2 MISSENSE MUTATIONS CAUSING TYROSINEMIA TYPE-1 WITH PRESENCE AND ABSENCE OF IMMUNOREACTIVE FUMARYLACETOACETASE

Hereditary tyrosinemia type 1, due to a deficiency of fumarylacetoacet ase (FAH), is characterized by progressive liver damage and renal tubu lar dysfunction and may occur in an acute or a chronic form. An Ala 13 4 to Asp (GCT to GAT) transition was found in one Turkish and two Norw egian patients with chronic tyrosinemia. SphI digestion of polymerase chain reaction (PCR) amplified genomic DNA identified the mutation and showed that the patients were heterozygous. All these patients had im munoreactive FAH protein in fibroblasts. Another Norwegian patient wit h chronic disease, without FAH immunoreactive material in fibroblasts, had a Pro 342 to Leu mutation (CCG to CTG). This mutation was identif ied by MspI digestion of PCR amplified genomic DNA, and the patient wa s heterozygous. Northern blotting showed FAH mRNA of normal size and a mounts in all patients. Site directed mutagenesis and translation in a rabbit reticulocyte lysate demonstrated that both mutations abolished FAH activity.