R. Rosipal et al., Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update, HUM MUTAT, 13(1), 1999, pp. 44-53
Hereditary coproporphyria (HC) is an acute hepatic porphyria with autosomal
dominant inheritance caused by deficient activity of coproporphyrinogen II
I oxidase (CPO), Clinical manifestations of the disease are characterized b
y acute attacks of neurological dysfunction often precipitated by drugs, fa
sting, cyclical hormonal changes, or infectious diseases. Skin photosensiti
vity may also be present. The seven exons, the exon/intron boundaries and p
art of 3' noncoding sequence of the CPO gene were systematically analyzed b
y an exon-by-exon denaturing gradient gel electrophoresis (DGGE) strategy f
ollowed by direct sequencing in seven unrelated heterozygous MC patients fr
om France, Holland, and Czech Republic. Seven novel mutations and two new p
olymorphisms were detected. Among these mutations: two are missense (G197W,
W427R), two are nonsense (Q306X, Q385X), two are small deletions (662del4b
p; 1168del3bp removing a glycine at position 390), and one is a splicing mu
tation (IVS1-15c-->g) which creates a new acceptor splice site. The patholo
gical significance of the point mutations G197W, W427R, and the in-frame de
letion 390delGly were assessed by their respective expression in a prokaryo
tic 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 prom
otor region, 142 bp upstream from the transcriptional initiation site (-142
C/G), and 2) a 6 bp deletion polymorphism in the 3' noncoding part of the C
PO 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 mut
ations making a total of nineteen CPO gene defects reported so far. Hum Mut
at 13:44-53, 1999, (C) 1999 Wiley-Liss, Inc.