Variants in pancreatic carboxypeptidase genes CPA2 and CPB1 are not associated with chronic pancreatitis

Eriko Nakano, Andrea Geisz, Atsushi Masamune, Tetsuya Niihori, Shin Hamada, Kiyoshi Kume, Yoichi Kakuta, Yoko Aoki, Yoichi Matsubara, Karolin Ebert, Maren Ludwig, Markus Braun, David A. Groneberg, Tooru Shimosegawa, Miklós Sahin-Tóth, Heiko Witt

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)G688-G694
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume309
Issue number8
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Loss-of-function variant
  • Misfolding
  • Next-generation sequencing
  • Secretion defect

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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