Tyrosinemia type 1 ? complex splicing defects and a missense mutation in the fumarylacetoacetase gene
| Autor: | Kari Høie, Ruud Berger, E A Kvittingen, Helge Rootwelt, Tom Kristensen |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Hydrolases RNA Splicing Molecular Sequence Data Biology Polymerase Chain Reaction Exon Genetics Humans Point Mutation Missense mutation RNA Messenger Child Amino Acid Metabolism Inborn Errors Genetics (clinical) DNA Primers Electrophoresis Agar Gel Splice site mutation Base Sequence Point mutation Alternative splicing Intron Infant Exons Molecular biology Child Preschool Mutation (genetic algorithm) RNA splicing Tyrosine Female |
| Zdroj: | Human Genetics. 94 |
| ISSN: | 1432-1203 0340-6717 |
| DOI: | 10.1007/bf00208276 |
| Popis: | Two mutations are reported in six tyrosinemia type 1 patients from northern Europe. In four patients, a G to A transition at nucleotide position 1009 (G1009--A) of the fumarylacetoacetase (FAH) coding sequence caused aberrant splicing by introducing an acceptor splice site within exon 12, thereby deleting the first 50 nucleotides of this exon. The following exon-intron boundary was frequently missed, and a cryptic donor splice site within intron 12 caused a partial intron 12 retention of 105 bp. This point mutation alternatively gave a glycine 337 to serine substitution in instances of correct splicing. The mutation is rapidly detected by PvuII digestion of polymerase chain reaction (PCR)-amplified genomic DNA. Another mutation, g+5--a in the intron 12 donor splice site consensus sequence (IVS12 g+5--a), was found in five of the patients. This caused alternative splicing with retention of the first 105 nucleotides of intron 12, exon 12 skipping, and a combined deletion of exons 12 and 13. Rapid detection of this mutation is achieved by restriction digestion of PCR-amplified genomic DNA; a mismatch primer combined with the point mutation creates a Tru9I restriction site. One patient who was homozygous for the G1009--A mutation had a chronic form of tyrosinemia. Three patients were combined heterozygotes for G1009--A and IVS12 g+5--a. Their clinical phenotypes varied from acute to chronic, indicating the impact of background genes and/or external factors on the presentation of tyrosinemia type 1. |
| Databáze: | OpenAIRE |
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