CFTR founder mutation causes protein trafficking defects in Chinese patients with cystic fibrosis. Issue 1 (13th November 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Molecular genetics & genomic medicine. Volume 5:Issue 1(2017)
• Page Start: 40
• Page End: 49
• Publication Date: 2016-11-13
• Subjects: Bronchiectasis -- Chinese -- cystic fibrosis -- founder mutation -- trafficking defects; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.258
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Cystic fibrosis (CF) is a rare condition in Asians. Since 1985, only about 30 Chinese patients have been reported with molecular confirmation. Method: 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. Results: 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. Conclusion: 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. Abstract : We identified a shared haplotype of CFTR:p.I1023R encompassing 381 SNPs. The estimated physical length of the haplotype was 1, 958, 052 bp, which was equivalent to a genetic distance of 1.28 cM. We did not identify the specific haplotype in any of the control samples. The haplotype analysis suggested that the mutation is a founder mutation among our population.