Discovering Novel Genetic Causes and Molecular Mechanisms of Atypical Hemolytic Uremic Syndrome

发现非典型溶血性尿毒症综合征的新遗传原因和分子机制

基本信息

批准号：
10677017
负责人：
Massimo Attanasio
金额：
$ 23.18万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10677017
关键词：
Acute Kidney Failure Affect Angiogenic Factor Arachidonic Acids Autocrine Communication Biological Assay Biology CXCR4 gene Cell physiology Cell surface Cells Childhood Collaborations Complement Complement Activation DNA Sequence Alteration Data Diacylglycerol Kinase Diglycerides Dinoprostone Disease End stage renal failure Endothelial Cells Endothelium Escherichia coli EHEC Escherichia coli Infections Etiology Future G-Protein-Coupled Receptors Genes Genetic Genetic Predisposition to Disease Goals Hemolytic Anemia Hemolytic-Uremic Syndrome Homeostasis Human In Vitro Individual KDR gene Kidney Diseases Knowledge Lipids Meleagris gallopavo Molecular Mus Mutation Nephrology Outcomes Research Paracrine Communication Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phosphatidic Acid Phosphatidylinositols Phosphorylation Phosphotransferases Play Production Protein Family Proteins Receptor Protein-Tyrosine Kinases Recurrence Research Role Signal Pathway Signal Transduction Signaling Molecule Survivors Testing Thrombocytopenia Tissues Transcriptional Activation Transgenic Mice Umbilical vein VEGFA gene Variant Vascular Diseases Vascular Endothelial Growth Factors chemokine cohort complement system conditional knockout disease-causing mutation early onset exome sequencing experience functional loss gene product genetic variant glomerular endothelium in vivo insight loss of function mouse model neutralizing antibody next generation sequencing novel patient population patient screening podocyte response therapeutic target therapy development thrombotic

项目摘要

Project Summary Atypical hemolytic uremic syndrome (aHUS, hemolytic anemia, thrombocytopenia and acute renal failure in the absence of Shiga-toxin producing E. coli infection) is an extremely severe disease, frequently of genetic origin. Many genetic mutations causing this disease have been found in genes encoding components of the complement cascade, but more recently we have identified mutations in the gene diacylglycerol kinase epsilon (DGKE), indicating that factors outside of the complement, possibly affecting the endothelium, are implicated in aHUS and may represent future therapeutic targets. Pathogenic genetic variants have been identified in about 50% of these cases, leaving the etiology of the other half undiscovered. In this project we propose to identify mutations in novel genes that cause aHUS in an extensive cohort of patients using next generation sequencing and to study how DGKE loss of-function affects the biology of the endothelium causing aHUS by using transgenic mouse models.

项目概要非典型溶血性尿毒症综合征（aHUS、溶血性贫血、血小板减少症和急性肾功能衰竭）没有产生志贺毒素的大肠杆菌感染）是一种极其严重的疾病，通常是遗传性的。在编码该疾病成分的基因中发现了许多导致这种疾病的基因突变。补体级联反应，但最近我们发现了二酰甘油激酶 epsilon 基因的突变（DGKE），表明补体之外的因素可能影响内皮细胞，与 aHUS 可能代表未来的治疗靶点。致病性遗传变异已在大约其中 50% 的病例，另一半的病因尚未发现。在这个项目中，我们建议确定使用下一代测序在大量患者中发现导致 aHUS 的新基因突变并研究 DGKE 功能丧失如何影响导致 aHUS 的内皮生物学转基因小鼠模型。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A splice site mutation in the TSEN2 causes a new syndrome with craniofacial and central nervous system malformations, and atypical hemolytic uremic syndrome.

TSEN2 的剪接位点突变会导致一种新的颅面和中枢神经系统畸形综合征，以及非典型溶血性尿毒症综合征。

DOI：
发表时间：
2022-03
期刊：
影响因子：
3.5
作者：
Canpolat, Nur;Liu, Dingxiao;Atayar, Emine;Saygili, Seha;Kara, Nazli Sila;Westfall, Trudi A;Ding, Qiong;Brown, Bartley J;Braun, Terry A;Slusarski, Diane;Karli Oguz, Kader;Ozluk, Yasemin;Tuysuz, Beyhan;Tastemel Ozturk, Tugba;Sever, Lale;Sezer
通讯作者：
Sezer