Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type 1

Am J Hum Genet. 1994 Oct;55(4):653-8.


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.

Publication types

  • Case Reports

MeSH terms

  • Alternative Splicing*
  • Amino Acid Metabolism, Inborn Errors / enzymology*
  • Amino Acid Metabolism, Inborn Errors / genetics*
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA / chemistry
  • DNA Primers
  • Exons
  • Humans
  • Hydrolases / genetics*
  • Infant
  • Introns
  • Male
  • Molecular Sequence Data
  • Point Mutation*
  • Polymerase Chain Reaction / methods
  • Tyrosine / metabolism*


  • DNA Primers
  • Tyrosine
  • DNA
  • Hydrolases
  • fumarylacetoacetase