title: Tyrosinemia type 1--complex splicing defects and a missense mutation in the fumarylacetoacetase gene.
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 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.
authors.affiliation: Institute of Clinical Biochemistry, University of Oslo, Rikshospitalet, Norway.
authors.forename: H
authors.initials: H
authors.lastname: Rootwelt
authors.forename: T
authors.initials: T
authors.lastname: Kristensen
authors.forename: R
authors.initials: R
authors.lastname: Berger
authors.forename: K
authors.initials: K
authors.lastname: Høie
authors.forename: E A
authors.initials: EA
authors.lastname: Kvittingen
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D004587:Electrophoresis, Agar Gel; D005091:Exons; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D014443:Tyrosine / Q000097:blood* / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D014443:Tyrosine; D006867:Hydrolases; C020156:fumarylacetoacetase