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J Med Genet 47:348-350 doi:10.1136/jmg.2009.072751
  • Short report

Uncertainties in the classification of human cationic trypsinogen (PRSS1) variants as hereditary pancreatitis-associated mutations

  1. Miklós Sahin-Tóth
  1. Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
  1. Correspondence to Miklós Sahin-Tóth, 72 East Concord Street, Evans-433; Boston, MA 02118, USA; miklos{at}bu.edu
  • Received 26 August 2009
  • Revised 9 December 2009
  • Accepted 10 December 2009

Abstract

Background Autosomal dominant hereditary pancreatitis has been conclusively linked with cationic trypsinogen (PRSS1) mutations p.R122H and p.N29I, which can be found in ∼90% of mutation-positive cases. To date, 35 additional rare or private PRSS1 variants have been identified in subjects with hereditary or sporadic, idiopathic chronic pancreatitis. Despite the lack of sufficient genetic and functional evidence, many of these rare variants have been labelled as pancreatitis associated. This problematic trend is notably illustrated by two recent studies that classified the p.A121T PRSS1 variant as pancreatitis associated, in large part owing to its intimate proximity to arginine-122, the residue affected by the disease causing p.R122H mutation.

Methods and Results Here we demonstrate that the p.A121T variant is functionally innocuous and shows no verifiable association with hereditary pancreatitis, on the basis of the available inconclusive data.

Conclusion This case cautions that assignment of clinical relevance to rare PRSS1 variants should not be based on a perceived analogy with genuine disease causing PRSS1 mutations, and further studies are required to prove or rule out possible low penetrance causality of rare PRSS1 variants.

Footnotes

  • Funding NIH.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.