The Role of Monoallelic Expression in Incomplete Penetrance of Primary Immunodeficiencies

项目摘要： 原发性免疫缺陷（PID）是免疫系统的单基因疾病。PID影响1/780 住院儿童PID的不完全消退是常见的，并且在很大程度上仍然无法解释。在此，我 假设PID中不完全等位基因也可以用单等位基因表达（MAE）来解释。 传统上，常染色体基因的转录被认为是从两个遗传基因发生的。最近的研究 表明高达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不依赖于其他基因， 导致转录水平上的细胞群体多样化。PID基因是否存在MAE尚不清楚。 JAK 1或PLCG 2突变的家族表现出不完全的疾病转移。我的初步数据 这表明JAK 1和PLCG 2都可以发生MAE。在本提案中，我的目标是：1）绘制PID的MAE 2）评估JAK 1中单等位基因表达的功能影响 和PLCG 2离体。该研究结果将为PID的生物学研究和临床遗传学提供信息 通过识别转录本多样性的阈值来驱动疾病的发生。此外，这些发现将 为其他遗传性疾病的类似工作提供了框架，同时为机制性疾病的研究奠定了基础。 针对控制MAE作为单基因疾病治疗的研究。

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.