Novel splice, missense, and nonsense mutations in the fumarylacetoacetase gene causing tyrosinemia type I
Journal Article
·
· American Journal of Human Genetics
OSTI ID:35497
- Univ. of Oslo (Norway)
- Wilhelmina Kinderziekenhuis, Utrecht (Netherlands)
- Children`s Hospital, Birmingham (United Kingdom)
- Hacettepe Univ., Ankara (Turkey)
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 G{sup 192} {yields} 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 A{sup 698} {yields} T mutation substituting aspartic acid 233 with valine. A Norwegian patient with an intermediate clinical phenotype was heterozygous for G{sup 786} {yields} 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 G{sup 192} {yields} T. Two other patients were homozygous and one was heterozygous for W262X. 21 refs., 4 figs.
- OSTI ID:
- 35497
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 4 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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