Identification and characterization of pathogenic mutations in GPI-anchor deficiencies

GPI-锚定缺陷致病突变的鉴定和表征

• 批准号: 290617713
• 负责人: Professor Dr. Uwe Kornak, since 6/2018
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290617713?language=en
• 关键词: Identification; characterization; pathogenic; mutations; GPI

GPI-anchor deficiencies are a new class of genetic disorders that are caused by germline, as well as somatic mutations in genes of the GPI-anchor synthesis. Patients with congenital GPI-anchor deficiencies have a syndromic form of intellectual disability and neurologic features such as epilepsies are of utmost clinical interest. In paroxysmal nocturnal hemoglobinuria cells of the myeloid system acquire somatic mutations and become attackable by the complement system.The pathogenic mutations that we found helped to deepen our understanding of the biochemical and biological mechanisms of the GPI-anchor synthesis pathway. In this project we intend to sequence patients with GPI-anchor deficiencies with unknown cause and we aim to identify further disease related genes with complex bioinformatics filtering methods. To increase our understanding of genotype phenotype correlations we plan to analyze specific pathogenic mutations in vitro and in vivo.Aim 1: Expansion of a cohort of patients with GPI-anchor deficiency of unknown causeAim 2: Bioinformatics analysis of whole genome sequences selected cases.Aim 3: Functional analysis of specific pathogenic mutations in mice with CRISPR/Cas9

GPI-锚缺陷是一类新的遗传性疾病，由生殖系和GPI-锚合成基因的体细胞突变引起。先天GPI-锚缺陷的患者有一种综合征形式的智能障碍，神经特征，如癫痫，是最有临床意义的。在阵发性睡眠性血红蛋白尿症中，髓系细胞获得体细胞突变，并成为补体系统的攻击对象，我们发现的致病突变有助于加深我们对GPI-锚合成途径的生化和生物学机制的理解。在这个项目中，我们打算对原因不明的GPI锚定缺陷患者进行测序，我们的目标是用复杂的生物信息学筛选方法识别更多与疾病相关的基因。为了增加我们对基因表型相关性的了解，我们计划在体外和体内分析特定的致病突变。目的1：扩大不明原因的GPI锚定缺陷患者队列。目的2：选定病例的全基因组序列的生物信息学分析。目的3：CRISPR/Cas9小鼠特定致病突变的功能分析