title: Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1.
abstract: In six unrelated patients with hereditary tyrosinemia type 1 (HT1), three different disease-causing mutations were found by DNA sequencing. Two Pakistani patients, with acute and intermediate forms of HT1, were homozygous for a G192-->T mutation in the last nucleotide of exon 2. This caused aberrant splicing with partial intron 2 retention and premature termination. Three Turkish patients with chronic and intermediate forms of HT1 were homozygous for an A698-->T mutation substituting aspartic acid 233 with valine. A Norwegian patient with an intermediate clinical phenotype was heterozygous for G786-->A, introducing a TGA stop codon for Trp262 (W262X). Site-directed mutagenesis and expression in a rabbit reticulocyte lysate system demonstrated that the nonsense and missense mutations abolished fumarylacetoacetase activity and gave reduced amounts of a truncated and a full-length protein, respectively. Simple tests were established to identify the three mutations by restriction digestion of PCR-amplified genomic DNA. Among 30 additional HT1 patients investigated, 2 were found to be homozygous and 1 heterozygous for G192-->T. Two other patients were homozygous and one was heterozygous for W262X.
authors.affiliation: Institute of Clinical Biochemistry, University of Oslo, Rikshospitalet, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Rootwelt
authors.forename: R
authors.initials: R
authors.lastname: Berger
authors.forename: G
authors.initials: G
authors.lastname: Gray
authors.forename: D A
authors.initials: DA
authors.lastname: Kelly
authors.forename: T
authors.initials: T
authors.lastname: Coşkun
authors.forename: E A
authors.initials: EA
authors.lastname: Kvittingen
mesh_terms: D017398:Alternative Splicing; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry; D017931:DNA Primers; D005091:Exons; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007223:Infant; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D014443:Tyrosine; D004247:DNA; D006867:Hydrolases; C020156:fumarylacetoacetase