角化病是一种克隆性角化病,其特征是孤立的,线性排列,或一般分布多个皮肤病变。先前的研究表明,MVK的遗传改变,PMVK,MVD,或甲羟戊酸途径中的FDPS基因引起遗传性汗孔角化病,皮肤病变在相反的等位基因上具有种系和病变特异性体细胞变异。这里,我们确定了与甲羟戊酸途径中另一个基因FDFT1表观遗传沉默相关的非遗传性孔角化病.广义型皮肤病变在FDFT1的相反等位基因上具有种系和病变特异性体细胞变异,代表了本研究中确定的FDFT1相关遗传性角化病。相反,单发或线性排列的局部形式的病变具有体细胞双等位基因启动子超甲基化或单等位基因启动子超甲基化,并在FDFT1的相反等位基因上发生体细胞遗传改变,表明非遗传性角化症.FDFT1定位在病灶内均匀减少,和病变来源的角质形成细胞显示对细胞生长的胆固醇依赖性和与细胞周期和表皮发育相关的基因表达的改变,证实通过FDFT1缺陷的角质形成细胞的克隆扩增形成病变。在一些具有本地化形式的个体中,FDFT1的基因特异性启动子超甲基化在与甲基化相关病变相邻但不在这些病变远端的形态正常表皮中检测到,这表明FDFT1的无症状体细胞表观遗传镶嵌使某些皮肤区域易于患病。最后,与其遗传病因一致,局部他汀类药物治疗可改善FDFT1缺陷性孔角化病的病变.总之,我们确定了FDFT1的双等位基因遗传和/或表观遗传改变是孔角化病的原因,并阐明了皮肤镶嵌症的发病机制,该机制涉及表观遗传改变细胞的克隆扩增.
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.