Awata H, Endo F, Tanoue A, Kitano A, Nakano Y, Matsuda I
Department of Pediatrics, Kumamoto University Medical School, Japan.
Biochim Biophys Acta. 1994 May 25;1226(2):168-72. doi: 10.1016/0925-4439(94)90025-6.
Fumarylacetoacetate hydrolase (FAH) is a metabolic enzyme functioning at the last step of tyrosine catabolism. Deficiency in this enzyme activity is associated with tyrosinemia type I, characterized by hypertyrosinemia, liver dysfunction, renal tubular dysfunction, liver cirrhosis, and hepatic tumors. We isolated from a human gene library a chromosomal gene related to FAH. The human FAH gene is 30 kilobases long and is split into 14 exons. All of the splice donor and acceptor sites conform to the GT/AG rule. We also analyzed findings in a patient with tyrosinemia type I with respect to the mutation responsible for defects in the enzyme. A nucleotide change from T to G was found in the exon 2 of the gene and this change was accompanied by an amino acid substitution (Phe62Cys). Transfection and expression analysis of the cDNA in cultured BMT-10 cells with the nucleotide substitution demonstrated that the substitution was indeed responsible for the decreased activity of the enzyme in the patient. These results confirmed that the T to G mutation was one of the causes of tyrosinemia type I. Structure of the FAH gene and tests for expression of the mutant FAH will facilitate further understanding of various aspects of FAH.
富马酰乙酰乙酸水解酶（FAH）是一种在酪氨酸分解代谢最后一步发挥作用的代谢酶。该酶活性缺乏与I型酪氨酸血症相关，其特征为高酪氨酸血症、肝功能障碍、肾小管功能障碍、肝硬化和肝肿瘤。我们从人类基因文库中分离出一个与FAH相关的染色体基因。人类FAH基因长30千碱基，被分割为14个外显子。所有的剪接供体和受体位点均符合GT/AG规则。我们还分析了一名I型酪氨酸血症患者中导致该酶缺陷的突变情况。在该基因的外显子2中发现了一个从T到G的核苷酸变化，并且这种变化伴随着一个氨基酸替换（Phe62Cys）。对具有该核苷酸替换的cDNA在培养的BMT - 10细胞中进行转染和表达分析表明，该替换确实是导致患者酶活性降低的原因。这些结果证实了从T到G的突变是I型酪氨酸血症的病因之一。FAH基因的结构以及突变型FAH的表达测试将有助于进一步了解FAH的各个方面。
