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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.
AuthorsAmr A Shady, Brandon R Colby, Luis F Cunha, Kenneth H Astrin, David F Bishop, Robert J Desnick
JournalBritish journal of haematology (Br J Haematol) Vol. 117 Issue 4 Pg. 980-7 (Jun 2002) ISSN: 0007-1048 [Print] England
PMID12060141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Uroporphyrinogen III Synthetase
Topics
  • Amino Acid Sequence
  • Base Sequence
  • DNA Mutational Analysis
  • Gene Deletion
  • Gene Rearrangement
  • Heterozygote
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Mutation, Missense
  • Porphyria, Erythropoietic (enzymology, genetics)
  • Uroporphyrinogen III Synthetase (genetics, metabolism)

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