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Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation

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Abstract

Hereditary pancreatitis, an autosomal dominant disease with ∼80% penetrance, can be caused by both ‘gain-of-function’ missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with hereditary pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3–5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent ‘double gain-of-function’ effect, acting simultaneously as a ‘quantitative’ copy number mutation and a ‘qualitative’ missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.

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Acknowledgments

We are grateful to Campbell R. Sheen (Christchurch, New Zealand) for critically reading an early version of this manuscript. E.M. is a PhD student supported by the Programme Hospitalier de Recherche Clinique (grant PHRC R 08–04), France. This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale), the PICRI (Partenariats Institutions Citoyens pour la Recherche et l’Innovation) project, the GIS Institut des Maladies Rares (project no. A07092NS), and the APCH (Association des Pancréatites Chroniques Héréditaires), France.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France

    Emmanuelle Masson, Cédric Le Maréchal, Jian-Min Chen & Claude Férec

  2. Faculté de Médecine et des Sciences de la Santé, Université de Bretagne Occidentale (UBO), 29238, Brest, France

    Emmanuelle Masson, Cédric Le Maréchal, Jian-Min Chen & Claude Férec

  3. Etablissement Français du Sang (EFS) – Bretagne, 46 rue Félix Le Dantec, 29220, Brest, France

    Emmanuelle Masson, Cédric Le Maréchal, Jian-Min Chen & Claude Férec

  4. Laboratoire de Génétique Moléculaire et d’Histocompatibilité, Centre Hospitalier Universitaire (CHU) Brest, Hôpital Morvan, 29220, Brest, France

    Cédric Le Maréchal & Claude Férec

  5. Service de Gastroentérologie, Centre Hospitalier Universitaire, Université de Picardie Amiens Nord, Amiens, France

    Richard Delcenserie

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  1. Emmanuelle Masson
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  2. Cédric Le Maréchal
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Correspondence to Jian-Min Chen.

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Masson, E., Le Maréchal, C., Delcenserie, R. et al. Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. Hum Genet 123, 521–529 (2008). https://doi.org/10.1007/s00439-008-0508-6

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  • DOI: https://doi.org/10.1007/s00439-008-0508-6

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