SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis

Pfützer, Roland H.; Barmada, M. Michael; Brunskill, Andrew P. J.; Finch, Robert A.; Hart, Patricia; Neoptolemos, John P.; Furey, W.; Whitcomb, David C.

doi:10.1053/gast.2000.18017

Cited by 464 publications

(412 citation statements)

References 34 publications

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“…Mutations in the best characterized risk genes PRSS1 (cationic trypsinogen), SPINK1 (pancreatic secretory trypsin inhibitor), and CTRC (chymotrypsin C) stimulate activation of trypsinogen and result in elevated trypsin activity in the pancreas [4][5][6][7][8][9]. More recently, loss-of-function variants in the CPA1 gene encoding carboxypeptidase A1 were shown to increase risk for early onset CP [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

et al. 2017

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Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39-0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.

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Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

et al. 2017

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“…This result is similar to that reported by Audrézet et al, 7 who reported the presence of the N34S mutation in 10% of ICP patients, and by Ockenga et al, 12 who reported a similar prevalence of SPINK1 mutations in a cohort of adult IP patients. A higher frequency of SPINK1 mutations was described by Witt et al 5 and by Pfützer et al, 6 where the frequency of N34S in CP patients was 18.75 and 40.3%, respectively.…”

Section: Resultsmentioning

confidence: 72%

“…The À41G4A variant, which was present in one IP and in no control individual, has been discussed by Audrézet et al 7 as having a possible role in transcription efficiency of the protein. However, it was also present in 6 so its relevance in IP remains to be determined. Interestingly, the N34S mutation was present in two patients who carried the 5T variant and in one who carried the L997F variant in the CFTR gene ( Table 2).…”

Section: Resultsmentioning

confidence: 99%

Mutations in the SPINK1 gene in idiopathic pancreatitis Italian patients

et al. 2003

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Idiopathic chronic and acute recurrent pancreatitis (IP) have been associated with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in the serine protease inhibitor Kazal 1 (SPINK1) have been described in some idiopathic chronic patients and it has been suggested that mutations in this gene could be responsible for a loss of trypsin inhibitor function. In this study, the 5 0 UTR region, and the four exons and exon -intron boundaries of the SPINK1 gene in 32 IP patients have been analyzed. Three IP patients (9.3%) and one control/100 carried the N34S mutation of the SPINK1 gene (Fisher's exact test, P ¼ 0.044) . No other mutation that could be associated with an altered function of the SPINK1 protein was observed. The N34S mutation was present in two patients who carried the CFTR-IVS8 5T variant and in one who carried the L997F variant in the CFTR gene. The association of SPINK1 with CFTR gene mutations in IP patients is statistically significant (3/32 IP cases and 0/100 control individuals carrying mutations in both genes; Fisher's exact test P ¼ 0.01).

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“…Hereditary pancreatitis often is associated with various mutations in the cationic trypsinogen gene that could render trypsinogen either more prone to premature activation or may render active trypsin more resistant to degradation by other proteases [32,33]. Mutations in the serine protease inhibitor, Kazal type 1 gene that might render pancreatic secretory trypsin inhibitor (PSTI) less effective are associated with certain forms of chronic pancreatitis [34][35][36].…”

Section: The Mechanism and Intracellular Site Of Zymogen Activationmentioning

confidence: 99%

Early events in acute pancreatitis

Halangk¹,

Lerch²

2004

Gastroenterology Clinics of North America

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SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis

Cited by 464 publications

References 34 publications

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Mutations in the SPINK1 gene in idiopathic pancreatitis Italian patients

Early events in acute pancreatitis

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