Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of Tyrosinemia Type I
Journal Article
·
· American Journal of Human Genetics
OSTI ID:56723
- Univ. of Oslo (Norway)
In healthy individuals, fumarylacetoacetase (FAH) activities close to the range found in hereditary tyrosinemia type 1 (HT1) patients indicated the existence of a pseudodeficiency allele. In an individual homozygous for pseudodeficiency of FAH and in three HT1 families also carrying the pseudodeficiency allele, western blotting of fibroblast extracts showed that the pseudodeficiency allele gave very little immunoreactive FAH protein, whereas northern analysis revealed a normal amount of FAH mRNA. Sequencing revealed an identical mutation, C{sup 1021} {yields} T (Arg341Trp), in all the pseudodeficiency alleles. Site-directed mutagenesis and expression in rabbit reticulocyte lysate system demonstrated that the C{sup 1021} {yields} T mutation gave reduced FAH activity and reduced amounts of the full-length protein. BsiEI restriction digestion of PCR products distinguished between the normal and the mutated sequences. Among 516 healthy volunteers of Norwegian origin, the C{sup 1021} {yields} T mutation was found in 2.2% of the alleles. Testing for the C{sup 1021} {yields} T mutation may solve the problem of prenatal diagnosis and carrier detection in families with compound heterozygote genotypes for HT1 and pseudodeficiency.
- OSTI ID:
- 56723
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: 6 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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