Characterization of two deletions of the CTRC locus

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 pancreatit...

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Bibliographic Details
Published in:Molecular genetics and metabolism 2013-07, Vol.109 (3), p.296-300
Main Authors: Masson, Emmanuelle, Hammel, Pascal, Garceau, Cécile, Bénech, Caroline, Quéméner-Redon, Sylvia, Chen, Jian-Min, Férec, Claude
Format: Article
Language:English
Subjects:
Adult
Breakpoints
Chronic pancreatitis
Chymotrypsin - genetics
Copy number mutation
CTRC
DNA Mutational Analysis
Gene Deletion
Genetic Loci
Genetics
Genotype–phenotype relationship
Heterozygote
Homozygote
Humans
Male
Pancreatitis, Chronic - diagnosis
Pancreatitis, Chronic - genetics
Pathogenesis
Pedigree
Young Adult
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Summary: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. •We characterized two distinct deletions of the CTRC locus.•We illustrated complexity of genotype–phenotype relationship in chronic pancreatitis.•A novel mutational mechanism was found to cause chronic pancreatitis.
ISSN:1096-7192
1096-7206
DOI:10.1016/j.ymgme.2013.04.022