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Reduced PPOX expression causes intrinsic pathogenicity in keratinocytes, contributing to the cutaneous Variegate Porphyria phenotype.

Christopher J Smith,Ahmed Al-Salihi,Jack L Williams,L. Chan,L. Metherell

Published 2025 in Journal of Investigative Dermatology

ABSTRACT

Variegate porphyria, caused by monoallelic mutations in protoporphyrinogen oxidase (PPOX), leads to acute visceral attacks and skin photosensitivity, presenting as blistering and fragility; a more severe phenotype occurs with rare biallelic mutations. This results from accumulation of intermediate porphyrins, such as 5'-aminolevulenic acid (5-ALA), near the skin surface, oxidised by sunlight and releasing free radicals. We hypothesise reduced PPOX expression in keratinocytes intrinsically contributes to the porphyria phenotype. We created two shRNA knockdown cell lines, KD1 and KD2 (50 & 25% residual expression), to simulate haploinsufficiency and biallelic hypomorphic expression. Both KD lines showed significantly reduced proliferation, with KD2 also having reduced migration. Keratinocytes were treated with 5-ALA and Deferoxamine (an iron chelator) to accumulate porphyrins, confirmed by increased fluorescent downstream porphyrins, which caused reduced proliferation, oxidative stress, and a lower GSH/GSSG ratio. Both clones expressed reduced differentiation in monolayer and 3D cultures, with KD2 showing reduced epidermal thickness, while porphyrin accumulation further disrupted stratification and differentiation. We propose an updated paradigm of porphyria skin manifestations: porphyrin excitation beneath the skin is facilitated by a thinner, less differentiated barrier. These 3D skin models offer a translational platform to investigate therapeutic strategies targeting porphyrin accumulation and barrier restoration in porphyria.

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