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.

皮肤镶嵌性疾病严重，罕见的遗传皮肤疾病，以应有的方式出现在胚胎发育过程中进行体细胞突变。突变的时机决定了受影响组织的身份和程度，并给出了外胚层（角质形成细胞）的贡献，中胚层（成纤维细胞，皮肤血管）和神经rest（黑色素细胞），一个或一个多种细胞类型可能会受到影响。我们发现，这种突变的后果可以严重，就像在快速增长的，治疗无反常的先天性血管瘤皮肤 - 骨骼低磷酸血症中的GNA14突变或严重的骨质核酸综合征是由于多线躯体激活RAS突变而引起的。下一代测序在皮肤镶嵌性疾病中发现了基因发现，我们已经成功确定了这些条件的几种新遗传原因。我们现在建议扩大我们的良好的表现皮肤摩西疾病的队列，以筛选潜在的突变病因基因，并在不反射的突变受试者中采用外显子组测序针对未解决病例的基因组测序，发现新的遗传原因。其中包括队列是增生/hart症，包括先天筋膜营养不良，nevus Comedonicus和先天性血管瘤，以及常见的稀有镶嵌表现包括痤疮，牛皮癣，地衣平面和盘状红斑狼疮在内的疾病，这些疾病提供一个机会来确定与自身免疫和炎症有关的途径。我们将利用患者衍生的细胞和组织来询问已鉴定出的新基因的功能，以及将采用转基因组织等效物研究和证明已鉴定的发病机理尽可能的突变。以前有限的引人入胜的新基因我们将无法与皮肤生物学相关，我们将采用鼠标模型敲除和CRISPR生成的敲除线以证明已鉴定突变的发病机理并提供对病理生物学的最初见解。这些研究将继续确定分子途径是表皮分化的复杂过程的中心，自我更新，和炎症，并将为未来的生物学研究和开发提供关键背景新颖的治疗学。

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）

Genetic investigation of childhood vascular tumor biology reveals pathways for therapeutic intervention.

DOI：
10.12688/f1000research.16160.1
发表时间：
2019-01-01
期刊：
F1000Research
影响因子：
0
作者：
Cheraghlou, Shayan;Lim, Young;Choate, Keith
通讯作者：
Choate, Keith

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

DOI：
10.1002/ajmg.a.61362
发表时间：
2019-12
期刊：
American journal of medical genetics. Part A
影响因子：
0
作者：
Atzmony L;Zaki TD;Antaya RJ;Choate KA
通讯作者：
Choate KA

Two percent lovastatin ointment as a pathogenesis-directed monotherapy for porokeratosis.

DOI：
10.1016/j.jdcr.2020.08.017
发表时间：
2020-10
期刊：
JAAD case reports
影响因子：
0
作者：
Ugwu N;Choate KA;Atzmony L
通讯作者：
Atzmony L

Association of Somatic ATP2A2 Damaging Variants With Grover Disease.

体细胞 ATP2A2 损伤性变异与格罗弗病的关联。

DOI：
10.1001/jamadermatol.2023.1139
发表时间：
2023
期刊：
JAMA dermatology
影响因子：
10.9
作者：
Seli,Devin;Ellis,KatharineT;Goldust,Mohamad;Shah,Khadim;Hu,Ronghua;Zhou,Jing;McNiff,JenniferM;Choate,KeithA
通讯作者：
Choate,KeithA

Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.