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.

Two deletion mutations in the hydroxymethylbilane synthase gene in two unrelated Japanese patients with acute intermittent porphyria

“…Recently, this mutation has been documented as the first mutation in AIP associated with a founder effect in North America with the identified founding couple (Greene-Davis et al 1997). Such a founder effect has been well documented in variegate porphyria, the other form of acute porphyria (Dean 1971;Meissner et al 1996;Warnich et al 1996;Groenewald et al 1998), and has also been observed in other AIP patients (De Siervi et al 1999). The other mutation in Japan, reported by Morita et al (1995), is a single base substitution C-to-T in exon 8 of the gene, which was the same as a common mutation in the Netherlands (Gu et al 1994).…”

Clinical, Biochemical and Molecular Characteristics of the Main Types of Porphyria

“…VP mutations also show high heterogeneity with the exception of founder effect mutations e.g. mutation R5 9W in South Africa [7,19].…”

“…AIP prevalence in Argentina is about 1/125 000 inhabitants [6]. VP is most frequently reported in South African Republic (1/300 inhabitants) due to founder effect [7]. VP prevalence in Finland is estimated at 2/100 000 inhabitants [8]; in Argentina at 1/600 000 [6].…”

Multiplex ligation-dependent probe amplification: a novel approach for genetic diagnosis of Porphyria

“…6 Genetic analysis would be the only reliable tool to establish a correct diagnosis of Porphyria even though the high genetic heterogeneity makes this approach difficult. Although restricted geographic areas seem to have a high prevalence of specific molecular abnormality, 7 most of the reported mutations have been detected in a single case or a family. [8][9][10] Moreover, approximately 10% of porphyria cases remain devoid of molecular diagnosis.…”