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Congenital erythropoietic porphyria: identification and expression of eight novel mutations in the uroporphyrinogen III synthase gene
Author(s) -
Shady Amr A.,
Colby Brandon R.,
Cunha Luis F.,
Astrin Kenneth H.,
Bishop David F.,
Desnick Robert J.
Publication year - 2002
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1046/j.1365-2141.2002.03558.x
Subject(s) - missense mutation , biology , porphyria , exon , microbiology and biotechnology , genetics , thermolabile , gene , uroporphyrinogen iii decarboxylase , mutation , enzyme , biochemistry , endocrinology , heme
Summary. 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.