Abstract
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 TVS12 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 typrosinemia type 1.
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Rootwelt, H., Kristensen, T., Berger, R. et al. Tyrosinemia type 1 — complex splicing defects and a missense mutation in the fumarylacetoacetase gene. Hum Genet 94, 235–239 (1994). https://doi.org/10.1007/BF00208276
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DOI: https://doi.org/10.1007/BF00208276