title: Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese.
abstract: Although cystic fibrosis is rare in Japanese, measurement of sweat Cl(-) has suggested mild dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) in some patients with chronic pancreatitis. In the present study, we have investigated the association of CFTR variants and chronic pancreatitis in Japanese and the functional characteristics of a Japanese- and pancreatitis-specific CFTR variant, L1156F. Seventy patients with alcoholic chronic pancreatitis, 18 patients with idiopathic chronic pancreatitis, and 180 normal subjects participated. All exons and their boundaries and promoter region of the CFTR gene were sequenced. Human embryonic kidney-293 cells were transfected with three CFTR variants (M470V, L1156F, and M470V+L1156F), and the protein expression was examined. Xenopus laevis oocytes were injected with the CFTR variants, and bicarbonate (HCO3 (-)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl(-)/HCO3 (-) exchange activity was examined. Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in the coding region of the CFTR gene. Cystic fibrosis-causing mutations were not found. The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly (P < 0.01) higher than those in normal subjects (0.6 and 1.9%). L1156F was linked with a worldwide CFTR variant, M470V. Combination of M470V and L1156F significantly reduced CFTR expression to ∼60%, impaired CFTR-mediated HCO3 (-)/Cl(-) transport activity to 50-60%, and impaired CFTR-coupled Cl(-)/HCO3 (-) exchange activity to 20-30%. The data suggest that the Japanese-specific CFTR variant L1156F causes mild dysfunction of CFTR and increases the risk of alcoholic chronic pancreatitis in Japanese.
authors.affiliation: Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Shiho
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Department of Nutrition, Nagoya University of Arts and Sciences, Nisshin, Japan;
authors.forename: Kotoyo
authors.initials: K
authors.lastname: Fujiki
authors.affiliation: Department of Systems Medicine, Keio University School of Medicine, Tokyo, Japan;
authors.forename: Shigeru B H
authors.initials: SB
authors.lastname: Ko
authors.affiliation: Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Akiko
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Miyuki
authors.initials: M
authors.lastname: Nakakuki
authors.affiliation: Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland; and.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Shcheynikov
authors.affiliation: Department of Nutrition, Nagoya University of Arts and Sciences, Nisshin, Japan;
authors.forename: Motoji
authors.initials: M
authors.lastname: Kitagawa
authors.affiliation: Miyoshi Municipal Hospital, Miyoshi, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Naruse
authors.affiliation: Department of Human Nutrition, Nagoya University Graduate School of Medicine, Nagoya, Japan; ishiguro@htc.nagoya-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishiguro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D016022:Case-Control Studies; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005787:Gene Frequency; D057809:HEK293 Cells; D006801:Humans; D017136:Ion Transport; D007564:Japan; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D019512:Pancreatitis, Alcoholic / Q000235:genetics*; D014981:Xenopus
chemical_list: D001639:Bicarbonates; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: CFTR gene; Japanese; L1156F; alcoholic chronic pancreatitis