TRPV6 – Pancreatitis

TRPV6 encodes a highly selective epithelial calcium channel critical for Ca²⁺ entry in multiple tissues. Recent NGS studies re-screening idiopathic pancreatitis cohorts for novel risk genes identified TRPV6 variants in 7.3% of patients, implicating it in pancreatic disease susceptibility (PMID:38657903).

Case–control sequencing in Japan found function-affecting TRPV6 variants in 13 of 300 patients with nonalcoholic chronic pancreatitis (4.3%) versus 1 of 1070 controls (0.1%; OR 48.4) (PMID:31930989). Early-onset cohorts (≤20 y) revealed 12 of 124 patients (9.7%) carrying such variants, and European replication demonstrated 18 of ∼880 patients (2.0%) versus 0 controls (PMID:31930989). A Chinese sequencing study further showed an enrichment of loss-of-function alleles in 9 of 669 patients (1.35%) versus 1 of 609 controls (0.16%; OR 8.29) (PMID:32383311).

Independent European cohorts from Poland and Germany confirmed overrepresentation of TRPV6 nonsense and deleterious missense variants (p.Arg174Ter, p.Arg342Gln, p.Leu576Arg) in early-onset chronic pancreatitis, with functional assays in HEK293T cells demonstrating significantly reduced intracellular Ca²⁺ levels (PMID:34538581).

Mechanistically, key missense variants (e.g., c.629C>T (p.Ala210Val)) severely impair Ca²⁺ uptake in vitro, and disruption of PDZK2-mediated regulation further reduces channel activity (PMID:17645868). In vivo, TRPV6mut/mut mice subjected to cerulein induction exhibit exacerbated pancreatic enzyme release, histologic damage, and fibrosis, mirroring human disease (PMID:31930989).

A three-member Indian family with hereditary pancreatitis harbors a novel TRPV6 frameshift, c.1474_1475del (p.Val492ThrfsTer136), segregating in father, son and daughter and demonstrating autosomal dominant inheritance with incomplete penetrance (PMID:36699452).

Collectively, genetic, functional and animal data support a Strong clinical validity for TRPV6 in pancreatitis via a loss-of-function mechanism disrupting pancreatic Ca²⁺ homeostasis. Incorporating TRPV6 into routine NGS panels will enhance diagnosis and inform management of early-onset and idiopathic chronic pancreatitis.

References

• Genetic testing in idiopathic pancreatitis including TRPV6 • 2023 • Gastroenterology PMID:38657903
• Variants that affect function of calcium channel TRPV6 are associated with early-onset chronic pancreatitis • 2020 • Gastroenterology PMID:31930989
• TRPV6 variants confer susceptibility to chronic pancreatitis in the Chinese population • 2020 • Human Mutation PMID:32383311
• Loss of function TRPV6 variants are associated with chronic pancreatitis in nonalcoholic early-onset Polish and German patients • 2021 • Pancreatology PMID:34538581
• PDZ domain-containing protein as a physiological modulator of TRPV6 • 2007 • Biochemical and Biophysical Research Communications PMID:17645868
• A novel frameshift mutation in TRPV6 is associated with hereditary pancreatitis • 2022 • Frontiers in Genetics PMID:36699452

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