Hereditary tyrosinemia type 1: Identification of nonsense, missense and splicesite mutations of the FAH gene
- Wilhelmina Children`s Hospital, Utrecht (Netherlands); and others
Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disease due to deficiency of the enzyme fumarylacetoacetase (FAH). The FAH gene has a length of 35 kb and contains 14 exons that encode an mRNA of 1400 nt. To get more insight into the molecular basis of the disorder, probands of nine unrelated HT1 families were screened for abnormalities in the FAH gene using PCR. SSCP analysis and direct sequencing of the amplified exons revealed 7 different mutations. Three mutations involve splice consensus sites viz. IVS6-1(g-a)(identified 4x), IVS7-1(del g)(2x) and IVS12+5(g-a)(7x). Analysis of the FAH mRNA by RT-PCR for the effect of these mutations showed a 1 nt frameshift for IVS7-1 and the skipping of exon 12 for IVS12+5. The IVS6-1 transition results in three different mRNAs: all three transcripts missed the first 5 nt of exon 7; one transcript showed in addition a 13 nt deletion in exon 8. Two nonsense mutations were identified viz. E357X(1x) and E364X (2x); both mutations result in a reduced level of FAH mRNA. One missense mutation has been found C193R(1x). A silent mutation N232N(1x) was detected in association with the skipping of exon 8. The data reveal a founder effect for several of the FAH mutations. Furthermore, they indicated the molecular heterogeneity of HT1.
- OSTI ID:
- 134283
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-1016
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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