The assessment of noncoding variant of PPOX gene in variegate porphyria reveals post-transcriptional role of the 5′ untranslated exon 1

The PPOX gene encodes for the protoporphyrinogen oxidase, which is involved in heme production. The partial deficiency of protoporphyrinogen oxidase causes variegate porphyria. The tissue-specific regulation of other heme biosynthetic enzymes is extensively studied, but the information concerning transcriptional and post-transcriptional regulation of PPOX gene expression is scarcely available. In this study, we characterized functions of three variants identified in the regulatory regions of the PPOX gene, which show a novel role for the 5′ untranslated exon 1. Using luciferase assays and RNA analysis, we demonstrated that only c.1-883G > C promoter variant causes a significant loss in the transcriptional activity of PPOX gene whereas c.1-413G > T 5′ UTR variant inhibits translation of PPOX mRNA and c.1-176G > A splicing variant causes 4 bp deletion in 5′ UTR of PPOX mRNA variant 2. These observations indicate that the regulation of PPOX gene expression can also occur through a post-transcriptional modulation of the amount of gene product and that this modulation can be mediated by 5′ untranslated exon 1. Moreover this study confirms that these regulatory regions represent an important molecular target for the pathogenesis of variegate porphyria.