TRPV6-related pancreatitis: natural history and the impact of the pancreas-specific deletion on pancreatitis in mice.

Abstract

BACKGROUND: The transient receptor potential cation channel subfamily V member 6 (TRPV6) gene, encoding a calcium-selective ion channel, was recently identified as a susceptibility gene for pancreatitis. This study aimed to clarify the natural history of TRPV6-related pancreatitis and the impact of pancreas-specific deletion of Trpv6 on pancreatitis in mice. METHODS: Clinical information of the patients carrying functionally impaired TRPV6 variants, defined by Caimaging and minigene assays, was collected from six international centers. Cumulative rates were assessed using Kaplan-Meier analysis. As controls, Japanese patients with alcohol-unrelated pancreatitis carrying pathogenic variants in PRSS1 or SPINK1, as well as those without pathogenic variants in pancreatitis susceptibility genes, were enrolled. A pancreas-specific Trpv6 conditional knockout mouse was established by crossing the Trpv6 floxed mouse and the Pdx-1-Cre mouse. Pancreatitis was induced by repeated intraperitoneal injections of caerulein. RESULTS: Ninety-four patients with functionally impaired TRPV6 variants, including six splice-site variants, were enrolled. The median age at symptom onset was 16 years. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 55.5%, 20.1%, 10.8%, and 41.6% at 30 years, and 81.5%, 49.6%, 45.4%, and 69.9% at 50 years, respectively. Pancreas-specific Trpv6 knockout mice developed more severe acute and chronic pancreatitis than the control mice. Caerulein treatment increased the TRPV6 expression in pancreatic acinar cells. CONCLUSIONS: Functionally impaired TRPV6 variants significantly influenced the clinical outcomes of chronic pancreatitis. TRPV6 in pancreatic acinar cells might play a protective role against pancreatitis in mice.