Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation |
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Authors: | Emmanuelle Masson Cédric Le Maréchal Jian-Min Chen " target="_blank">Claude Férec |
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Institution: | Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France. |
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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.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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