CPA1 – Hereditary Chronic Pancreatitis

Hereditary chronic pancreatitis (HP) is an autosomal dominant disorder characterised by recurrent pancreatic inflammation leading to exocrine insufficiency and fibrosis. CPA1 encodes carboxypeptidase A1, a digestive protease expressed in pancreatic acinar cells. Loss-of-function CPA1 variants predispose to HP through misfolding and endoplasmic reticulum (ER) stress, disrupting acinar cell homeostasis.

Several unrelated probands harbour rare CPA1 variants. A novel loop-stabilising missense change c.749G>C (p.Gly250Ala) was identified in a young HP patient and caused abolished secretion and pronounced ER stress, mirroring previously characterised p.Asn256Lys effects (PMID:36555104). In a Pakistani cohort of 50 HP patients from 44 families, two CPA1 variants, c.763A>G (p.Arg255Gly) and the splice-region change c.586-3C>A, were discovered in heterozygous form (PMID:37603299). Additionally, the recurrent c.768C>G (p.Asn256Lys) variant has been reported in early-onset sporadic cases (PMID:30045879).

Functional assessment in cell models demonstrates that misfolding CPA1 variants, including p.Gly250Ala and p.Asn256Lys, are retained intracellularly with reduced secretion and induce ER stress (PMID:36555104). A knock-in mouse model carrying the human p.Asn256Lys mutation develops hallmark features of chronic pancreatitis — acinar cell atrophy, inflammation, fibrosis, and acinar-ductal metaplasia — confirming pathogenicity in vivo (PMID:30045879).

Contrasting evidence comes from a large Chinese idiopathic chronic pancreatitis cohort (1,112 cases, 1,580 controls) where rare and functionally impaired CPA1 variants showed no significant enrichment in patients versus controls (P=0.57–0.68) (PMID:28497564), suggesting variable penetrance or population differences.

Overall, there is moderate clinical validity for CPA1 in hereditary chronic pancreatitis. Four unrelated probands with deleterious CPA1 variants and strong concordant functional and animal model data support a causal role, tempered by inconsistent replication in large cohorts. Mechanistically, CPA1 mutations drive disease via misfolding-induced ER stress and likely haploinsufficiency.

Key Take-home: Genetic testing for CPA1 variants can aid HP diagnosis, particularly for misfolding-prone loop mutations, but negative findings do not exclude genetic predisposition.

References

• Human mutation • 2017 • No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort. PMID:28497564
• International journal of molecular sciences • 2022 • Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1). PMID:36555104
• Gut • 2019 • Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice. PMID:30045879
• Unspecified journal • 2023 • Genetic insight of hereditary chronic pancreatitis in Pakistani children PMID:37603299

Evidence Based Scoring (AI generated)