Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Chymotrypsin C (CTRC) is a pancreatic serine protease that protects against pancreatitis by degrading prematurely activated trypsinogen. Heterozygous loss-of-function variants in CTRC diminish this protective activity and predispose carriers to hereditary chronic pancreatitis (HP) by disrupting intrapancreatic protease balance (PMID:34798985). HP is characterized by recurrent acute pancreatitis episodes, progression to chronic pancreatitis, and eventual exocrine insufficiency.
Genetic evidence from multiple cohorts supports an autosomal dominant inheritance with incomplete penetrance. A meta-analysis of four relatively common CTRC variants—p.Ala73Thr, p.Val235Ile, p.Lys247_Arg254del, and p.Arg245Trp—revealed odds ratios (OR) of 6.5, 4.5, 5.4, and 2.6, respectively, for chronic pancreatitis risk (PMID:35594281). In a pediatric cohort (n = 136) without alcohol or smoking history, p.Arg254Trp heterozygotes showed OR 19.1 and p.Lys247_Arg254del OR 5.5, while the common c.180C>T (p.Gly60=) haplotype (c.180TT) conferred OR 2.0 (PMID:28968289). In 44 unrelated Pakistani HP families (50 affected children), CTRC missense variant c.719G>A (p.Arg240Gln) was identified in 4% of cases (PMID:37603299).
The variant spectrum in HP includes at least 27 missense changes (e.g., c.217G>A (p.Ala73Thr)), several splice-site mutations, frameshifts (e.g., p.Trp164fs), and the synonymous risk haplotype c.180C>T (p.Gly60=). The c.180C>T allele occurs in 14.2% of CP patients versus 8.7% of controls, and homozygotes (TT) further elevate risk (genotypic OR 5.29) (PMID:37321941).
Functional assays demonstrate that CTRC variants cause pathogenic loss of function by one or more mechanisms: impaired secretion, reduced catalytic activity, or increased proteolytic degradation. Of 32 missense mutants studied, 11 exhibited marked LOF, three showed moderate defects, and the remainder were functionally neutral (PMID:22942235). The p.Ala73Thr variant induces endoplasmic reticulum stress in acinar cells with BiP and CHOP upregulation and apoptosis, linking misfolding to pancreatic damage (PMID:19951900).
In vivo evidence from a C57BL/6N mouse model restored for functional Ctrc confirms the protective role of CTRC: cerulein-induced pancreatitis severity was significantly ameliorated, with reduced intrapancreatic trypsin activation upon CTRC restoration (PMID:31211695). These data support a haploinsufficiency mechanism with dominant predisposition and variable penetrance.
Although variants in the 5′ regulatory region of CTRC were explored, none showed independent disease association after accounting for linkage disequilibrium with c.180C>T (PMID:39765393).
Key Take-home: CTRC heterozygous loss-of-function variants confer a 3–7-fold increased risk of hereditary chronic pancreatitis; inclusion of CTRC in genetic testing panels and functional assays for novel variants is recommended for accurate risk stratification.
Gene–Disease AssociationStrongOver 200 unrelated cases across multiple cohorts; functional concordance in vitro and in vivo Genetic EvidenceStrongHeterozygous LOF CTRC variants identified in >300 probands; multiple independent case-control and family studies demonstrating OR 3–7 Functional EvidenceModerateComprehensive in vitro analyses of 27 variants revealing LOF mechanisms; ER stress assays; protective role confirmed in mouse model |