title: Characterization of two deletions of the CTRC locus.
abstract: Novel variants associated with chronic pancreatitis are being increasingly reported. However, most studies have so far only analyzed point mutations and small insertions or deletions. Here we report the characterization of two distinct deletions of the CTRC locus. Variants in four chronic pancreatitis genes, PRSS1, SPINK1, CTRC and CFTR, were systematically analyzed in the studied cases. Copy number change of the CTRC gene was analyzed by quantitative fluorescent multiplex PCR (QFM-PCR). Walking QFM-PCR followed by long-range PCR and direct sequencing were employed to identify the deletion breakpoints at the nucleotide level. A heterozygous CTRC-deleting complex rearrangement, which was co-inherited with different trans variants in SPINK1, CFTR or PRSS1, is associated with variable phenotypes (chronic pancreatitis; pancreatic cancer and chronic pancreatitis; and type 1 diabetes). Moreover, a different homozygous deletion of the CTRC locus was found in an unrelated patient with asymptomatic chronic pancreatitis. Our findings revealed a hitherto unrecognized level of complexity of genotype-phenotype correlation in chronic pancreatitis. The CTRC-deleting complex rearrangement probably resulted from LINE-1-mediated Alu insertion, which represents a novel mutational mechanism causing chronic pancreatitis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), U1078, Brest, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Masson
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Cécile
authors.initials: C
authors.lastname: Garceau
authors.forename: Caroline
authors.initials: C
authors.lastname: Bénech
authors.forename: Sylvia
authors.initials: S
authors.lastname: Quéméner-Redon
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Chen
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D000328:Adult; D002918:Chymotrypsin / Q000235:genetics*; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D056426:Genetic Loci; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D050500:Pancreatitis, Chronic / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D055815:Young Adult
chemical_list: D002918:Chymotrypsin; C117569:chymotrypsin C