ArticleAmerican journal of human genetics2024
Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.
Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- A Case of Refractory Giant Porokeratosis, Treated With a New Treatment Approach Consisting of Ablative COClinical case reports · 2026Article
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- Dysregulated cholesterol metabolism in genodermatoses: implications for systemic disease and therapeutic strategies.Frontiers in cell and developmental biology · 2026Review
- Genome sequencing provides high diagnostic yield and new etiological insights for intellectual disability and developmental delay.NPJ genomic medicine · 2025Article
- Improved multiancestry fine-mapping identifies cis-regulatory variants underlying molecular traits and disease risk.Nature genetics · 2025Article
- The Role of Somatic Mutation in Hereditary Hemorrhagic Telangiectasia Pathogenesis.Journal of clinical medicine · 2025Review
- Advanced phasing techniques in congenital skin diseases.The Journal of dermatology · 2025Review
- Somatic mutations in arteriovenous malformations in hereditary hemorrhagic telangiectasia support a bi-allelic two-hit mutation mechanism of pathogenesis.American journal of human genetics · 2024Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Article
- Considerations for reporting variants in novel candidate genes identified during clinical genomic testing.bioRxiv : the preprint server for biology · 2024Article
- Eruptive Disseminated Superficial Porokeratosis and Multiple Dermatofibromas in a Patient with Systemic Lupus Erythematosus under Belimumab Therapy: A Case Report.Case reports in dermatologyArticle
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Authors and funding
19 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.
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