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A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria.

Abstract
Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by a deficient activity of coproporphyrinogen IX oxidase (CPX). We previously described harderoporphyria, a homozygous variant form of coproporphyria in three siblings, characterized by a massive excretion of harderoporphyrin and a marked decrease of coproporphyrinogen IX oxidase activity. In this kindred, the transmission of the disease was autosomal recessive. In the present study, sequencing of cDNA and genomic DNA from these patients revealed a point mutation resulting in a lysine to glutamic acid substitution (K304E) in exon 6 of the gene and the absence of the normal allele, suggesting a homozygous state for the mutation. Expression studies of normal and mutated cDNAs in E. coli demonstrated that this amino acid substitution was responsible for the important decrease in the enzyme activity and for the accumulation of harderoporphyrin. The Michaelis constant of the mutated enzyme was 10-fold higher than normal suggesting that the lysine at position 304 is important for binding the substrate: a slightly increased sensitivity to thermal denaturation was also observed.
AuthorsJ Lamoril, P Martasek, J C Deybach, V Da Silva, B Grandchamp, Y Nordmann
JournalHuman molecular genetics (Hum Mol Genet) Vol. 4 Issue 2 Pg. 275-8 (Feb 1995) ISSN: 0964-6906 [Print] England
PMID7757079 (Publication Type: Journal Article)
Chemical References
  • DNA, Complementary
  • Coproporphyrinogen Oxidase
Topics
  • Amino Acid Sequence
  • Base Sequence
  • Coproporphyrinogen Oxidase (genetics)
  • DNA, Complementary
  • Escherichia coli (genetics)
  • Family Health
  • Female
  • Gene Expression
  • Genetic Variation
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Porphyrias, Hepatic (etiology, genetics)

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