Nine novel mutations in the protoporphyrinogen oxidase gene in Swedish families with variegate porphyria

Abstract

Variegate porphyria (VP) is an autosomal-dominant disorder that is caused by inheritance of a partial deficiency of the enzyme protoporphyrinogen oxidase (EC 1.3.3.4). It is characterized by cutaneous photosensitivity and/or various neurological manifestations. Protoporphyrinogen oxidase catalyses the penultimate step of haem biosynthesis, and mutations in the PPOX gene have been coupled to VP. In the present study, sequencing analysis revealed 10 different mutations in the PPOX gene in 14 out of 17 apparently unrelated Swedish VP families. Six of the identified mutations, 3G > A (exon 2), 454C > T (exon 5), 472G > C (exon 6), 614C > T (exon 6), 988G > C (exon 10) and IVS12 + 2T > G (intron 12), are single nucleotide substitutions, while 604delC (exon 6), 916-17delCT (exon 9) and 1330-31delCT (exon 13) are small deletions, and IVS12 + 2-3insT (intron 12) is a small insertion. Only one of these 10 mutations has been reported previously. Three of the mutations were each identified in two or more families, while the remaining mutations were specific for an individual family. In addition to the 10 mutations, one previously unreported single nucleotide polymorphism was identified. Mutation analysis of family members revealed two adults and four children who were silent carriers of the VP trait. Genetic analysis can now be added to the conventional biochemical analyses and used in investigation of putative carriers of a VP trait in these families.

A recurrent mutation in variegate porphyria patients from Chile and Sweden: Evidence for a common genetic background?

“…Interestingly, the same frameshift mutation has been previously described in Swedish VP patients [4]. The carriers showed different clinical symptoms and some were even asymptomatic, suggesting that there is no genotype-phenotype correlation for c.1330_1331delCT.…”

Partial protoporphyrinogen oxidase (PPOX) gene deletions, due to different Alu-mediated mechanisms, identified by MLPA analysis in patients with variegate porphyria

“…The prevalence of VP in Sweden has been estimated to be 1:100 000 and the mutation pattern in fourteen families has been reported [5]. Before the present study a total of 20 different mutations have been found among the Swedish VP patients (unpublished data).…”

“…The patients included in this study belong to five apparently unrelated Swedish families (Figure 1). The genetic analysis, that includes 845 nucleotides of the promoter region and the non-coding exon 1 of the PPOX gene, as well as the biochemical investigations used to identify patients and latent carriers have been previously described [5]. …”

“…The activity of the PPOX enzyme, located in the mitochondrial membrane, is measured in lymphocytes or fibroblasts [4]. Further DNA investigations are usually required in order to easily detect asymptomatic/latent relatives [5]. The detection of carriers is of extreme importance and VP patients or latent carriers, as in all acute porphyrias, shall be encouraged to avoid porphyrogenic agents as e.g.…”

Liver Transplantation in Acute Hepatic Porphyria and Erythropoietic Protoporphyria

“…11 The prevalence of VP also varies between countries 12,13 but is mostly 0.5-1:100,000. [14][15][16] South Africa has a very high prevalence in the population of European origin (3:1000) which is also a consequence of a founder mutation. 17 The worldwide prevalence of HCP is not known.…”