期刊
HUMAN MUTATION
卷 25, 期 4, 页码 343-347出版社
WILEY-BLACKWELL
DOI: 10.1002/humu.20148
关键词
pancreatitis; chronic; gene conversion; trypsinogen; cationic; serine protease 1; PRSS1; trypsinogen; anionic; serine protease 2; PRSS2; SPINK1
资金
- NIDDK NIH HHS [R01 DK058088-04, R01 DK058088-04S1, DK 58088, R01 DK058088-05A1, R01 DK058088, R01 DK058088-03] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK058088] Funding Source: NIH RePORTER
Gene conversion-the substitution of genetic material from another gene-is recognized as the underlying cause of a growing number of genetic diseases. While in most cases conversion takes place between a normal gene and its pseudogene, here we report an occurrence of disease-associated gene conversion between two functional genes. Chronic pancreatitis in childhood is frequently associated with mutations of the cationic trypsinogen gene (serine protease 1; PRSS1). We have analyzed PRSS1 in 1106 patients with chronic pancreatitis, and identified a novel conversion event affecting exon 2 and the subsequent intron. The recombination replaced at least 289 nucleotides with the paralogous sequence from the anionic trypsinogen gene (serine protease 2; PRSS2), and resulted in the PRSS1 mutations c.86 A > T and c.161 A > G, causing the amino acid substitutions N29I and N54S, respectively. Analysis of the recombinant N29I-N54S double mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N291 mutation. In conclusion, we have demonstrated that gene conversion between two functional paralogous trypsinogen genes can occur and cause genetically determined chronic pancreatitis. (c) 2005 Wiley-Liss, Inc.
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