Discovery of modifier genes in cardiomyopathy

心肌病修饰基因的发现

基本信息

批准号：
10397475
负责人：
LU LU
金额：
$ 62.96万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397475
关键词：
Adult Affect Animal Model Animals Bioinformatics Blood Candidate Disease Gene Cardiac Myocytes Cardiomyopathies Chromosome Mapping Clinical Complex Cytoskeletal Proteins DNA Data Data Set Diagnosis Dideoxy Chain Termination DNA Sequencing Dilated Cardiomyopathy Disease Disease Progression Environmental Risk Factor Exhibits Family Family member Fibrosis Gene Expression Genes Genetic Genetic Counseling Genetic Variation Genetic study Genotype Goals Heart Heart Hypertrophy Heart Transplantation Heart failure Heritability Human Hypertrophic Cardiomyopathy Inbreeding Individual Induced Mutation Inherited Joints Knock-in Knock-in Mouse Lead Left Ventricular Hypertrophy Maps Modeling Molecular Mus Mutation Outcome Parents Pathway interactions Patients Penetrance Phenotype Population Predisposition Prognosis Proteins Published Comment Recombinant Inbred Strain Recombinants Research Restrictive Cardiomyopathy Sampling Severities Severity of illness Source Sudden Death Symptoms System Testing Tissue Sample Translating Transplantation Validation Variant Weight Work base cardiac muscle disease causal variant clinical heterogeneity cohort disorder risk effective therapy exome sequencing forward genetics gene network genetic analysis genetic approach genetic variant genome wide association study genomic locus heart function high risk human study human subject individual patient inherited cardiomyopathy mouse genetics mouse model multidisciplinary mutant myopalladin novel pediatric patients personalized care resilience reverse genetics screening sudden cardiac death trait transcriptome transcriptomics translational potential

项目摘要

Abstract Cardiomyopathies (CMs) are group of inherited heterogeneous diseases of heart muscle with no definite effective treatment, ultimately resulting in heart failure (HF), transplant or sudden cardiac death (SCD) in many patients. Despite decades of intense research, it is still difficult to predict CM phenotypes and explain clinical heterogeneity, severity and prognosis. The likely reason for poor genotype-phenotype association is that mutations in single gene do not completely determine disease course; rather interactions of multiple genes, causal and modifier, may be required to explain CM phenotypes. We have screened adult and pediatric patients with various types of CMs, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) using whole exome sequencing (641 patients) and direct Sanger sequencing (900 patients), and identified myopalladin (MYPN), encoding a cytoskeletal Z-disk protein, as a strong causal gene associated with heterogeneous CM phenotypes with clinical expressions ranging from asymptomatic left ventricular hypertrophy to dilation with progressive HF to SCD or transplant. The CM symptoms are highly varied among individual patients, even within the same family members who carry identical mutations. These variations are influenced by modifier genes that alter the effect of causal gene at major locus. However, modifier genes of MYPN remain largely unidentified and are likely to depend on the interaction of multiple genes in MYPN related gene pathways and gene networks. The identification of modifier genes is now a crucial goal of research in CMs from the viewpoints of diagnosis, treatment and genetic counseling, but it remains very challenging in clinical cohorts. The objective of the current study is to determine modifier genes and molecular networks that modulate severity of MYPN induced CMs using powers of combined reverse and forward genetics and systems genetic analysis. Systems genetics is such an approach to understand complex diseases by focusing on how genes work together in groups rather than singly. We have confirmed that mutation Q529X of MYPN associated with heterogeneous phenotypes in humans causes CM in knock-in mice. We have developed the largest and best characterized mouse genetic reference population (GRP) composed of over 150 lines derived from crosses between C57BL/6J (B6) and DBA/2J (D2) parents. The D2 strain has been identified as mouse CM model, and CM phenotypes from D2 mouse is segregated among the BXD family of strains, which makes BXD family as an excellent platform to identify CM modifiers. Moreover, we have introduced Q526X-Mypn mutation (homologous to human Q529X-MYPN) into BXD genetic background to examine how different genetic background modifies the effect of Mypn mutation on CM phenotypes. This proposal is one of the first multidisciplinary collaborative efforts to identify modifier genes in MYPN induced CM in both human and mouse. Using cross-species validation sources and powerful systems genetics, we will define and validate novel modifier genes that interact with Mypn and are responsible for CM variations.

抽象的心肌病（CM）是一组遗传性异质性心肌疾病，目前尚无明确有效的治疗方法治疗，最终导致许多患者出现心力衰竭（HF）、移植或心源性猝死（SCD）。尽管经过数十年的深入研究，预测 CM 表型和解释临床异质性仍然很困难，严重程度和预后。基因型-表型关联性较差的可能原因是单个基因的突变基因不能完全决定病程；相反，多个基因、因果和修饰因素的相互作用，可能需要解释 CM 表型。我们筛查了患有各种类型 CM 的成人和儿童患者，使用全外显子组测序包括扩张型 (DCM)、肥大型 (HCM) 和限制型 (RCM)（641 名患者）和直接桑格测序（900 名患者），并鉴定出编码细胞骨架 Z 盘的肌钯蛋白 (MYPN) 蛋白，作为与异质性 CM 表型相关的强因果基因，其临床表达范围广泛从无症状的左心室肥厚到进行性心力衰竭，再到 SCD 或移植。 CM 即使在携带病毒的同一家庭成员中，个体患者的症状也有很大差异。相同的突变。这些变异受到修饰基因的影响，修饰基因在主要方面改变了因果基因的作用。轨迹。然而，MYPN 的修饰基因在很大程度上仍未被识别，并且可能取决于 MYPN 相关基因通路和基因网络中的多个基因。修饰基因的鉴定现在是一个从诊断、治疗和遗传咨询的角度来看，CM 研究的重要目标，但它仍然在临床队列中非常具有挑战性。当前研究的目的是确定修饰基因和使用反向和联合的力量调节 MYPN 诱导的 CM 严重程度的分子网络正向遗传学和系统遗传分析。系统遗传学是一种理解复杂的方法通过关注基因如何在群体中而不是单独发挥作用来治疗疾病。我们已经确认了突变与人类异质表型相关的 MYPN Q529X 在敲入小鼠中引起 CM。我们有开发了最大且特征最完善的小鼠遗传参考群体 (GRP)，由 150 多个源自 C57BL/6J (B6) 和 DBA/2J (D2) 亲本之间杂交的品系。 D2菌株已被鉴定作为小鼠 CM 模型，来自 D2 小鼠的 CM 表型在 BXD 品系家族中分离，其中使 BXD 系列成为识别 CM 修饰符的优秀平台。此外，我们还推出了Q526X-Mypn 突变（与人类 Q529X-MYPN 同源）进入 BXD 遗传背景，以检查不同的遗传背景改变了 Mypn 突变对 CM 表型的影响。该提案是最早的提案之一多学科合作努力鉴定 MYPN 诱导的人类和小鼠 CM 中的修饰基因。利用跨物种验证来源和强大的系统遗传学，我们将定义和验证新颖的修饰剂与 Mypn 相互作用并导致 CM 变异的基因。