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A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.

Authors :
Lee JH
Choi JH
Namkung W
Hanrahan JW
Chang J
Song SY
Park SW
Kim DS
Yoon JH
Suh Y
Jang IJ
Nam JH
Kim SJ
Cho MO
Lee JE
Kim KH
Lee MG
Source :
Human molecular genetics [Hum Mol Genet] 2003 Sep 15; Vol. 12 (18), pp. 2321-32.
Publication Year :
2003

Abstract

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.

Details

Language :
English
ISSN :
0964-6906
Volume :
12
Issue :
18
Database :
MEDLINE
Journal :
Human molecular genetics
Publication Type :
Academic Journal
Accession number :
12952861
Full Text :
https://doi.org/10.1093/hmg/ddg243