title: Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis.
abstract: Genetic alterations in the carboxypeptidase A1 gene (CPA1) are associated with early onset chronic pancreatitis (CP). Besides CPA1, there are two other human pancreatic carboxypeptidases (CPA2 and CPB1). Here we examined whether CPA2 and CPB1 alterations are associated with CP in Japan and Germany. All exons and flanking introns of CPA2 and CPB1 were sequenced in 477 Japanese patients with CP (234 alcoholic, 243 nonalcoholic) and in 497 German patients with nonalcoholic CP by targeted next-generation sequencing and/or Sanger sequencing. Secretion and enzymatic activity of CPA2 and CPB1 variants were determined after transfection into HEK 293T cells. We identified six nonsynonymous CPA2 variants (p.V67I, p.G166R, p.D168E, p.D173H, p.R237W, and p.G388S), eight nonsynonymous CPB1 alterations (p.S65G, p.N120S, p.D172E, p.R195H, p.D208N, p.F232L, p.A317V, and p.D364Y), and one splice-site variant (c.687+1G>T) in CPB1. Functional analysis revealed essentially complete loss of function in CPA2 variants p.R237W and p.G388S and CPB1 variants p.R110H and p.D364Y. None of the CPA2 or CPB1 variants, including those resulting in a marked loss of function, were overrepresented in patients with CP. In conclusion, CPA2 and CPB1 variants are not associated with CP.
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Eriko
authors: E
authors: Nakano
authors: Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts;
authors: Andrea
authors: A
authors: Geisz
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan; amasamune@med.tohoku.ac.jp.
authors: Atsushi
authors: A
authors: Masamune
authors: Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Tetsuya
authors: T
authors: Niihori
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Shin
authors: S
authors: Hamada
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Kiyoshi
authors: K
authors: Kume
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Yoichi
authors: Y
authors: Kakuta
authors: Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Yoko
authors: Y
authors: Aoki
authors: National Research Institute for Child Health and Development, Tokyo, Japan;
authors: Yoichi
authors: Y
authors: Matsubara
authors: Pediatric Nutritional Medicine, Klinikum rechts der Isar; Else Kröner-Fresenius-Zentrum für Ernährungsmedizin & Zentralinstitut für Ernährungs-und Lebensmittelforschung, Technische Universität München, Munich, Germany; and.
authors: Karolin
authors: K
authors: Ebert
authors: Pediatric Nutritional Medicine, Klinikum rechts der Isar; Else Kröner-Fresenius-Zentrum für Ernährungsmedizin & Zentralinstitut für Ernährungs-und Lebensmittelforschung, Technische Universität München, Munich, Germany; and.
authors: Maren
authors: M
authors: Ludwig
authors: Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt am Main, Germany.
authors: Markus
authors: M
authors: Braun
authors: Institute of Occupational Medicine, Social Medicine and Environmental Medicine, Goethe-University, Frankfurt am Main, Germany.
authors: David A
authors: DA
authors: Groneberg
authors: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors: Tooru
authors: T
authors: Shimosegawa
authors: Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts;
authors: Miklós
authors: M
authors: Sahin-Tóth
authors: Pediatric Nutritional Medicine, Klinikum rechts der Isar; Else Kröner-Fresenius-Zentrum für Ernährungsmedizin & Zentralinstitut für Ernährungs-und Lebensmittelforschung, Technische Universität München, Munich, Germany; and.
authors: Heiko
authors: H
authors: Witt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D043424:Carboxypeptidase B / Q000235:genetics* / Q000378:metabolism; D043422:Carboxypeptidases A / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D014644:Genetic Variation; D005858:Germany; D006801:Humans; D007223:Infant; D007564:Japan; D008297:Male; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D044465:White People; D055815:Young Adult
chemical_list: C058173:CPB1 protein, human; D043422:Carboxypeptidases A; D043424:Carboxypeptidase B
keywords: loss-of-function variant; misfolding; next-generation sequencing; secretion defect