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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：
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
项目类别：
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

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.

摘要