title: Spectrum of mutations in the fumarylacetoacetate hydrolase gene of tyrosinemia type 1 patients in northwestern Europe and Mediterranean countries.
abstract: Hereditary tyrosinemia type 1 (HT1) is a rare metabolic disease caused by a deficient activity of the enzyme fumarylacetoacetase (FAH). To investigate the molecular heterogeneity of tyrosinemia, the geographic distribution and the genotype-phenotype relationship, we have analyzed the FAH genotype of 25 HT1 patients. Mutation screening was performed by PCR amplification of exons 1-14 of the FAH gene, followed by SSCP analysis and direct sequencing of the amplified exons. Fourteen different mutations were found, of which seven were novel, viz. three missense mutations (G158D, P261L, F405H), a deletion of three nucleotides causing a deletion of serine (DEL366S) and three splice site mutations: IVS2+1(g-t), IVS6-1(g-c), IVS8-1(g-c). The splice site mutations IVS6-1(g-t) and IVS12+5(g-a) were frequently found in countries around the Mediterranean and northwestern Europe, respectively. No clear correlation between the genotype and the three major HT1 subtypes could be established.
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, The Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: I E
authors.initials: IE
authors.lastname: van den Berg
authors.forename: W
authors.initials: W
authors.lastname: Brink
authors.forename: B T
authors.initials: BT
authors.lastname: Poll-The
authors.forename: J K
authors.initials: JK
authors.lastname: Ploos van Amstel
authors.forename: R
authors.initials: R
authors.lastname: Berger
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D001483:Base Sequence; D004247:DNA; D005060:Europe / Q000453:epidemiology; D018740:Genetic Heterogeneity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D019083:Mediterranean Region / Q000453:epidemiology; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D014443:Tyrosine / Q000097:blood*
chemical_list: D014443:Tyrosine; D004247:DNA; D006867:Hydrolases; C020156:fumarylacetoacetase