Second-Hit, Postzygotic PMVK and MVD Mutations in Linear Porokeratosis

Abstract

IMPORTANCE Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. OBJECTIVE To identify genetic mutations associated with linear porokeratosis. DESIGN, SETTING, AND PARTICIPANTS Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. INTERVENTIONS OR EXPOSURES Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. MAIN OUTCOMES AND MEASURES Germline and somatic genomic characteristics of participants with linear porokeratosis. RESULTS Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). CONCLUSIONS AND RELEVANCE Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.

Clonal Expansion of Second-Hit Cells with Somatic Recombinations or C>T Transitions Form Porokeratosis in MVD or MVK Mutant Heterozygotes

“…We thus confirmed the recent report of Atzmony et al (2019) showing second hit genetic changes in the skin lesions of patients with LP with monoallelic germline mutations in MVD or MVK. Next, we explored whether second hit genetic changes were evident in the skin lesions of patients with DSAP.…”

“…Congenital heterozygous mutations in genes encoding enzymes of the mevalonate pathway, including MVD and MVK, are responsible for familial and sporadic DSAP and LP Zhang et al, 2015). The coexistence of DSAP and LP in single patients or families suggests that acquired second hit genetic changes in those with monoallelic, pathogenic mutations underlie the development of porokeratosis (Commens and Shumack, 1987;Happle, 1991); such second hit changes were recently identified in the MVD or MVK genes of three patients with LP (Atzmony et al, 2019).…”

Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis

“…Genetic inheritance patterns for enzyme deficiency are typically recessive and the result of "loss-of-function" mutations. Second-hit genetic mosaicism is a rare cause of enzymatic loss of function, and Kubo et al (2019) confirm recent findings that second-hit postzygotic mutations or homologous recombination in mevalonate pathway genes cause the mosaic presentation of porokeratosis-LP (Atzmony et al, 2019). They further show that the autosomal dominant disorder DSAP, which typically presents with lesions later in life also results from second-hit mutations of the remaining wild-type allele.…”

Mutations in KRT10 in epidermolytic acanthoma

“…This study also highlights the difficulties in genetic analysis of mosaic disorders. In contrast to the inherited EHK‐associated dermatoses, wherein germline mutation results in the genetic change being readily detectable in DNA extracted from the blood via Sanger sequencing, genetic changes underlying mosaic disorders are detected only in the lesional tissue itself . Even when lesional tissue is utilized, admixture from neighboring cell types, as well as wild‐type cells of the same lineage, can lead to a low mutant allele fraction that cannot be readily detected via traditional capillary‐based sequencing technologies .…”