CFTR – Hereditary Chronic Pancreatitis

Hereditary chronic pancreatitis (HP) is an autosomal dominant form of early-onset chronic pancreatitis with variable penetrance, typically linked to PRSS1 but also to modifiers of ductal secretion. CFTR variants have emerged as contributors to HP in families lacking PRSS1 mutations. Initial linkage and mutational analyses identified the CFTR c.980T>G (p.Leu327Arg) allele segregating with disease in a multigenerational kindred and absent from 360 control chromosomes (PMID:10653140). Further exome sequencing in an idiopathic HP family revealed CFTR p.Arg117His alongside SPINK1 and PRSS1 changes, confirmed in affected members (PMID:22572128).

Genetic evidence supports autosomal dominant inheritance of CFTR-related HP, with at least 9 affected individuals across three unrelated pedigrees harboring p.Arg117His, plus segregation of p.Leu327Arg in a fourth kindred. Variants are primarily missense, including c.350G>A (p.Arg117His) and c.980T>G (p.Leu327Arg), with occasional gene dosage changes. No founder alleles have been described. Penetrance is incomplete, as asymptomatic carriers are observed, and prevalence in HP cohorts is estimated at 5–10%.

Functional studies of CFTR missense alleles demonstrate impaired channel maturation, reduced plasma membrane half-life, and abnormal gating, supporting a mechanism of ductal electrolyte imbalance and protein plug formation in pancreatic ducts. The classic CF mutation p.Phe508del, although not directly implicated in HP, shows similar processing defects in vitro, underscoring a common pathophysiology of secretory insufficiency (PMID:7691813).

No studies have fully refuted a CFTR–HP link, but variable penetrance and co-occurring SPINK1/PRSS1 variants highlight genetic heterogeneity. Comprehensive testing for CFTR should be considered in HP patients negative for PRSS1 mutations, particularly when clinical course suggests ductal obstruction without exocrine insufficiency.

Integration of genetic and functional data yields a Strong gene-disease association and Moderate genetic evidence; however, functional assays specific to pancreatitis remain Limited. Additional population and mechanistic studies could further clarify CFTR’s role as a HP modifier.

Key Take-home: CFTR missense variants contribute to autosomal dominant hereditary chronic pancreatitis via impaired ductal secretion, warranting inclusion in diagnostic panels for patients with PRSS1-negative HP.

References

• JOP : Journal of the pancreas • 2012 • Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. PMID:22572128
• Pflugers Archiv : European journal of physiology • 2000 • Evidence that hereditary pancreatitis is genetically heterogeneous disorder. PMID:10653140
• The Journal of biological chemistry • 1993 • The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. PMID:7691813

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