A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria - PubMed (original) (raw)
A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria
P N Meissner et al. Nat Genet. 1996 May.
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.
Comment in
- The South African malady.
Jenkins T. Jenkins T. Nat Genet. 1996 May;13(1):7-9. doi: 10.1038/ng0596-7. Nat Genet. 1996. PMID: 8673106 No abstract available.
Similar articles
- Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family.
Corrigall AV, Hift RJ, Hancock V, Meissner D, Davids L, Kirsch RE, Meissner PN. Corrigall AV, et al. Hum Mutat. 1998;12(6):403-7. doi: 10.1002/(SICI)1098-1004(1998)12:6<403::AID-HUMU6>3.0.CO;2-X. Hum Mutat. 1998. PMID: 9829909 - Identification of three mutations and associated haplotypes in the protoporphyrinogen oxidase gene in South African families with variegate porphyria.
Warnich L, Kotze MJ, Groenewald IM, Groenewald JZ, van Brakel MG, van Heerden CJ, de Villiers JN, van de Ven WJ, Schoenmakers EF, Taketani S, Retief AE. Warnich L, et al. Hum Mol Genet. 1996 Jul;5(7):981-4. doi: 10.1093/hmg/5.7.981. Hum Mol Genet. 1996. PMID: 8817334 - Recurrent missense mutation in the protoporphyrinogen oxidase gene underlies variegate porphyria.
Frank J, Jugert FK, Breitkopf C, Goerz G, Merk HF, Christiano AM. Frank J, et al. Am J Med Genet. 1998 Aug 27;79(1):22-6. Am J Med Genet. 1998. PMID: 9738863 - Variegate porphyria.
Kirsch RE, Meissner PN, Hift RJ. Kirsch RE, et al. Semin Liver Dis. 1998;18(1):33-41. doi: 10.1055/s-2007-1007138. Semin Liver Dis. 1998. PMID: 9516676 Review. - Variegate porphyria: identification of a nonsense mutation in the protoporphyrinogen oxidase gene.
Frank J, Jugert FK, Kalka K, Goerz G, Merk HF, Christiano AM. Frank J, et al. J Invest Dermatol. 1998 Apr;110(4):449-51. doi: 10.1046/j.1523-1747.1998.00147.x. J Invest Dermatol. 1998. PMID: 9540990 Review.
Cited by
- Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs.
Balogun O, Nejak-Bowen K. Balogun O, et al. Semin Liver Dis. 2024 May;44(2):209-225. doi: 10.1055/s-0044-1787076. Epub 2024 May 17. Semin Liver Dis. 2024. PMID: 38772406 Free PMC article. Review. - Generation and characterization of human U-2 OS cell lines with the CRISPR/Cas9-edited protoporphyrinogen oxidase IX gene.
Novakova Z, Milosevic M, Kutil Z, Ondrakova M, Havlinova B, Kasparek P, Sandoval-Acuña C, Korandova Z, Truksa J, Vrbacky M, Rohlena J, Barinka C. Novakova Z, et al. Sci Rep. 2022 Oct 12;12(1):17081. doi: 10.1038/s41598-022-21147-x. Sci Rep. 2022. PMID: 36224252 Free PMC article. - Heterologous expression and purification of recombinant human protoporphyrinogen oxidase IX: A comparative study.
Novakova Z, Khuntsaria D, Gresova M, Mikesova J, Havlinova B, Shukla S, Kolarova L, Vesela K, Martasek P, Barinka C. Novakova Z, et al. PLoS One. 2021 Nov 18;16(11):e0259837. doi: 10.1371/journal.pone.0259837. eCollection 2021. PLoS One. 2021. PMID: 34793488 Free PMC article. - Monokaryotic Pleurotus sapidus Strains with Intraspecific Variability of an Alkene Cleaving DyP-Type Peroxidase Activity as a Result of Gene Mutation and Differential Gene Expression.
Krahe NK, Berger RG, Witt M, Zorn H, Omarini AB, Ersoy F. Krahe NK, et al. Int J Mol Sci. 2021 Jan 29;22(3):1363. doi: 10.3390/ijms22031363. Int J Mol Sci. 2021. PMID: 33573012 Free PMC article. - Pitfalls of relying on genetic testing only to diagnose inherited metabolic disorders in non-western populations - 5 cases of pyruvate dehydrogenase deficiency from South Africa.
Meldau S, Fratter C, Bhengu LN, Sergeant K, Khan K, Riordan GT, Berman PAM. Meldau S, et al. Mol Genet Metab Rep. 2020 Jul 22;24:100629. doi: 10.1016/j.ymgmr.2020.100629. eCollection 2020 Sep. Mol Genet Metab Rep. 2020. PMID: 32742935 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases