Background: The transient receptor potential cation channel subfamily V member 6 (TRPV6) gene, which encodes a calcium-selective ion channel, was recently identified as a novel pancreatitis susceptibility gene. 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 based on the Ca2+ imaging and minigene assays, was retrospectively collected from 7 international centers. Cumulative rates were assessed by using the Kaplan-Meier method. As controls, Japanese patients with pancreatitis carrying pathogenic variants in PRSS1, SPINK1, or those without them were enrolled. Pancreas-specific Trpv6 conditional knockout mouse was established by crossing the Trpv6 floxed mouse and the Pdx-1-Cre mouse. Pancreatitis was induced by repetitive injections of caerulein for 2 days.
Results: Ninety-four patients with functionally impaired TRPV6 variants, including six splice-site ones, were enrolled. The median age at symptom onset was 16.5 years old. The cumulative rates of pancreatic calcification, pancreatic exocrine insufficiency, diabetes mellitus, and interventions for pancreatitis were 54.1%, 20.1%, 7.2%, and 41.6% at 30 years, and 80.7%, 49.6%, 20.0%, and 69.9% at 50 years, respectively. Patients with TRPV6-related pancreatitis presented earlier symptom onset and development of complications than those without pathogenic variants, similar to those with SPINK1-related pancreatitis. Pancreas-specific Trpv6 knockout mice developed more severe pancreatitis than the control mice.
Conclusions: Pathogenic TRPV6 variants influence the natural history of pancreatitis. Pancreatic TRPV6 plays a protective role against pancreatitis in mice.