Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update

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Abstract
Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase (CPO). Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs, fasting, cyclical hormonal changes, or infectious diseases. Skin photosensitivity may also be present. The seven exons, the exon/intron boundaries and part of 3′ noncoding sequence of the CPO gene were systematically analyzed by an exon‐by‐exon denaturing gradient gel electrophoresis (DGGE) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France, Holland, and Czech Republic. Seven novel mutations and two new polymorphisms were detected. Among these mutations: two are missense (G197W, W427R), two are nonsense (Q306X, Q385X), two are small deletions (662del4bp; 1168del3bp removing a glycine at position 390), and one is a splicing mutation (IVS1–15c→g) which creates a new acceptor splice site. The pathological significance of the point mutations G197W, W427R, and the in‐frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site‐directed mutagenesis. These mutations resulted in the absence or a dramatic decrease of CPO activity. The two polymorphisms were localized in noncoding part of the gene: 1) a C/G polymorphism in the promotor region, 142 bp upstream from the transcriptional initiation site (–142C/G), and 2) a 6 bp deletion polymorphism in the 3′ noncoding part of the CPO gene, 574 bp downstream of the last base of the normal termination codon (+574 delATTCTT). Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far. Hum Mutat 13:44–53, 1999.