Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria

Introduction: Variegate porphyria (VP; OMIM 176200) is one of the acute hepatic porphyrias, and it is characterized by the partial deficiency of protoporphyrinogen oxidase (PPDX). The unusual homozygous variant with mutations on both alleles of PPDX is distinguished with general heterozygous VP by several typical points such as severe defect in PPDX enzyme activity, early onset of photosensitivity before puberty, and skeletal deformity. Material and method: In this study, we describe a very rare case of autosomal recessive form of true homozygous VP found in a Chinese patient with consanguineous parents. Sanger sequencing of the PPDX gene showed a novel homozygous variant located at the first base of exon 8 of the gene, i.e., NM_000309.3c.808G > T. To investigate aberrant splicing induced by the mutant, wild-type exon 8 and mutant exon 8 were expressed in pET01 vector as minigene in cultured-cells and analyzed by RT-PCR. Results: The wildtype PPDX showed an expected band in the gel electrophoresis after RT-PCR. The PPDX c.808G > T only showed a band similar to the band size of the vector only control. This result suggested c.808G > T mutant is an exonic mutation inducing aberrant splicing of pre-mRNA of the PPDX gene. Conclusion: This study showed a very rare case of homozygous VP with autosomal recessive homoallelic pattern. In comparison with previous cases of homozygous VP presenting brachydactyly, it is notable that our patient did not have any skeletal deformities.

Automated summary

This study described a very rare case of true homozygous variegate porphyria in a Chinese patient, with a novel homozygous variant identified in the PPDX gene through sequencing. Analysis of aberrant splicing induced by the mutation showed that the variant led to abnormal splicing of pre-mRNA of the PPDX gene. Comparing with previous cases, this patient did not have any skeletal deformities typically associated with homozygous variegate porphyria.