Identification of a stop mutation in five Finnish patients suffering from hereditary tyrosinemia type I.

Hereditary tyrosinemia type I is a metabolic disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH, EC 3.7.1.2), the last enzyme in the catabolic pathway of tyrosine. The molecular basis of FAH deficiency was examined in five Finnish patients suffering from this severe metabolic disease. No immunoreactive FAH nor enzymatic activity were found in their liver. Direct sequencing of the 14 exons of the FAH gene showed a G to A transition, which predicts a change from tryptophan to a stop codon (TGG-->TGA) at position 262 (W262X). Four of the five patients examined were homozygous for the mutation. Allele specific oligonucleotide hybridization showed a predominance of the W262X mutation in Finland (9 of 10 alleles) and the absence of this mutant allele in patients from other parts of the world. The loss of a BsaJI restriction site in those patients may be used for diagnosis.