Re-evaluating the role of TRPV6 deficiency in human and mouse pancreatitis

Functionally defective genetic variants of the calcium channel TRPV6 have been shown to markedly increase the risk for chronic pancreatitis in humans. Genetic inactivation of Trpv6 in mice worsened the severity of pancreatitis induced by secretagogue hyperstimulation. The aims of the present study were to re-examine the role of loss-of-function TRPV6 gene variants in an adult Hungarian cohort with non-alcoholic chronic pancreatitis and to characterize cerulein-induced pancreatitis in a novel Trpv6-deleted mouse strain. We found that 2.1% of chronic pancreatitis patients carried defective TRPV6 variants, whereas no such variants were identified in control subjects. Homozygous deletion of Trpv6 in C57BL/6N mice ( Trpv6-KO) caused no spontaneous pancreatitis but slightly increased the severity of cerulein-induced acute pancreatitis and delayed recovery after an acute episode in a subset of mice. Cerulein-induced intrapancreatic trypsin and chymotrypsin activity was unchanged in Trpv6-KO mice relative to C57BL/6N controls. Crossing homozygous Trpv6-KO mice with heterozygous Spink1-KO mice did not result in spontaneous pancreatitis. Our results confirmed the association of defective TRPV6 variants with human chronic pancreatitis in a non-alcoholic cohort. Furthermore, we found that TRPV6 played a relatively minor role in cerulein-induced murine pancreatitis, highlighting the need for better animal models for studying human TRPV6 variants.