A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin

α-T-连环蛋白突变患者的一种新型自身炎症性皮肤病

基本信息

批准号：
10197026
负责人：
Bryce Binstadt
金额：
$ 18.54万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-17 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197026
关键词：
10 year old Actin-Binding Protein Actins Affect Affinity Anatomy Architecture Arrhythmia Arrhythmogenic Right Ventricular Dysplasia Bacteria Binding Proteins Biochemistry Biological Process Biology Biopsy Specimen Blood CRISPR/Cas technology Cadherins Cell Line Cell-Cell Adhesion Cells Child Complex Cultured Cells Cytoskeleton Data Disease Environment Eye Eyelid structure Fever Functional disorder Gene Expression Genes Genetic Gland Growth Hair follicle structure Heart Heart Diseases Hereditary Disease Homodimerization Host Defense Human Hyperkeratosis Immune Immune system Immunity Immunologics Impairment Infection prevention Inflammation Inflammatory Intercalated disc Interferon Type I Interferons Knowledge Lead Life Ligands Link Lipids Maps Measures Mediating Missense Mutation Mucous Membrane Mus Mutagenesis Mutation Nonsense Codon Nutrient Ocular Pathology Organ Organism Patients Pattern Phenotype Production Proteins Recombinants Recording of previous events Recurrence Reporter Reporting Sebaceous Glands Sebum Site Skin Skin colonization Sterility Structure System Testing Tissues Up-Regulation Viral alpha catenin alphaT catenin antimicrobial peptide appendage autoinflammatory beta catenin boys chemokine cohesion commensal microbes cytokine genetic signature human disease immunomodulatory therapies improved in vitro testing insight keratinocyte link protein meibomian gland dysfunction metagenomic sequencing mutant novel pathogen premature protein function skin barrier skin disorder skin microbiome skin microbiota stem systemic inflammatory response three dimensional cell culture

项目摘要

Abstract Inborn errors of immunity comprise over 300 distinct disorders. Among these are an expanding number of monogenic auto-inflammatory disorders, characterized by sterile inflammation systemically or in specific organs. This proposal stems from the identification of a child who appears to have a novel autoinflammatory disease characterized by inflammatory skin disease and associated with increased type I interferon production but without recurrent fever. This patient has compound heterozygous mutations in the gene encoding αT- catenin: CTNNA3. The α-catenins are actin-binding proteins that interact with cadherins to mediate cell-cell adhesion and tissue organization. Different mutations in CTNNA3 are linked with a specific cardiac disease in humans, arrhythmogenic right ventricular dysplasia, but this child does not have cardiac disease. Importantly, there are no prior associations of mutations in CTNNA3 with inflammatory skin disease. Here we seek to understand how this patient’s mutant αT-catenin drives skin inflammation and increased type I interferon production. Our preliminary data demonstrate that αT-catenin is highly expressed in sebaceous glands in healthy human skin. The skin serves as a barrier between an organism and the surrounding environment. Hair follicles breach this anatomic barrier and provide a potential portal of entry for pathogens; they are thus a site of much immunologic activity. Anatomically associated with hair follicles, sebaceous glands secrete lipids that contribute to skin barrier function and serve as nutrients for commensal microbiota. Sebaceous glands also produce antimicrobial peptides, cytokines, and chemokines to modulate skin immunity. Mice lacking sebaceous glands develop a phenotype similar to this patient. The central hypothesis of this proposal is that αT-catenin is critical for normal sebaceous gland function. Further, we propose that this patient’s CTNNA3 mutations disrupt αT-catenin function, altering sebaceous gland activity and culminating in inflammatory skin disease. We will first determine how this patient’s CTNNA3 mutations affect the fundamental biology of αT- catenin, its association with binding proteins, and its subcellular localization. Next we will characterize how the mutant αT-catenin affects sebaceous gland structure and function, using a combination of patient skin biopsy samples and cultured human sebaceous gland cells (sebocytes). Finally, we will test the hypothesis that the increased type I interferon signature in this patient stems either from a direct effect on skin cells or indirectly through effects of altered sebaceous gland activity on the skin flora. The proposed studies will allow us to characterize a novel autoinflammatory skin disease and the first human disease associated with reduced sebaceous gland function; they may also provide insight to improve treatment of this patient’s skin disease. Additionally, we will gain new knowledge of how the skin and its appendages (e.g. sebaceous glands) interface with the environment, the immune system, and commensals to provide sophisticated barrier immunity.

抽象的先天性免疫缺陷包括 300 多种不同的疾病，其中数量不断增加。单基因自身炎症性疾病，其特征是全身或特定部位的无菌性炎症该提议源于对一名似乎患有新型自身炎症的儿童的鉴定。以炎症性皮肤病为特征并与 I 型干扰素产生增加相关的疾病但该患者的αT-编码基因存在复合杂合突变，但没有反复发烧。连环蛋白：CTNNA3 是肌动蛋白结合蛋白，与钙粘蛋白相互作用以介导细胞间作用。 CTNNA3 的不同突变与特定的心脏病有关。人类，致心律失常性右心室发育不良，但这个孩子没有心脏病。此前，CTNNA3 突变与炎症性皮肤病之间没有关联。了解该患者的突变 αT-连环蛋白如何导致皮肤炎症和 I 型干扰素增加我们的初步数据表明，αT-连环蛋白在皮脂腺中高度表达。健康的人体皮肤是有机体和周围环境之间的屏障。毛囊突破了这一解剖屏障，为病原体提供了潜在的进入门户；皮脂腺具有许多免疫活性，在解剖学上与毛囊相关。有助于皮肤屏障功能，也可作为共生微生物群的营养物质。产生抗菌肽、细胞因子和趋化因子来调节缺乏皮肤免疫力的小鼠。皮脂腺形成与该患者相似的表型该提议的中心假设是： αT-连环蛋白对于正常皮脂腺功能至关重要。此外，我们建议该患者的 CTNNA3。突变破坏 αT-连环蛋白功能，改变皮脂腺活动并最终导致皮肤炎症我们将首先确定该患者的 CTNNA3 突变如何影响 αT- 的基本生物学。连环蛋白、其与结合蛋白的关联及其亚细胞定位。结合患者皮肤活检，突变 αT-连环蛋白影响皮脂腺结构和功能最后，我们将检验以下假设：该患者 I 型干扰素特征的增加源于对皮肤细胞的直接影响或间接影响通过改变皮脂腺活动对皮肤菌群的影响，拟议的研究将使我们能够描述了一种新型自身炎症性皮肤病，也是第一种与减少相关的人类疾病皮脂腺功能；它们还可以为改善该患者皮肤病的治疗提供见解。此外，我们将获得有关皮肤及其附属器（例如皮脂腺）如何相互作用的新知识与环境、免疫系统和共生体一起提供复杂的屏障免疫。