Molecular characterization of Porokeratosis in Tunisian patients with intraindividual and intrafamilial clinical heterogeneity

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Abstract Background Porokeratosis (PK) is a group of rare acquired or inherited clonal keratinization disorders characterized by annular or linear hyperkeratotic plaques with central atrophy and raised borders. Cornoid lamella is the common histological feature between PK forms. Genes of the mevalonate pathway are implicated in the pathogenesis of this pathology. To date, the exact underlying molecular mechanisms remain misunderstood. Results In this study, we investigated two unrelated Tunisian families with heterogeneous PK for whom we reported a clinical heterogeneity with a simultaneous presence of three clinical forms of PK in two individuals. We identified two PMVK variants, nonsense and synonymous, in affected individuals and unaffected relatives. We suggest that the PK profiles of our Tunisian patients result from the germline nonsense mutation c.412A > T (p.R138*) responsible for the haploinsufficiency of the PMVK protein via the degradation of the mutant mRNA by the nonsense-mediated mRNA decay (NMD) mechanism and d a second hit postzygotic mutation in skin lesions. We suggest that the synonymous variant c.147A > G (p.E49=) could be a genetic predisposition factor increasing the susceptibility to the second hit mutation in the PMVK gene or another gene. Conclusion We report the first molecular characterization of PK within the Tunisian and North African populations. Our findings support the common molecular background of different clinical subtypes of PK and the fact that they can be considered a single disorder.

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