title: Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene.
abstract: Mutations in the uroporphyrinogen III synthase (URO-synthase) gene cause congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of haem biosynthesis. Molecular analysis of the URO-synthase gene in seven unrelated CEP patients revealed eight novel mutations. These included four missense mutations (A69T, E81D, G188W and I219S), a deletion (21delG), two insertions (398insG and 672ins28) and one complex mutation (627del6ins39), as well as three previously reported mutations, C73R, T228M, and -86C-->A. When the four novel missense mutations were expressed in Escherichia coli, only E81D expressed significant enzymatic activity (30% of expressed wild-type activity), which was thermolabile. In addition, reverse transcription polymerase chain reaction studies demonstrated that E81D, which altered the penultimate nucleotide in exon 4, impaired splicing and caused about 85% exon 4 skipping. The identification and expression of these mutations provided genotype-phenotype correlations and further evidence of the molecular heterogeneity underlying this erythropoietic porphyria.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York University, Fifth Avenue at 100th Street, New York, NY 10029, USA.
authors.forename: Amr A
authors.initials: AA
authors.lastname: Shady
authors.forename: Brandon R
authors.initials: BR
authors.lastname: Colby
authors.forename: Luis F
authors.initials: LF
authors.lastname: Cunha
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Astrin
authors.forename: David F
authors.initials: DF
authors.lastname: Bishop
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D015321:Gene Rearrangement; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D017092:Porphyria, Erythropoietic / Q000201:enzymology / Q000235:genetics*; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics* / Q000378:metabolism
chemical_list: D014576:Uroporphyrinogen III Synthetase