Grompe M, Lindstedt S, al-Dhalimy M, Kennaway N G, Papaconstantinou J, Torres-Ramos C A, Ou C N, Finegold M
Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland 97201, USA.
Nat Genet. 1995 Aug;10(4):453-60. doi: 10.1038/ng0895-453.
Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.
遗传性I型酪氨酸血症是一种严重的常染色体隐性代谢疾病，会影响肝脏和肾脏，由延胡索酰乙酰乙酸水解酶（FAH）缺乏引起。FAH基因敲除的纯合小鼠具有因肝功能障碍导致的新生儿致死表型，不能代表人类疾病的合适模型。在此我们证明，用2 -（2 - 硝基 - 4 - 三氟甲基苄基）-1,3 - 环己二酮治疗患病动物可消除新生儿致死性，纠正肝功能，并使肝脏mRNA的改变表达模式部分正常化。患病动物寿命延长导致了类似于人类I型酪氨酸血症的表型，包括肝细胞癌。成年FAH - / - 小鼠将作为研究遗传性I型酪氨酸血症以及肝癌的病理生理学和治疗的有用模型。
