Keratinocyte differentiation is a tightly controlled process that is essential for survival. The mevalonate/isoprenoid biosynthesis pathway has a central role in protein isoprenylation as well as in cholesterol synthesis by the epidermis, contributing to the processes of terminal differentiation and barrier formation in the skin. Disseminated superficial actinic porokeratosis (DSAP) is the most common form of porokeratosis, a group of inherited keratinization disorders characterized by lesions containing hyperkeratotic ridges that correlate histopathologically with the presence of a cornoid lamella. Several causal DSAP mutations have previously been identified in members of the mevalonate pathway, including mevalonate kinase (MVK). In this study, a 50 year old woman with a 15-year history of non-pruritic 3-5 mm pink papules with scaly rims on her arms and legs presented to the clinic. The diagnosis of DSAP was made based upon family history, characteristic clinical appearance of the lesions, and histologic findings on skin biopsy. Sanger sequencing of the MVK exons was performed on genomic DNA extracted from a paraffin-embedded biopsy specimen. A novel heterozygous missense mutation was identified in exon 5 (c.455:G>A), resulting in the substitution of tyrosine for cysteine (p.C152Y) in a predicted functional domain of the MVK enzyme. Impaired keratinocyte differentiation and apoptosis and defective sterol-mediated barrier formation resulting from mevalonate pathway mutations can account for the clinical DSAP phenotype.
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