title: A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.
abstract: Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.
authors.affiliation: Lennox Eales Porphyria Laboratories, MRC/UCT Liver Research Centre, University of Cape Town Dept. of Medicine, South Africa.
authors.forename: P N
authors.initials: PN
authors.lastname: Meissner
authors.forename: T A
authors.initials: TA
authors.lastname: Dailey
authors.forename: R J
authors.initials: RJ
authors.lastname: Hift
authors.forename: M
authors.initials: M
authors.lastname: Ziman
authors.forename: A V
authors.initials: AV
authors.lastname: Corrigall
authors.forename: A G
authors.initials: AG
authors.lastname: Roberts
authors.forename: D M
authors.initials: DM
authors.lastname: Meissner
authors.forename: R E
authors.initials: RE
authors.lastname: Kirsch
authors.forename: H A
authors.initials: HA
authors.lastname: Dailey
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001412:Bacillus subtilis / Q000201:enzymology; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000097:blood / Q000302:isolation & purification; D017931:DNA Primers; D005260:Female; D005420:Flavoproteins; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D016941:Myxococcus xanthus / Q000201:enzymology; D009426:Netherlands / Q000208:ethnology; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010375:Pedigree; D010920:Placenta / Q000201:enzymology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017094:Porphyrias, Hepatic / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D011247:Pregnancy; D015995:Prevalence; D050768:Protoporphyrinogen Oxidase; D011994:Recombinant Proteins / Q000378:metabolism; D015183:Restriction Mapping; D013019:South Africa / Q000453:epidemiology
chemical_list: D017931:DNA Primers; D005420:Flavoproteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D004247:DNA; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; C493979:Ppox protein, mouse; D050768:Protoporphyrinogen Oxidase