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

• 批准号: 10055124
• 负责人: Bryce Binstadt
• 金额: $ 23.68万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055124
• 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; three dimensional cell culture

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.

摘要 先天免疫缺陷包括300多种不同的疾病。其中包括数量不断增加的 单基因自体炎症障碍，以全身或特定的无菌炎症为特征 器官。这一建议源于对一名儿童的诊断，该儿童似乎患有一种新型的自体炎症 以炎症性皮肤病为特征的疾病，与I型干扰素的产生增加有关 但没有反复发烧。这位患者在编码αT-的基因上有复合杂合性突变。 连环蛋白：CTNNA3。α-连环蛋白是一种肌动蛋白结合蛋白，它与钙粘附素相互作用，介导细胞间的相互作用。 粘连和组织结构。CTNNA3的不同突变与一种特定的心脏病有关 人类，致心律失常性右室发育不良，但这个孩子没有心脏病。重要的是 CTNNA3基因突变与炎症性皮肤病此前没有关联。在这里，我们试图 了解患者突变的αT-连环蛋白如何导致皮肤炎症和I型干扰素增加 制作。我们的初步数据表明，αT-连环蛋白在小鼠皮脂腺中高度表达。 健康的人类皮肤。皮肤是有机体和周围环境之间的屏障。头发 卵泡突破了这一解剖屏障，为病原体提供了一个潜在的进入门户；因此，它们是一个部位 有很强的免疫活性。从解剖学上讲，皮脂腺与毛囊有关，它分泌的脂类 有助于皮肤屏障功能，作为共生微生物区系的营养物质。皮脂腺也 产生抗菌肽、细胞因子和趋化因子来调节皮肤免疫力。小鼠缺乏 皮脂腺的表型与本例相似。这项提议的中心假设是 αT-连环蛋白对皮脂腺的正常功能至关重要。此外，我们建议该患者的CTNNA3 突变扰乱αT-连环蛋白功能，改变皮脂腺活性，最终导致皮肤发炎 疾病。我们将首先确定该患者的CTNNA3突变如何影响αT-T的基础生物学。 连环蛋白，其与结合蛋白的结合，以及其亚细胞定位。接下来，我们将描述 结合患者皮肤活检，突变的αT-连环蛋白影响皮脂腺的结构和功能 标本和培养的人皮脂腺细胞(皮脂腺细胞)。最后，我们将测试假设 这位患者的I型干扰素签名增加源于对皮肤细胞的直接作用或间接作用。 通过皮脂腺活动改变对皮肤菌群的影响。拟议的研究将使我们能够 一种新的自体炎症性皮肤病的特征和第一种与减少相关的人类疾病 皮脂腺功能；他们也可能提供洞察力，以改善该患者的皮肤病的治疗。 此外，我们还将获得有关皮肤及其附属物(如皮脂腺)如何相互作用的新知识 与环境、免疫系统和共生体共同提供复杂的屏障免疫力。