A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases.
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.
Lee
Ji Hyun
JH
Department of Pharmacology, Yonsei University College of Medicine, 134 Sinchon-Dong, Seoul 120-752, Korea.
Choi
Ji Ha
JH
Namkung
Wan
W
Hanrahan
John W
JW
Chang
Joon
J
Song
Si Young
SY
Park
Seung Woo
SW
Kim
Dong Soo
DS
Yoon
Joo-Heon
JH
Suh
Yousin
Y
Jang
In-Jin
IJ
Nam
Joo Hyun
JH
Kim
Sung Joon
SJ
Cho
Mi-Ook
MO
Lee
Jong-Eun
JE
Kim
Kyung Hwan
KH
Lee
Min Goo
MG
D000483:Alleles; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001987:Bronchiectasis / Q000235:genetics; D016466:CHO Cells; D016022:Case-Control Studies; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D017136:Ion Transport; D007723:Korea; D018895:Microsatellite Repeats; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010182:Pancreatic Diseases / Q000235:genetics*; D010195:Pancreatitis / Q000235:genetics; D011110:Polymorphism, Genetic; D012137:Respiratory System / Q000503:physiopathology*
D001639:Bicarbonates; C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator