title: Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis.
abstract: Mutations in the serine protease inhibitor Kazal type 1 gene (SPINK1) encoding pancreatic secretory trypsin inhibitor (PSTI) have recently been found to be associated with chronic pancreatitis. Nevertheless, knowledge of severe mutations is particularly scarce, both in terms of number and in the extent of clinical information. The aim of this study was to expand the known spectrum of such mutations. 46 unrelated families, each including at least two pancreatitis patients and carrying neither cationic trypsinogen (PRSS1) mutations nor the frequent SPINK1 N34S mutation, participated in this study. The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing. A heterozygous microdeletion mutation (c.27delC), which occurs within a symmetric element, was identified in two families. In one family, c.27delC showed segregation with the disease across two generations, with a penetrance of up to 75%. But in the other family, however, the same mutation manifested as a low-penetrance susceptibility factor. In addition, a novel heterozygous splicing mutation, c.87+1G>A (G>A substitution at nucleotide +1 of intron 2) was found in one family with familial pancreatitis. Our results also helped to resolve the sharply differing views about PSTI's role in pancreatitis.
authors.affiliation: INSERM 01 15, Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang-Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire de Morvan, Brest, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Maréchal
authors.affiliation: INSERM 01 15, Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang-Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire de Morvan, Brest, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Hépatogastroentérologie Nutrition, Hôpital édouard Herriot, Lyon, France.
authors.forename: C
authors.initials: C
authors.lastname: Le Gall
authors.affiliation: Departement Génétique et Reproduction, Centre Hospitalier Universitaire de Caen, Caen, France.
authors.forename: G
authors.initials: G
authors.lastname: Plessis
authors.affiliation: Service de Chirurgie Générale et Digestive, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: J
authors.initials: J
authors.lastname: Chipponi
authors.affiliation: Department of Computer Science, Cardiff University, Cardiff, United Kingdom.
authors.forename: N A
authors.initials: NA
authors.lastname: Chuzhanova
authors.affiliation: INSERM 01 15, Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang-Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire de Morvan, Brest, France.
authors.forename: O
authors.initials: O
authors.lastname: Raguénès
authors.affiliation: INSERM 01 15, Génétique Moléculaire et Génétique Epidémiologique, Etablissement Français du Sang-Bretagne, Université de Bretagne Occidentale, Centre Hospitalier Universitaire de Morvan, Brest, France.
authors.forename: C
authors.initials: C
authors.lastname: Férec
mesh_terms: D000328:Adult; D002648:Child; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics; D014359:Trypsin Inhibitor, Kazal Pancreatic / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D014359:Trypsin Inhibitor, Kazal Pancreatic