Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese

Shiho Kondo, Kotoyo Fujiki, Shigeru Ko, Akiko Yamamoto, Miyuki Nakakuki, Yasutomo Ito, Nikolay Shcheynikov, Motoji Kitagawa, Satoru Naruse, Hiroshi Ishiguro

Research output: Contribution to journalArticle

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Abstract

Although cystic fibrosis is rare in Japanese, measurement of sweat Cl<sup>–</sup> 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 (HCO(formula presented)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl<sup>–</sup>/HCO(formula presented) 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 HCO(formula presented)/Cl<sup>–</sup> transport activity to 50–60%, and impaired CFTR-coupled Cl<sup>–</sup>/HCO(formula presented) 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.

Original languageEnglish
Pages (from-to)G260-G269
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number4
DOIs
Publication statusPublished - 2015 Aug 18

Fingerprint

Alcoholic Pancreatitis
Cystic Fibrosis Transmembrane Conductance Regulator
Chronic Pancreatitis
Regulator Genes
Cystic Fibrosis
Sweat
Xenopus laevis
Bicarbonates

Keywords

  • Alcoholic chronic pancreatitis
  • CFTR gene
  • Japanese
  • L1156F

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. / Kondo, Shiho; Fujiki, Kotoyo; Ko, Shigeru; Yamamoto, Akiko; Nakakuki, Miyuki; Ito, Yasutomo; Shcheynikov, Nikolay; Kitagawa, Motoji; Naruse, Satoru; Ishiguro, Hiroshi.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 309, No. 4, 18.08.2015, p. G260-G269.

Research output: Contribution to journalArticle

Kondo, S, Fujiki, K, Ko, S, Yamamoto, A, Nakakuki, M, Ito, Y, Shcheynikov, N, Kitagawa, M, Naruse, S & Ishiguro, H 2015, 'Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 309, no. 4, pp. G260-G269. https://doi.org/10.1152/ajpgi.00015.2014
Kondo, Shiho ; Fujiki, Kotoyo ; Ko, Shigeru ; Yamamoto, Akiko ; Nakakuki, Miyuki ; Ito, Yasutomo ; Shcheynikov, Nikolay ; Kitagawa, Motoji ; Naruse, Satoru ; Ishiguro, Hiroshi. / Functional characteristics of L1156F-CFTR associated with alcoholic chronic pancreatitis in Japanese. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2015 ; Vol. 309, No. 4. pp. G260-G269.
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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 (HCO(formula presented)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl–/HCO(formula presented) 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 HCO(formula presented)/Cl– transport activity to 50–60{\%}, and impaired CFTR-coupled Cl–/HCO(formula presented) 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.",
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AB - 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 (HCO(formula presented)) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl–/HCO(formula presented) 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 HCO(formula presented)/Cl– transport activity to 50–60%, and impaired CFTR-coupled Cl–/HCO(formula presented) 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.

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