SPINK1 – Hereditary Chronic Pancreatitis

Hereditary chronic pancreatitis is characterized by recurrent pancreatic inflammation leading to fibrosis, exocrine insufficiency, and an elevated lifetime risk of pancreatic malignancy. SPINK1 encodes the pancreatic secretory trypsin inhibitor (PSTI), a key regulator of intrapancreatic trypsin activity. Loss-of-function variants in SPINK1 reduce inhibitor levels, predisposing to premature trypsinogen activation. The gene–disease relationship follows an autosomal recessive pattern, with homozygous or compound heterozygous carriers demonstrating the highest risk.

Large genetic studies have demonstrated a significant association between the SPINK1 N34S variant and idiopathic chronic pancreatitis. In a cohort of 327 individuals from 217 families, N34S prevalence increased from 2.5% in controls to 13% in true idiopathic chronic pancreatitis patients ([PMID:11950815]). This enrichment supports moderate genetic evidence for SPINK1 as a susceptibility gene.

A seminal case report detailed a 44-year-old woman with homozygous N34S who developed chronic calcifying pancreatitis and pancreatic adenocarcinoma, with segregation of the same genotype in her affected sister and heterozygosity in unaffected parents ([PMID:15084977]). This report provides additional familial segregation evidence and highlights cancer risk in SPINK1-related hereditary pancreatitis.

Variant spectrum in SPINK1 spans missense, splice-site, and promoter changes. The predominant allele c.101A>G (p.Asn34Ser) is reported recurrently in both homozygous and heterozygous contexts. Rare missense variants (e.g., c.199C>T (p.Arg67Cys)) and splice-disrupting intronic mutations have also been documented, often in compound genotypes alongside CFTR or PRSS1 alleles.

Functional assays in HEK293T and CHO cells revealed that certain missense variants (D50E, Y54H, R67C) cause intracellular retention and degradation of PSTI, abolishing secretion ([PMID:17525091]). In contrast, N34S retains trypsin inhibitory activity in vitro but may affect regulatory elements in the SPINK1 haplotype.

Biochemical analyses of recombinant PSTI proteins under variable pH and calcium conditions showed unaltered N34S inhibitory function compared with wild type, suggesting that non-conformational mechanisms or distal regulatory variants (e.g., c.-4141G>T) drive the N34S haplotype association ([PMID:12483248], [PMID:34828289]).

Despite robust evidence for SPINK1 as a disease modifier, some studies report incomplete segregation and variable penetrance of N34S, indicating that it acts mainly as a risk factor rather than a standalone causative mutation. Conflicting data underscore the multifactorial nature of hereditary chronic pancreatitis.

Collectively, genetic and experimental data support a Moderate clinical validity for SPINK1 in hereditary chronic pancreatitis. Functional studies are concordant with a loss-of-function mechanism. SPINK1 testing should be integrated into genetic panels for hereditary pancreatitis to inform risk stratification and surveillance strategies.

References

• Gut • 2002 • The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. PMID:11950815
• Pancreas • 2004 • Hereditary pancreatitis as the premalignant disease: a Japanese case of pancreatic cancer involving the SPINK1 gene mutation N34S. PMID:15084977
• Gut • 2007 • Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. PMID:17525091
• Journal of gastroenterology • 2002 • Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. PMID:12483248
• Genes • 2021 • Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large. PMID:34828289

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