A molecular defect in coproporphyrinogen oxidase gene causing harderoporphyria, a variant form of hereditary coproporphyria |
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Authors: | Lamoril Jerome; Martasek Pavel; Deybach Jean-Charles; Silva Vasco Da; Grandchamp Bernard; Nordmann Yves |
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Institution: | Centre Français des Porphyries, INSERM U.409, Hopital Louis Mourier 92701 Colombes cedex
1Laboratoire de Génétique Moléculaire, INSERM U409, Faculté de Médecine X.Bichat, Université Paris 7 75018 Paris, France |
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Abstract: | Hereditary coproporphyria (HC) is an acute hepatic porphyriawith autosomal dominant inheritance caused by a deficient activityof coproporphyrinogen IX oxidase (CPX). We previously describedhardero-porphyria, a homozygous variant form of coproporphyriain three siblings, characterized by a massive excretion of harderoporphyrinand a marked decrease of coproporphyrinogen IX oxidase activity.In this kindred, the transmission of the disease was autosomalrecessive. In the present study, sequencing of cDNA and genomicDNA from these patients revealed a point mutation resultingin a lysine to glutamic acid substitution (K304E) in exon 6of the gene and the absence of the normal allele, suggestinga homozygous state for the mutation. Expression studies of normaland mutated cDNAs in E.coll demonstrated that this amino acidsubstitution was responsible for the important decrease in theenzyme activity and for the accumulation of harderoporphyrin.The Michaelis constant of the mutated enzyme was 10-fold higherthan normal suggesting that the lysine at position 304 is importantfor binding the substrate: a slightly increased sensitivityto thermal denaturation was also observed. |
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