The Role of Monoallelic Expression in Incomplete Penetrance of Primary Immunodeficiencies

单等位基因表达在原发性免疫缺陷不完全外显中的作用

基本信息

批准号：
10752095
负责人：
O'Jay Stewart
金额：
$ 5.02万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2023-06-22 至 2024-12-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10752095
关键词：
Affect Alleles B-Lymphocytes Biological Biological Assay Blood Cells Cell Degranulation Cell Line Cell division Cells Child Health Chromatin Classification Clinical Management Clone Cells Complex Data Disease Disease Management Exhibits Family Family member Flow Cytometry Foundations Future Gene Cluster Gene Expression Gene Mutation Gene Silencing Genes Genetic Genetic Diseases Genetic Transcription Hereditary Disease Heterogeneity Heterozygote Hospitalized Child Human Immune Immune System Diseases Immune system Individual Inherited Interferons JAK1 gene Maps Medical Genetics Mendelian disorder Mitochondrial DNA Mitotic Mutation Natural Killer Cells Other Genetics Outcome PLCG2 gene Parents Patients Penetrance Peripheral Blood Mononuclear Cell Phenotype Physiological Population Population Heterogeneity Prevalence Reporting Role Severity of illness Signal Transduction Single Nucleotide Polymorphism Sorting Surface System T-Lymphocyte Therapeutic Time Transcript Variant Work X Chromosome X Inactivation autosome cell type congenital immunodeficiency cytokine disease phenotype exome sequencing gain of function gain of function mutation human disease imprint mast cell mutant release of sequestered calcium ion into cytoplasm response selective expression single-cell RNA sequencing transcriptome transcriptome sequencing

项目摘要

Project Summary: Primary immunodeficiencies (PIDs) are monogenic disorders of the immune system. PIDs affect 1 in 780 hospitalized children. Incomplete penetrance of PIDs is common and remains largely unexplained. Herein I hypothesize that incomplete penetrance in PIDs may also be explained by monoallelic expression (MAE). Traditionally, transcription of autosomal genes is thought to occur from both inherited genes. Recent studies indicate that up to 10% of autosomal genes can randomly commit to gene expression from a single allele, termed monoallelic expression. Unlike X-inactivation or imprinting, MAE is independent of other genes and leads to a diverse population of cells at the transcript level. The existence of MAE of PID genes is unknown. Families with mutations in JAK1 or PLCG2 exhibit incomplete disease penetrance. My preliminary data suggests that both JAK1 and PLCG2 can undergo MAE. Within this proposal I aim to 1) Map MAE of PID genes in primary immune cells and 2) evaluate the functional impact of monoallelic expression in JAK1 and PLCG2 ex vivo. The findings of this proposal will inform the biological study and clinical genetics of PIDs by identifying thresholds of transcript diversity which drive disease penetrance. In addition, these findings will provide a framework for similar work in other genetic diseases, while setting a foundation for mechanistic studies directed at the control of MAE as a therapeutic for monogenic disease.

项目概要：原发性免疫缺陷（PID）是免疫系统的单基因疾病。 PID 影响 780 分之一住院的儿童。 PID 的不完全外显很常见，但在很大程度上仍无法解释。在此我假设 PID 中的不完全外显率也可以通过单等位基因表达 (MAE) 来解释。传统上，常染色体基因的转录被认为是由两个遗传基因发生的。最近的研究表明多达 10% 的常染色体基因可以随机地从单个等位基因进行基因表达，称为单等位基因表达。与 X 失活或印记不同，MAE 独立于其他基因，并且导致转录水平上的细胞群体多样化。 PID 基因的 MAE 是否存在尚不清楚。 JAK1 或 PLCG2 突变的家族表现出不完全的疾病外显率。我的初步数据表明 JAK1 和 PLCG2 都可以经历 MAE。在这个提案中，我的目标是 1) 映射 PID 的 MAE 原代免疫细胞中的基因，2) 评估 JAK1 中单等位基因表达的功能影响和PLCG2离体。该提案的研究结果将为 PID 的生物学研究和临床遗传学提供信息通过确定驱动疾病外显率的转录多样性阈值。此外，这些发现将为其他遗传疾病的类似工作提供框架，同时为机制奠定基础旨在控制 MAE 作为单基因疾病治疗方法的研究。