title: Molecular characterization of homozygous variegate porphyria.
abstract: Variegate porphyria (VP) is a low penetrance, autosomal dominant disorder that results from partial deficiency of protoporphyrinogen oxidase (PPOX) activity caused by mutation in the PPOX gene. The rare homozygous variant of VP is characterized by severe PPOX deficiency, onset of photosensitization by porphyrins in early childhood, skeletal abnormalities of the hand and, less constantly, short stature, mental retardation and convulsions. We have identified PPOX mutations on both alleles of five of the 11 unrelated patients with homozygous VP reported to date. Two patients were homoallelic for missense mutations (D349A and A433P), while three were heteroallelic. Functional analysis by prokaryotic expression showed that the D349A and A433P and one missense mutation in each of the three heteroallelic patients (G358R in two patients and A219KANA) preserved some PPOX activity (9.5-25% of wild-type). Mutations on the other allele of the heteroallelic patients abolished or markedly decreased activity. There was no relation between genotype assessed by functional analysis and the presence or severity of non-cutaneous manifestations. The mutations were absent from 104 unrelated patients with autosomal dominant VP. Our findings define the molecular pathology of homozygous VP and suggest that mild PPOX mutations occur in the general population but have very low or no clinical penetrance in heterozygotes.
authors.affiliation: Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Roberts
authors.forename: H
authors.initials: H
authors.lastname: Puy
authors.forename: T A
authors.initials: TA
authors.lastname: Dailey
authors.forename: R R
authors.initials: RR
authors.lastname: Morgan
authors.forename: S D
authors.initials: SD
authors.lastname: Whatley
authors.forename: H A
authors.initials: HA
authors.lastname: Dailey
authors.forename: P
authors.initials: P
authors.lastname: Martasek
authors.forename: Y
authors.initials: Y
authors.lastname: Nordmann
authors.forename: J C
authors.initials: JC
authors.lastname: Deybach
authors.forename: G H
authors.initials: GH
authors.lastname: Elder
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D004247:DNA / Q000032:analysis / Q000235:genetics; D004252:DNA Mutational Analysis; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D005260:Female; D005420:Flavoproteins; D005816:Genetic Complementation Test; D020180:Heteroduplex Analysis; D006720:Homozygote; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins; D009154:Mutation; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011164:Porphyrias / Q000235:genetics*; D050768:Protoporphyrinogen Oxidase; D017384:Sequence Deletion
chemical_list: D005420:Flavoproteins; D024101:Mitochondrial Proteins; D004247:DNA; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C493978:PPOX protein, human; D050768:Protoporphyrinogen Oxidase