Abstract
Hereditary pancreatitis (HP) is an autosomal dominant disease. Two heterozygous missense mutations, R122H (R117H) and N29I (N21I), in the cationic trypsinogen gene have been clearly associated with HP. The ‘self-destruct’ model proposed for the R122H mutation is discussed in connection with the existing theory of pancreatitis, and the basic biochemistry and physiology of trypsinogen, with particular reference to R122 as the primary autolysis site of the cationic trypsinogen. Two different genetic mechanisms are identified which cause the R122H mutation, and gene conversion is the likely cause of the N29I mutation. A unifying model, which highlights an indirect impairment on the R122 autolysis site is hypothesised for the N29I mutation. Possible predisposition to pancreatitis by additional DNA variants in the gene, such as the A16V signal peptide cleavage site mutation and the K23R activation peptide cleavage site mutation is suspected, but not proven. Evidence of genetic heterogeneity of HP is reviewed and cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations detected in HP families are re-evaluated. Finally, large scale association studies are expected to clarify the additional variants' role in pancreatitis and to identify new HP genes.
Similar content being viewed by others
Article PDF
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, JM., Ferec, C. Molecular basis of hereditary pancreatitis. Eur J Hum Genet 8, 473–479 (2000). https://doi.org/10.1038/sj.ejhg.5200492
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.ejhg.5200492
Keywords
This article is cited by
-
Strong purifying selection against gene conversions in the trypsin genes of primates
Human Genetics (2012)
-
Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis
Human Genetics (2008)
-
Detection of a large genomic deletion in the pancreatic secretory trypsin inhibitor (SPINK1) gene
European Journal of Human Genetics (2006)
-
Mutations in SBDS are associated with Shwachman–Diamond syndrome
Nature Genetics (2003)
-
Cationic trypsinogen and pancreatic secretory trypsin inhibitor gene mutations in neonatal hypertrypsinaemia
European Journal of Human Genetics (2003)