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.

The CFTR gene variants in Japanese children with idiopathic pancreatitis

“…No patients in our study had any of the common CF-causing variants in Caucasians, consistent with other studies in Asian patients 12–16,24 . This suggests that Asian or Japanese populations may have different variants of CFTR than European populations.…”

“…There does not seem to be an obvious correlation between variant type and age of onset. In this study, patients with abnormal findings of endoscopic retrograde cholangiopancreatography and/or magnetic resonance cholangiopancreatography, such as stones and pancreatic duct dilatation, had a non-synonymous variant of R31C, E217G or Q1352H, which has been previously reported in chronic pancreatitis in adult patients 14,16,24 (Table 2).…”

“…This suggests that Asian or Japanese populations may have different variants of CFTR than European populations. Of the eight non-synonymous variants found in the patients, it appears that two variants, L1156F and R1453W, are unique to Japanese patients 12–16,24 and Q1352H is known to be unique in Asian patients 13,14,16,24 . These reports were all in the Japanese or Asian samples, and data from 1000 Genomes studies suggest no variants are found in other ethnicities.…”

“…Nine out of 28 patients had a V470M variant (Table 2). It is known that channel activity of V470 CFTR protein is lower than that of M470 CFTR 23,24 . Cuppens et al 23 suggested that M470 CFTR proteins matured more slowly than V470 CFTR, although M470 CFTR had higher channel activity than V470 CFTR.…”

SPINK1 , PRSS1 , CTRC , and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis

“…Over the past two decades, it has been increasingly appreciated that ICP has a strong genetic basis, to which rare pathogenic variants (defined here as having a minor allele frequency of <1% 8 , 9 ) in the CFTR (encoding cystic fibrosis transmembrane conductance regulator; MIM# 602421) gene 10 , 11 and the three trypsin-dependent pathway genes 12 , namely PRSS1 (encoding cationic trypsinogen; MIM# 276000) 13 , SPINK1 (encoding pancreatic secretory trypsin inhibitor; MIM# 167790) 14 , and CTRC (encoding chymotrypsin C, MIM# 601405) 15 , 16 , make an important contribution 7 , 17 , 18 . Some rare pathogenic variants in these four genes have also been found to be overrepresented in patients with alcoholic chronic pancreatitis (ACP) 15 , 19 – 21 .…”