Genetics and Pathobiology of Cutaneous Mosaic Disorders

皮肤马赛克疾病是严重的，罕见的遗传性皮肤疾病出现的模式， 在胚胎发育过程中发生体细胞突变。突变的时间决定了 受影响组织的身份和程度，以及外胚层（角质形成细胞）的贡献， 中胚层（成纤维细胞、皮肤血管）和神经嵴（黑素细胞）至皮肤，一个或多个细胞， 可以影响多种细胞类型。我们已经发现，这种突变的后果可以 严重，如快速生长、治疗无反应的先天性血管瘤， GNA 14突变或皮肤-骨骼低磷血症中的严重骨软化 多谱系体细胞激活RAS突变引起的综合征。下一代测序 为皮肤镶嵌性疾病的基因发现提供了动力，我们已经成功地 发现了这些疾病的几种新的遗传原因。我们现在建议扩大我们的 表型良好的皮肤镶嵌性疾病队列，以筛选潜在的 致病基因，并采用外显子组测序突变未知的主题反射， 对未解决的病例进行基因组测序，以发现新的遗传原因。纳入本 队列为增殖性/错构瘤性疾病，包括先天性筋膜营养不良、痣 粉刺，先天性血管瘤，以及罕见的马赛克介绍常见的 包括痤疮、银屑病、扁平苔藓和盘状红斑狼疮在内的疾病， 提供了一个机会，以确定相关的途径，自身免疫和炎症。我们将 利用患者来源的细胞和组织来询问所鉴定的新基因的功能，以及 将采用转基因组织等同物来研究和证明已鉴定的 如果可能的话。对于有限数量的引人注目的，新的基因， 由于未被认识到与皮肤生物学相关，我们将采用小鼠模型，包括 敲除和CRISPR产生的敲入系，以证明鉴定的突变的发病机制 并提供疾病病理学的初步见解。这些研究将继续确定 表皮分化，自我更新， 和炎症，并将为未来的生物学研究和发展提供关键的背景， 新疗法。

Cutaneous mosaic disorders are severe, rare genetic skin disorders appearing in patterns due to somatic mutation during embryonic development. The timing of mutation determines the identity and extent of affected tissue, and given contributions of ectoderm (keratinocytes), mesoderm (fibroblasts, cutaneous vessels), and neural crest (melanocytes) to the skin, one or multiple cell types can be affected. We have found that consequences of such mutations can be severe as in rapidly-growing, treatment-unresponsive congenital hemangiomas due to GNA14 mutation, or severe osteomalacia in the cutaneous-skeletal hypophosphatemia syndrome due to multi-lineage somatic activating RAS mutations. Next generation sequencing has powered gene discovery in cutaneous mosaic disorders, and we have successfully identified several novel genetic causes of these conditions. We now propose to expand our cohort of well-phenotyped cutaneous mosaic disorders, to screen for mutations in potential causative genes, and to employ exome sequencing in mutation-unknown subjects with reflex to genome sequencing for unsolved cases to discover novel genetic causes. Included in this cohort are proliferative/hamartomatous conditions including congenital fascial dystrophy, nevus comedonicus, and congenital hemangiomas, as well as rare mosaic presentations of common disorders including acne, psoriasis, lichen planus, and discoid lupus erythematosus, which provide an opportunity to identify pathways relevant to autoimmunity and inflammation. We will utilize patient-derived cells and tissue to interrogate the function of identified novel genes, and will employ transgenic tissue equivalents to study and prove pathogenesis of identified mutations when possible. For a limited number of compelling, novel genes previously unrecognized to be relevant to cutaneous biology, we will employ mouse models including knockout and CRISPR-generated knockin lines to prove pathogenesis of identified mutations and to provide initial insights into disease pathobiology. These studies will continue to identify molecular pathways central to the complex processes of epidermal differentiation, self-renewal, and inflammation, and will provide critical context for future biologic studies and development of novel therapeutics.