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A novel genetic mutation reveals the molecular and cellular mechanisms of severe recurrent skin inflammation

一种新的基因突变揭示了严重复发性皮肤炎症的分子和细胞机制

基本信息

批准号：
10679177
负责人：
Hwi (Deborah) M Gil
金额：
$ 3.3万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679177
关键词：
Affect Affinity Amino Acids Apoptosis Apoptotic Autophagocytosis Bar Codes Binding Binding Sites CASP8 gene CRISPR/Cas technology Catalytic Domain Cell Culture Techniques Cell Death Cell Death Signaling Process Cells Childhood Clinical Co-Immunoprecipitations Color Complex Computing Methodologies DNA Damage DNA Sequence Alteration Defect Development Enzymes Equilibrium Excision Flow Cytometry Genetic Diseases Germ-Line Mutation Hereditary Disease Heterodimerization Homeostasis Human Immune Immune signaling Immune system Immunity Immunologist In Vitro Infection Inflammasome Inflammation Interferons Knock-out Maintenance Mediating Mendelian disorder Methods Missense Mutation Mitosis Modification Molecular Mus Mutation Nature Necrosis Pathway interactions Patients Phenotype Phosphorylation Play Post-Translational Protein Processing Predisposition Proteins Proteome Pyoderma Gangrenosum Qualifying RIPK1 gene RIPK3 gene Recurrence Reporting Research Resources Role Signal Pathway Signal Transduction Signaling Molecule Skin Specificity Stable Isotope Labeling Symptoms Syndrome System Techniques Tertiary Protein Structure Testing Tumor Necrosis Factor Receptor Ubiquitin Ubiquitination Western Blotting autoinflammatory cell type clinical phenotype cytokine therapy disease-causing mutation exome sequencing experimental study human disease inhibitor inorganic phosphate keratinocyte neutrophil novel prevent programs protein complex rare genetic disorder response retroviral transduction skin disorder therapeutic target ubiquitin isopeptidase

项目摘要

PROJECT ABSTRACT Inborn errors of immunity (IEI) are genetic disorders caused by monogenic germline mutations and have broad clinical manifestations. Here, we present two patients affected by pyoderma gangrenosum (PG), an extremely rare and severe neutrophilic necrotic skin disorder, without severe systemic autoinflammatory symptoms. Whole exome sequencing (WES) revealed a homozygous R57C OTULIN missense mutation in each patient. OTULIN encodes a deubiquitinase that is the only known enzyme that specifically cleaves linear ubiquitin chains that have been added to target proteins by the linear ubiquitin chain assembly complex (LUBAC). The balance between removal and addition of ubiquitin is crucial for immune homeostasis and responses to infection. Previously reported germline OTULIN mutations affect this protein’s catalytic domain and cause a severe systemic autoinflammatory largely driven by overactivation of NF-B signaling called OTULIN-related autoinflammatory syndrome (ORAS). Here, we define a new monogenic disease caused by mutations in a different domain of OTULIN and causing a distinct clinical phenotype. We have demonstrated that the R57C mutation prevents OTULIN from binding to the LUBAC component HOIP but the ability to downregulate NF-B activity remains intact suggesting a context-specific function of OTULIN. These patients’ unique phenotype suggests that a previously unrecognized function for OTULIN in the skin. The overall hypothesis of this proposal is that OTULIN’s function in keratinocytes differs from that in other cellular contexts, and this novel mutation leads to development of pyoderma gangrenosum in patients. We will use computational method and cutting-edge in vitro and ex vivo approaches to identify the roles of post-translational modification in regulating OTULIN-dependent immune signaling. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies for maintaining immune homeostasis.

项目摘要