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Article Dans Une Revue Human Mutation Année : 2021

Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis

Reiko Sakaguchi
Ryotaro Matsumoto
  • Fonction : Auteur
Yu Tanaka
  • Fonction : Auteur
Kazuhiro Kikuta
  • Fonction : Auteur
Fumiya Kataoka
  • Fonction : Auteur
Hela Audin
  • Fonction : Auteur
Bernard Caumont
  • Fonction : Auteur
Raphael Besnard
  • Fonction : Auteur
Thierry Lamireau
Xavier de Koninck
  • Fonction : Auteur
Grepan Study Group
  • Fonction : Auteur
David N. Cooper
  • Fonction : Auteur
Yasuo Mori
  • Fonction : Auteur
Atsushi Masamune

Résumé

The recent discovery of TRPV6 as a pancreatitis susceptibility gene served to identify a novel mechanism of chronic pancreatitis (CP) due to Ca(2+) dysregulation. Herein, we analyzed TRPV6 in 81 probands with hereditary CP (HCP), 204 probands with familial CP (FCP) and 462 patients with idiopathic CP (ICP) by targeted next-generation sequencing. We identified 25 rare nonsynonymous TRPV6 variants, 18 of which had not been previously reported. All 18 variants were characterized by a Ca(2+) imaging assay, with 8 being identified as functionally deficient. Evaluation of functionally deficient variants in the three CP cohorts revealed two novel findings: (i) functionally deficient TRPV6 variants appear to occur more frequently in HCP/FCP patients than in ICP patients (3.2% vs. 1.5%) and (ii) functionally deficient TRPV6 variants found in HCP and FCP probands appear to be more frequently co-inherited with known risk variants in SPINK1, CTRC and/or CFTR than those found in ICP patients (66.7% vs 28.6%). Additionally, genetic analysis of available HCP and FCP family members revealed complex patterns of inheritance in some families. Our findings confirm that functionally deficient TRPV6 variants represent an important contributor to CP. Importantly, functionally deficient TRPV6 variants account for a significant proportion of cases of HCP/FCP. This article is protected by copyright. All rights reserved.

Dates et versions

hal-03535241 , version 1 (19-01-2022)

Identifiants

Citer

Shin Hamada, Emmanuelle Masson, Jian Min Chen, Reiko Sakaguchi, Vinciane Rebours, et al.. Functionally deficient TRPV6 variants contribute to hereditary and familial chronic pancreatitis. Human Mutation, 2021, ⟨10.1002/humu.24315⟩. ⟨hal-03535241⟩
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