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锚定缺陷是由种系引起的一类新的遗传疾病，以及GPI锚合成基因的体细胞突变。先天性GPI锚定缺乏症患者具有智力障碍的综合征形式，癫痫病等神经系统疾病特征具有最大的临床感兴趣。在阵发性的夜间血红蛋白尿细胞中，髓样系统的血红蛋白细胞获得了体细胞突变并被补体系统攻击。我们发现的致病突变有助于加深我们对GPI-Cannor合成途径的生化和生物学机制的理解。在这个项目中，我们打算将患者与不明原因的GPI锚定缺陷序列序列，并旨在通过复杂的生物信息学过滤方法来鉴定进一步的疾病相关基因。为了增加我们对基因型表型相关性的理解，我们计划在体外和体内分析特定的致病突变。IAM1：扩展一群gpi bandor缺乏症的患者的causeaim 2：整个基因组序列的生物信息学分析。 3：CRISPR/CAS9小鼠特定致病突变的功能分析