他先前突变，本文中特定的奠基者突变表明中国南方人群中存在独特的突变谱，这一发现对于改善中国CF患者的分子检测和突变特异性治疗具有重要意义。
