SPINK1 – Tropical Pancreatitis

Tropical pancreatitis (MONDO:0011986) is a severe idiopathic chronic pancreatitis endemic in tropical regions, subdivided into fibrocalculous pancreatic diabetes (FCPD) and tropical calcific pancreatitis (TCP). Serine protease inhibitor Kazal type 1 (SPINK1; HGNC:11244) encodes a trypsin inhibitor that protects against premature intrapancreatic trypsin activation. Early sequencing studies identified two SPINK1 mutations, c.101A>G (p.Asn34Ser) and c.194+2T>C, in 6 of 8 Bangladeshi FCPD patients but not in 4 TCP patients or controls (p < 0.03) (PMID:12120202).

A larger Bangladeshi cohort (22 FCPD, 15 TCP, 43 type 2 diabetes mellitus, 76 controls) confirmed the N34S allele in 55% of FCPD, 20% of TCP, and 14% of non-insulin-dependent diabetes cases versus 1.3% of controls (OR 83, p < 0.00001; OR 11.2, p = 0.04; OR 11.9, p = 0.009) and identified a novel p.Tyr54His variant in TCP (n = 1) (PMID:12360464). In a north Indian TCP series (n = 66 unrelated patients, 92 controls), N34S was present in 44% (including 9 homozygotes) compared with 2.2% of controls (PR 20.2; p < 0.0001); no phenotypic differences were observed by zygosity or diabetes status (PMID:12360463). Together these studies encompass 80 probands carrying SPINK1 risk alleles across diverse populations.

Genetic evidence supports an autosomal recessive risk model with SPINK1 N34S acting as a strong susceptibility allele. Segregation analysis in 6 affected relatives further underlines cosegregation with disease (PMID:12360463). The variant spectrum in TCP is dominated by missense changes—predominantly N34S—and splice‐site mutations like c.194+2T>C, with rare variants (p.Tyr54His, p.Arg67Cys) observed in individual cases.

Functional assays demonstrate that N34S does not impair canonical trypsin inhibitory activity under in vitro conditions (PMID:12483248), suggesting other mechanisms underlie its pathogenicity. In contrast, variants p.Asp50Glu, p.Tyr54His, p.Arg67Cys, and signal‐peptide changes (p.Leu14Arg) exhibit intracellular retention, reduced secretion, or loss of inhibitory function in cell models (PMID:17525091), consistent with haploinsufficiency. Molecular dynamics studies confirm structural destabilization for D50E and Y54H mutants (PMID:22955423).

There is no compelling evidence disputing SPINK1’s role in tropical pancreatitis; environmental cofactors modulate penetrance. Recent fine‐mapping of the N34S haplotype pinpointed c.-4141G>T disrupting a PTF1L‐binding site as the causal variant driving the association, rather than N34S itself (PMID:34828289).

In summary, SPINK1 variants, primarily the N34S‐containing haplotype and rare loss‐of‐function alleles, confer a strong genetic risk for tropical pancreatitis through impaired trypsin inhibition. Genetic testing for SPINK1 mutations aids diagnosis and risk stratification in endemic areas.

Key Take-home: SPINK1 loss-of-function alleles are major genetic risk factors for tropical pancreatitis, supporting routine gene testing to inform clinical management.

References

• Pancreatology • 2001 • SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh. A preliminary report. PMID:12120202
  
• Gastroenterology • 2002 • SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh. PMID:12360464
  
• Gastroenterology • 2002 • Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. PMID:12360463
  
• Journal of gastroenterology • 2002 • Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. PMID:12483248
  
• Gut • 2007 • Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. PMID:17525091
  
• 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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