title: Overrepresentation of the founder PPOX gene mutation R59W in a South African patient with severe clinical manifestation of porphyria.
abstract: A patient, who presented with abdominal pain and severe photosensitivity that resulted in scarring and mutilation of the fingers, nose and ears, was referred for biochemical assessment of porphyria and DNA screening. Although these clinical manifestations were suggestive of both acute porphyria and congenital erythropoietic porphyria, the biochemical profile was consistent with variegate porphyria (VP). Analysis of the protoporphyrinogen oxidase (PPOX) gene underlying VP resulted in the identification of the founder mutation R59W in a heterozygous state in this patient. Despite extensive mutation analysis, no other potential disease-causing genetic alterations could be detected in the PPOX gene or the uroporphyrinogen III synthase gene. Slight overrepresentation of the mutant PPOX allele was however, observed repeatedly in DNA of the proband compared to other R59W heterozygotes, including his mother who also tested positive for mutation R59W using restriction enzyme analysis and direct DNA sequencing. Confirmation of this phenomenon by real-time polymerase chain reaction analysis and microsatellite analysis, using highly informative markers flanking the PPOX gene, raised the possibility of partial homozygosity for VP in this patient. This study represents the first report of overrepresentation of mutation R59W in a patient with a severe form of VP. A homozygote for the R59W mutation has never been detected, and the severe clinical manifestation observed in our patient is consistent with the hypothesis that such a genotype will not be compatible with life.
authors.affiliation: Division of Human Genetics, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: J Nico P
authors.initials: JN
authors.lastname: de Villiers
authors.forename: Maritha J
authors.initials: MJ
authors.lastname: Kotze
authors.forename: Carel J
authors.initials: CJ
authors.lastname: van Heerden
authors.forename: Annalene
authors.initials: A
authors.lastname: Sadie
authors.forename: Helena F J
authors.initials: HF
authors.lastname: Gardner
authors.forename: Juanita
authors.initials: J
authors.lastname: Liebenberg
authors.forename: René
authors.initials: R
authors.lastname: van Zyl
authors.forename: Lana
authors.initials: L
authors.lastname: du Plessis
authors.forename: Matti
authors.initials: M
authors.lastname: Kimberg
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.forename: Louise
authors.initials: L
authors.lastname: Warnich
mesh_terms: D001483:Base Sequence; D004247:DNA / Q000737:chemistry; D005192:Family Health; D005420:Flavoproteins; D018703:Founder Effect; D020440:Gene Duplication; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D024101:Mitochondrial Proteins; D009030:Mosaicism; D020125:Mutation, Missense / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D046350:Porphyria, Variegate / Q000097:blood / Q000175:diagnosis / Q000235:genetics; D011164:Porphyrias / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D050768:Protoporphyrinogen Oxidase; D013019:South Africa; D044366:Transition Temperature; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D004247:DNA; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase; D014576:Uroporphyrinogen III Synthetase