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A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis

https://doi.org/10.1016/S0016-5085(99)70543-3Get rights and content

Abstract

Background & Aims: In pancreatitis, a key role has been attributed to the inappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pancreatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP). Methods: DNA samples from 44 unrelated children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The cationic trypsinogen gene was screened for mutations by single-strand conformation polymorphism analysis and DNA sequencing. Results: A mutation in the cationic trypsinogen gene was detected in 5 patients: in 2 patients with a family history of CP and in 3 patients with idiopathic CP. In 1 patient the formerly described R122H mutation was detected. In 4 patients a hitherto unknown mutation was found at the signal peptide cleavage site leading to an alanine to valine exchange in codon 16. The mutations were inherited in all cases. In 95 unrelated control individuals the A16V mutation was not found. Conclusions: Heterozygosity for the A16V mutation is strongly associated with CP. These results indicate that a significant percentage of patients with idiopathic CP may have a genetic basis for their disorder; therefore, genetic testing should be included in the diagnostic evaluation of these patients.

GASTROENTEROLOGY 1999;117:7-10

Section snippets

Participants

Forty-four unrelated children and adolescents with CP and 56 first-degree relatives were enrolled for genetic analysis. All patients were white. CP was arbitrarily defined as a condition characterized by at least two clearly separated episodes of recurring abdominal pain, increase in serum lipase and/or amylase levels, and pathological sonographic findings. This definition was necessary because the recently revised and simplified classification of pancreatitis in acute pancreatitis and CP is

Results

Analysis of the complete coding region of the cationic trypsinogen gene revealed mutations in 5 of 44 patients: an altered migration of PCR products of exon 2 was detected in 4 patients by SSCP analysis. DNA sequencing identified a heterozygous C to T transition at position 131906 of the DNA sequence according to Rowen et al.11 This substitution leads to a missense mutation at codon 16 by exchange of an alanine residue by valine (GCCb → GTC, A16V; numbering of amino acids begins at the

Discussion

To our knowledge this is the first study to determine the frequency of mutations in the cationic trypsinogen gene in unrelated patients with CP. In contrast, previous studies focusing exclusively on hereditary pancreatitis included families with several affected members. Because predisposing factors such as alcohol abuse are uncommon in children and adolescents, this age group was thought to be suitable for a prevalence study of genetic defects of cationic trypsinogen.

In 4 of 44 patients, we

Acknowledgements

The authors thank the members of the Gesellschaft für Pädiatrische Gastroenterologie und Ernährung (GPGE) for providing samples.

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Address requests for reprints to: Heiko Witt, M.D., Kinderklinik, Charité/Campus Virchow-Klinikum, Humboldt-Universität, Augustenburger Platz 1, 13353 Berlin, Germany. e-mail: [email protected]; fax: (49) 30-450-66917.

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