We have found that the probability of the privileged conformations of hPPO can be correlated very well with the k(cat)/K(m) of PPO (correlation coefficient, R(2) > 0.9), and the catalytic activity of 44 clinically reported VP-causing mutants can be accurately predicted.
These results reinforce the importance of molecular genetic analysis for VP diagnosis and especially the usefulness of prokaryotic expression of missense mutations to assess their deleterious effect on PPOX activity.MM and BXG contributed equally to the publication.RES and MVR share senior authorship.
A partial deficiency in Protoporphyrinogen oxidase (PPOX) produces the mixed disorder Variegate Porphyria (VP), the second acute porphyria more frequent in Argentina.
Using polymerase chain reaction-based techniques we identified a missense mutation in exon 7 on the paternal allele and a frameshift mutation in exon 13 on the maternal allele of the protoporphyrinogen oxidase gene that harbours the mutations underlying VP.
Variegate porphyria is an autosomal dominant disorder of heme metabolism resulting from a deficiency in protoporphyrinogen oxidase, an enzyme located on the inner mitochondrial membrane.
Variegate porphyria (VP), also known as South African porphyria, is a low-penetrance, autosomal dominant disorder as the result of a partial deficiency of protoporphyrinogen oxidase (PPOX).
The effects of various protoporphyrinogen oxidase (PPOX) mutations responsible for variegate porphyria (VP), the roles of the arginine-59 residue and the glycines in the conserved flavin binding site, in catalysis and/or cofactor binding, were examined.
Two new mutations that predicted amino acid substitutions with significant effects on enzyme function were detected in conserved regions of the protoporphyrinogen oxidase gene in one Aboriginal variegate porphyria patient and the possible fourth case.
Identification of the first variegate porphyria mutation in an indigenous black South African and further evidence for heterogeneity in variegate porphyria.
Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder characterized clinically by skin lesions and acute neurovisceral attacks that occur separately or together.
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.