Human Molecular Genetics, Vol 7, 1921-1925, Copyright © 1998 by Oxford University Press
AG Roberts, H Puy, TA Dailey, RR Morgan, SD Whatley, HA Dailey, P Martasek, Y Nordmann, JC Deybach and GH Elder
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.
ARTICLES
Molecular characterization of homozygous variegate porphyria
Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
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