title: Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation.
abstract: Hereditary pancreatitis, an autosomal dominant disease with approximately 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U613, 29220, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Masson
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Maréchal
authors.forename: Richard
authors.initials: R
authors.lastname: Delcenserie
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D002908:Chronic Disease; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics; D020125:Mutation, Missense; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree; D014357:Trypsin / Q000235:genetics*; D014362:Trypsinogen / Q000235:genetics*
chemical_list: D050506:Mutant Chimeric Proteins; C064831:PRSS2 protein, human; D014362:Trypsinogen; C489303:PRSS1 protein, human; D014357:Trypsin