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

Ji Hyun Lee, Ji Ha Choi, Wan Namkung, John W. Hanrahan, Joon Chang, Si Young Song, Seung Woo Park, Dong Soo Kim, Joo Heon Yoon, Yousin Suh, In Jin Jang, Joo Hyun Nam, Sung Joon Kim, Mi Ook Cho, Jong Eun Lee, Kyung Hwan Kim, Min Goo Lee

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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.

Original languageEnglish (US)
Pages (from-to)2321-2332
Number of pages12
JournalHuman Molecular Genetics
Volume12
Issue number18
DOIs
StatePublished - Sep 15 2003
Externally publishedYes

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Cystic Fibrosis Transmembrane Conductance Regulator
Pancreatic Diseases
Haplotypes
Mutation
Regulator Genes
Bronchiectasis
Chronic Pancreatitis
Cystic Fibrosis
Population
Genes
Anions
Case-Control Studies
Membranes
DNA

ASJC Scopus subject areas

  • Genetics

Cite this

Lee, J. H., Choi, J. H., Namkung, W., Hanrahan, J. W., Chang, J., Song, S. Y., ... Lee, M. G. (2003). A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Human Molecular Genetics, 12(18), 2321-2332. https://doi.org/10.1093/hmg/ddg243

A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. / Lee, Ji Hyun; Choi, Ji Ha; Namkung, Wan; Hanrahan, John W.; Chang, Joon; Song, Si Young; Park, Seung Woo; Kim, Dong Soo; Yoon, Joo Heon; Suh, Yousin; Jang, In Jin; Nam, Joo Hyun; Kim, Sung Joon; Cho, Mi Ook; Lee, Jong Eun; Kim, Kyung Hwan; Lee, Min Goo.

In: Human Molecular Genetics, Vol. 12, No. 18, 15.09.2003, p. 2321-2332.

Research output: Contribution to journalArticle

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 2003, 'A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases', Human Molecular Genetics, vol. 12, no. 18, pp. 2321-2332. https://doi.org/10.1093/hmg/ddg243
Lee, Ji Hyun ; Choi, Ji Ha ; Namkung, Wan ; Hanrahan, John W. ; Chang, Joon ; Song, Si Young ; Park, Seung Woo ; Kim, Dong Soo ; Yoon, Joo Heon ; Suh, Yousin ; Jang, In Jin ; Nam, Joo Hyun ; Kim, Sung Joon ; Cho, Mi Ook ; Lee, Jong Eun ; Kim, Kyung Hwan ; Lee, Min Goo. / A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. In: Human Molecular Genetics. 2003 ; Vol. 12, No. 18. pp. 2321-2332.
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AU - Choi, Ji Ha

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AU - Hanrahan, John W.

AU - Chang, Joon

AU - Song, Si Young

AU - Park, Seung Woo

AU - Kim, Dong Soo

AU - Yoon, Joo Heon

AU - Suh, Yousin

AU - Jang, In Jin

AU - Nam, Joo Hyun

AU - Kim, Sung Joon

AU - Cho, Mi Ook

AU - Lee, Jong Eun

AU - Kim, Kyung Hwan

AU - Lee, Min Goo

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N2 - 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.

AB - 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.

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