Human Molecular Genetics, 2003, Vol. 12, No. 18 2321-2332
DOI: 10.1093/hmg/ddg243
© 2003 Oxford University Press
A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases
1Department of Pharmacology and Brain Korea 21 Project for Medical Science, 2Department of Internal Medicine, 3Department of Pediatrics and 4Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, Korea, 5Department of Physiology, McGill University, Montreal, Quebec Canada, H3G 1Y6, 6Department of Biochemistry and Molecular Biology and 7Department of Pharmacology, Seoul National University College of Medicine, Seoul 110-799, Korea, 8Department of Physiology, Sungkyunkwan University School of Medicine, Suwon 440-746, Korea, 9Metagentech Co., 207-10 Poi-Dong, Kangnam-Gu, Seoul 135-963, Korea and 10DNA Link Inc., 15-1 Yonhee-Dong, Seodaemun-Gu, Seoul 120-110, Korea
Received April 21, 2003; Revised June 20, 2003; Accepted July 7, 2003
Aberrant membrane transport caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is associated with a wide spectrum of respiratory and digestive diseases as well as cystic fibrosis. Using a gene scanning method, we found 11 polymorphisms and mutations of the CFTR gene in the Korean population. Individual variants at these sites were analyzed by conventional DNA screening in 117 control and 75 patients having bronchiectasis or chronic pancreatitis. In a haplotype determination based on a Bayesian algorithm, 15 haplotypes were assembled in the 192 individuals tested. Several haplotypes, especially with Q1352H, IVS8 T5, and E217G, were found to have disease associations in a case–control study. Notably, a common polymorphism of M470V appears to affect the intensity of the disease association. Among the two haplotypes having IVS8 T5, the T5-V470 haplotype showed higher disease association than the T5-M470 haplotype. In addition, a Q1352H mutation found in a V470 background showed the strongest disease association. The physiological significances of the identified mutations were rigorously analyzed. Non-synonymous E217G and Q1352H mutations in the M470 background caused a 60–80% reduction in CFTR-dependent Cl- currents and HCO3--transport activities. Surprisingly, the additional M470V polymorphic variant with the Q1352H mutation completely abolished CFTR-dependent anion transport activities. These findings provide the first evidence on the importance of CFTR mutations in the Asian population. Importantly, the results also reveal that interactions between multiple genetic variants in cis affect the final function of the gene products.
* To whom correspondence should be addressed at: Department of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Korea. Tel: +82 2 361 5221; Fax: +82 2 313 1894; Email: mlee{at}yumc.yonsei.ac.kr
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