Variegate porphyria in western Europe: Identification of PPOX gene mutations in 104 families, extent of allelic heterogeneity, and absence of correlation between phenotype and type of mutation

Variegate porphyria (VP) is a low-penetrance, autosomal dominant disorder c haracterized clinically by skin lesions and acute neurovisceral attacks tha t occur separately or together. It results from partial deficiency of proto porphyrinogen oxidase encoded by the PPOX gene. VP is relatively common in South Africa, where most patients have inherited the same mutation in the P POX gene from a common ancestor, but few families from elsewhere have been studied. Here we describe the molecular basis and clinical features of 108 unrelated patients from France and the United Kingdom. Mutations in the PPO X gene were identified by a combination of screening (denaturing gradient g el electrophoresis, heteroduplex analysis, or denaturing high-performance l iquid chromatography) and direct automated sequencing of amplified genomic DNA. A total of GO novel and 6 previously reported mutations (25 missense, 24 frameshift, 10 splice site, and 7 nonsense) were identified in 104 (96%) of these unrelated patients, together with 3 previously unrecognized singl e-nucleotide polymorphisms. VP is less heterogeneous than other acute porph yrias; 5 mutations were present in 28 (26%) of the families, whereas 47 mut ations were restricted to 1 family; only 2 mutations were found in both cou ntries. The pattern of clinical presentation was identical to that reported from South Africa and was not influenced by type of mutation. Our results define the molecular genetics of VP in western Europe, demonstrate its alle lic heterogeneity outside South Africa, and show that genotype is not a sig nificant determinant of mode of presentation.