title: Haplotype analysis excludes the functional protoporphyrinogen oxidase promoter polymorphism -1081G>A as a modifying factor in the clinical expression of variegate porphyria.
abstract: Variegate porphyria (VP) is caused by the founder-type protoporphyrinogen oxidase (PPOX) gene mutation R59W in the majority of South African patients. VP is inherited as an autosomal dominant disease with incomplete penetrance and no genotype-phenotype association has been established to date. In an attempt to determine whether a relatively common mutation in the promoter region of the gene (-1081G>A) represents a low-expression allele that may influence clinical manifestation of the disease when inherited from the non-carrier (R59W-negative) parent, we have studied the effect of the mutated allele using an in vitro luciferase assay. Haplotype analysis was furthermore used to evaluate the added information obtained by considering the possible influence of this mutation in combination with a polymorphism in intron 2 (206G>C) of the gene in a genotype-phenotype correlation study. Although the mutation at nucleotide -1081 resulted in a significant reduction in transcriptional activity relative to the reference wild type, no evidence could be obtained that a specific haplotype inherited from the normal parent affects clinical expression of the disease. We thus conclude that other factors such as modifier loci unrelated to the PPOX gene may determine clinical manifestation of VP.
authors.affiliation: Department of Genetics, University of Stellenbosch, Matieland Stellenbosch, South Africa. lw@sun.ac.za
authors.forename: Louise
authors.initials: L
authors.lastname: Warnich
authors.forename: Matti
authors.initials: M
authors.lastname: Kimberg
authors.forename: Maritha J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohashi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Taketani
authors.forename: Bill J H
authors.initials: BJ
authors.lastname: Louw
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005192:Family Health; D005420:Flavoproteins; D015870:Gene Expression / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000235:genetics; D024101:Mitochondrial Proteins; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017094:Porphyrias, Hepatic / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050768:Protoporphyrinogen Oxidase; D013019:South Africa; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D008156:Luciferases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase