Genetics and Pathobiology of Cutaneous Mosaic Disorders

皮肤马赛克疾病的遗传学和病理学

基本信息

批准号：
10376195
负责人：
KEITH A CHOATE
金额：
$ 55.53万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376195
关键词：
Acne Affect Autoimmunity Biochemical Biological Biological Assay Biology Biopsy Blood Candidate Disease Gene Cell Proliferation Cells Childhood Clustered Regularly Interspaced Short Palindromic Repeats Complex Congenital Hemangioma Cutaneous DNA Dermatology Dermatopathology Development Discoid Lupus Erythematosus Disease Ectoderm Embryo Embryonic Development Enrollment Epidermal nevus Epidermis Epithelial Etiology Fibroblast Growth Factor Receptors Fibroblasts Future GNA14 gene Generations Genes Genetic Genetic study Hairy Nevus Hypophosphatemia In Vitro Inflammation Inflammatory Investigation Knock-in Knock-out Knockout Mice Lichen Planus Linear sebaceous nevus sequence Lupus Medical Records Mesoderm Modeling Molecular Mosaicism Mutation Neural Crest Nevus Normal tissue morphology Osteomalacia Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Physiology Preparation Process Proteins Psoriasis Public Health Rare Diseases Reflex action Resources Saliva Sampling Site Skin Somatic Mutation Syndrome Tissues Transgenic Organisms Variant Vitiligo Work biomedical referral center cell type cohort cost disease phenotype exome sequencing experimental study gain of function gene discovery genetic disorder diagnosis genetic technology genetically modified cells genome editing genome sequencing genomic locus in vivo Model insight keratinocyte loss of function melanocyte mouse model mutation screening new therapeutic target next generation sequencing novel novel therapeutics progenitor reconstitution screening screening panel self-renewal skeletal skin disorder therapeutic target tissue archive treatment response viral gene delivery

项目摘要

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.

皮肤马赛克病是一种严重的、罕见的遗传性皮肤病，其出现的模式是由于胚胎发育过程中体细胞突变。突变的时间决定了受影响组织的身份和范围，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）到皮肤，一种或多种多种细胞类型可能受到影响。我们发现这种突变的后果可以严重如因快速生长、治疗无反应的先天性血管瘤 GNA14 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。下一代测序推动了皮肤镶嵌疾病的基因发现，我们已经成功确定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疾病队列，以筛选潜在的突变致病基因，并在突变未知的受试者中采用外显子组测序，以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。包含在这个队列是增殖性/错构瘤病症，包括先天性筋膜营养不良、痣粉刺和先天性血管瘤，以及常见的罕见马赛克表现包括痤疮、牛皮癣、扁平苔藓和盘状红斑狼疮在内的疾病提供了一个机会来确定与自身免疫和炎症相关的途径。我们将利用患者来源的细胞和组织来询问已识别的新基因的功能，以及将采用转基因组织等效物来研究和证明已识别的发病机制可能的话进行突变。对于之前有限数量的引人注目的新颖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 生成的敲入系以证明已识别突变的发病机制并提供对疾病病理学的初步见解。这些研究将继续确定分子途径对于表皮分化、自我更新、和炎症，并将为未来的生物学研究和开发提供重要背景新疗法。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.

POFUT1 功能丧失突变在以节段性色素沉着伴湿疹和毛囊中心病变为特征的疾病中的表型扩展。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Atzmony, Lihi;Zaki, Theodore D;Antaya, Richard J;Choate, Keith A
通讯作者：
Choate, Keith A

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

线性汗孔角化症的第二次打击、合子后 PMVK 和 MVD 突变。

DOI：
发表时间：
2019
期刊：
影响因子：
10.9
作者：
Atzmony, Lihi;Khan, Habib M;Lim, Young H;Paller, Amy S;Levinsohn, Jonathan L;Holland, Kristen E;Mirza, Fatima Nadeem;Yin, Emily;Ko, Christine J;Leventhal, Jonathan S;Choate, Keith A
通讯作者：
Choate, Keith A

Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.

合子后 ACTB 突变是先天性平滑肌错构瘤的基础。

DOI：
发表时间：
2020-08
期刊：
影响因子：
1.7
作者：
Atzmony, Lihi;Ugwu, Nelson;Zaki, Theodore D;Antaya, Richard J;Choate, Keith A
通讯作者：
Choate, Keith A

Topical trametinib for epidermal and sebaceous nevi in a child with Schimmelpenning-Feuerstein-Mims syndrome.

局部曲美替尼治疗患有 Schimmelpenning-Feuerstein-Mims 综合征的儿童的表皮和皮脂痣。

DOI：
发表时间：
2024-01-25
期刊：
影响因子：
1.5
作者：
Haller, Courtney N;Leszczynska, Maria A;Brichta, Lars;Maier, Esther;Riddington, Ian M;Choate, Keith A;Levy, Moise L
通讯作者：
Levy, Moise L

Second-Hit Somatic Mutations in Mevalonate Pathway Genes Underlie Porokeratosis.

甲羟戊酸途径基因的二次体细胞突变导致汗孔角化症。