Saito Sonoko, Saito Yuki, Sato Showbu, Aoki Satomi, Fujita Harumi, Ito Yoshihiro, Ono Noriko, Funakoshi Takeru, Kawai Tomoko, Suzuki Hisato, Sasaki Takashi, Tanaka Tomoyo, Inoie Masukazu, Hata Kenichiro, Kataoka Keisuke, Kosaki Kenjiro, Amagai Masayuki, Nakabayashi Kazuhiko, Kubo Akiharu
Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Gastroenterology, Keio University School of Medicine, Tokyo 160-8582, Japan; Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Am J Hum Genet. 2024 May 2;111(5):896-912. doi: 10.1016/j.ajhg.2024.03.017. Epub 2024 Apr 22.
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.
汗孔角化症是一种克隆性角化障碍性疾病，其特征为单发、呈线状排列或广泛分布的多发性皮肤损害。既往研究表明，甲羟戊酸途径中的MVK、PMVK、MVD或FDPS基因的遗传改变可导致遗传性汗孔角化症，皮肤损害在相对的等位基因上存在种系和损害特异性体细胞变异。在此，我们鉴定出与甲羟戊酸途径中的另一个基因FDFT1的表观遗传沉默相关的非遗传性汗孔角化症。泛发型的皮肤损害在FDFT1的相对等位基因上存在种系和损害特异性体细胞变异，代表了本研究中鉴定出的与FDFT1相关的遗传性汗孔角化症。相反，单发或线状排列的局限性损害在FDFT1中存在体细胞双等位基因启动子高甲基化或单等位基因启动子高甲基化，并在相对的等位基因上存在体细胞遗传改变，提示为非遗传性汗孔角化症。FDFT1在损害内的定位均一性降低，且损害来源的角质形成细胞显示细胞生长依赖胆固醇，且与细胞周期和表皮发育相关的基因表达改变，证实损害是由FDFT1缺陷的角质形成细胞的克隆性扩增形成的。在一些局限性损害的个体中，在与甲基化相关损害相邻但非这些损害远端的形态学正常表皮中检测到FDFT1的基因特异性启动子高甲基化，提示FDFT1无症状的体细胞表观遗传镶嵌现象使某些皮肤区域易患该病。最后，与其遗传病因一致，局部使用他汀类药物治疗可改善FDFT1缺陷型汗孔角化症的损害。总之，我们鉴定出FDFT1的双等位基因遗传和/或表观遗传改变是汗孔角化症的病因，并阐明了涉及表观遗传改变细胞克隆性扩增的皮肤镶嵌现象的发病机制。
