title: Tyrosinaemia type I--de novo mutation in liver tissue suppressing an inborn splicing defect.
abstract: Many patients with tyrosinaemia type 1 have a mosaic pattern of fumarylacetoacetase (FAH) immunopositive or immunonegative nodules in liver tissue. This phenomenon has been explained by a spontaneous reversion of the mutation in one allele to a normal genotype, but only a few nodules have been examined. We now report on a Norwegian patient, compound heterozygous for the mutations IVS12g(+5)-->a and G(1009-->)A, with liver mosaicism, but with an immunopositive nodule in which both primary mutations were intact. In the immunopositive hepatocytes of this nodule, genetic analyses showed a new mutation, C(1061-->)A, 6 bp upstream of the primary mutation IVS12g(+5)-->a in the FAH gene. The splicing defect caused by the primary mutation is most likely suppressed by the new mutation due to improvement of the splicing site. In the same liver we demonstrate another nodule of regenerating immunopositive tissue due to reversion of one of the primary mutations to a normal genotype. Together with the original cells this makes a triple mosaicism of hepatocytes with one, two or three point mutations in the FAH gene.
authors.affiliation: Institute of Clinical Biochemistry, University of Oslo, 0027 Oslo, Norway.
authors.forename: Y T
authors.initials: YT
authors.lastname: Bliksrud
authors.forename: E
authors.initials: E
authors.lastname: Brodtkorb
authors.forename: P A
authors.initials: PA
authors.lastname: Andresen
authors.forename: I E T
authors.initials: IE
authors.lastname: van den Berg
authors.forename: E A
authors.initials: EA
authors.lastname: Kvittingen
mesh_terms: D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors; D019943:Amino Acid Substitution; D003001:Cloning, Molecular; D003062:Codon; D004252:DNA Mutational Analysis; D005091:Exons; D006801:Humans; D006867:Hydrolases / Q000172:deficiency; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000378:metabolism / Q000601:surgery; D009030:Mosaicism; D009664:Norway; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D017422:Sequence Analysis, DNA; D012694:Serine / Q000378:metabolism; D020176:Tyrosinemias / Q000235:genetics* / Q000378:metabolism
chemical_list: D003062:Codon; D012694:Serine; D006867:Hydrolases; C020156:fumarylacetoacetase