STRUCTURAL ORGANIZATION AND ANALYSIS OF THE HUMAN FUMARYLACETOACETATEHYDROLASE GENE IN TYROSINEMIA TYPE-I

Fumarylacetoacetate hydrolase (FAH) is a metabolic enzyme functioning at the last step of tyrosine catabolism. Deficiency in this enzyme act ivity is associated with tyrosinemia type I, characterized by hypertyr osinemia, liver dysfunction, renal tubular dysfunction, liver cirrhosi s, and hepatic tumors. We isolated from a human gene library a chromos omal 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 con form to the GT/AG rule. We also analyzed findings in a patient with ty rosinemia 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 substitu tion (Phe62Cys). Transfection and expression analysis of the cDNA in c ultured BMT-10 cells with the nucleotide substitution demonstrated tha t the substitution was indeed responsible for the decreased activity o f the enzyme in the patient. These results confirmed that the T to G m utation was one of the causes of tyrosinemia type I. Structure of the FAH gene and tests for expression of the mutant FAH will facilitate fu rther understanding of various aspects of FAH.