The significance of human jagged 1 mutations detected in severe cases of extrahepatic biliary atresia

被引:83
作者
Kohsaka, T
Yuan, ZR
Guo, SX
Tagawa, M
Nakamura, A
Nakano, M
Kawasasaki, H
Inomata, Y
Tanaka, K
Miyauchi, J
机构
[1] Natl Ctr Child Hlth & Dev, Childrens Med Res Ctr, Dept Hepato Entero Nephrol, Tokyo 1578535, Japan
[2] Natl Ctr Child Hlth & Dev, Childrens Med Res Ctr, Dept Immunol, Tokyo 1578535, Japan
[3] Natl Ctr Child Hlth & Dev, Childrens Med Res Ctr, Dept Pediat Surg, Tokyo 1578535, Japan
[4] Natl Ctr Child Hlth & Dev, Childrens Med Res Ctr, Dept Pathol, Tokyo 1578535, Japan
[5] Univ Tokyo, Dept Pediat Surg, Tokyo, Japan
[6] Kyoto Univ, Dept Transplantat Immunol, Kyoto, Japan
关键词
D O I
10.1053/jhep.2002.35820
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Mutations of human jagged 1 (JAG1) gene are responsible for Alagille Syndrome (AGS), whose 2 main symptoms are intrahepatic bile duct hypoplasia and pulmonary stenosis. We examined the JAG1 mutation in extrahepatic biliary atresia (EHBA), which is similar in phenotype to AGS, although a different pathogenesis is suggested. In 102 cases of EHBA, 9 missense mutations were detected, including 2 intrafamilial expressions in the propositus and an aunt of one family. These mutations were all missense and sporadic except for those of this particular family. The JAG1 gene mutations were generally found in severely ill patients subjected to liver transplantation at less than 5 years of age. None of the 9 cases of EHBA revealed any of the 5 major symptoms of AGS nor any identical pathological findings after 3 years of follow-up. Our cases were clearly separated from AGS by pathological findings and clinical features, and could be diagnosed as EHBA and not as atypical AGS. The increase of interleukin 8 (IL-8) production induced by tumor necrosis factor alpha(TNF-alpha) in Hub 7 cells was suppressed by the coexistence of JAG I protein. We examined the different influences between wild-type cells and the 3 kinds of mutants detected in EHBA on Hub 7 cells and found that 2 of 3 mutants showed about half of the repressed activity compared with that of wild type. In conclusion, these results suggest that the JAG1 gene abnormality may be an aggravating factor in EHBA.
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页码:904 / 912
页数:9
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