The Coexistence of TRPV6 Variants With Other Pancreatitis-Associated Genes Affects Pediatric-Onset Pancreatitis

Abstract

Objectives: Recently, a genetic risk for chronic pancreatitis (CP) was found to be conferred by pathogenic variants in the transient receptor potential cation channel, subfamily V, member 6 (TRPV6). Interestingly, 20%–57% of patients with functionally defective TRPV6 variants have other susceptibility genes such as cationic trypsinogen, serine protease inhibitor Kazal type 1, chymotrypsin C, cystic fibrosis transmembrane conductance regulator, and carboxypeptidase A1. In this study, we focused on pediatric patients with acute recurrent pancreatitis or CP with at least 1 variant in these 5 genes and investigated the presence of coexisting TRPV6 mutations. Methods: Ninety Japanese pediatric patients (median age at first onset, 8.0 years) who had at least 1 variant of these 5 genes were enrolled in this study. DNA samples were extracted for analysis from peripheral blood leukocytes. Coding regions of TRPV6 were screened by Sanger sequencing. Results: Regardless of functional defects or non-defects in TRPV6 variants, 14 of the 90 patients (15.6%) were trans-heterozygous for TRPV6 variants [p.A18S (n = 3), p.C197R (n = 3), p.I223T (n = 3), p.D324N (n = 4), p.M418V (n = 3), p.V540F (n = 1), p.A606T (n = 1), and p.M721T (n = 3)] and the 5 susceptibility genes noted above. Of these variants, p.D324N, p.V540F, and p.A606T are associated with pancreatitis. Three patients had the ancestral haplotype [p.C197R + p.M418V + p.M721T]. Conclusions: Overall, 4 of 90 patients (4.4%) had the coexistence of clearly pathogenic TRPV6 variants with pancreatitis-associated variants. The cumulative accumulation of these genetic factors may contribute to the development of pancreatitis at a young age.

Does the Complex of CELA3B Variants With Other Pancreatitis-Related Genes Affect Developing Childhood Pancreatitis?

“…Interestingly, 6 of the 9 patients with CELA3B c.129 + 1G>A were trans-heterozygous for mutations in cationic trypsinogen ( PRSS1 ), serine protease inhibitor gene ( SPINK1 ), and cystic fibrosis transmembrane conductance regulator ( CFTR ), but not chymotrypsin C ( CTRC ), carboxypeptidase A1 ( CPA1 ), and the transient receptor potential cation channel subfamily V member 6 ( TRPV6 ) gene variants (1). Recently, we reported that the coexistence of TRPV6 variants with other pancreatitis-associated genes affects pediatric-onset pancreatitis (2). CELA3B had not been analyzed in this study because of the limited information at that time; therefore, we reanalyzed all 8 CELA3B exons by Sanger sequencing using the same population (Ethics Committee Approval Number: E22-0142).…”

“…There were 90 Japanese patients [50 girls; median age at onset, 8.0 years (range, 2–15 years)] with acute recurrent pancreatitis or CP, who had already been identified as having variants of at least 1 of above‐mentioned 6 gene variants (2). The CELA3B codon 90 change, a gain‐of‐function missense variant (3,4), was not found.…”

A narrative review on the role of genetics in children with acute recurrent pancreatitis and chronic pancreatitis

“…Their significance is most pronounced in increasing the risk of early‐onset pancreatitis in carriers when combined with variants from other genes or other factors contributing to pancreatitis. 24 , 26 , 48 , 49 , 50 , 51 , 52 …”