Discovery of modifier genes in cardiomyopathy

心肌病修饰基因的发现

• 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
• 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

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.

摘要 心肌病(CMS)是一组遗传性、异质性的心肌疾病，无明确疗效 在许多患者中，治疗最终导致心力衰竭(HF)、移植或心脏性猝死(SCD)。 尽管经过几十年的密集研究，预测CM表型和解释临床异质性仍然是困难的。 严重程度和预后。基因-表型相关性差的可能原因是单个基因的突变 基因并不完全决定疾病的进程；相反，多个基因的相互作用，包括因果关系和修饰因素，可能 需要解释CM表型。我们对患有不同类型CMS的成人和儿童患者进行了筛查， 包括扩张型(DCM)、肥厚型(HCM)和限制性型(RCM)外显子全测序(641例患者) 和直接Sanger测序(900名患者)，并确定了编码细胞骨架Z盘的Myopalladin(MYPN) 蛋白质作为一种与异质性CM表型相关的强致病基因，其临床表现多种多样 从无症状的左心室肥厚到扩张性心力衰竭，再到SCD或移植。中央情报局 症状在不同患者之间差异很大，即使是在携带 完全相同的突变。这些变异受修饰基因的影响，这些修饰基因主要改变因果基因的效果。 轨迹。然而，MYPN的修饰基因在很大程度上仍未确定，可能依赖于 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种 从诊断、治疗和遗传咨询的角度研究CMS的关键目标，但它仍然 在临床队列中非常具有挑战性。目前研究的目标是确定修饰基因和 分子网络调节MYPN诱导的CMS的严重程度 正向遗传学和系统遗传学分析。系统遗传学就是这样一种理解复杂事物的方法 通过关注基因如何在群体中而不是单独地工作来防治疾病。我们已经确认了这种突变 与人类不同表型相关的MYPN Q529X导致敲入鼠的CM。我们有 开发了最大和最具特征的小鼠遗传参考种群(GRP)，由超过150只小鼠组成 由C57BL/6J(B6)与DBA/2J(D2)亲本杂交产生的品系。已鉴定出D2毒株 作为小鼠CM模型，D2小鼠的CM表型分离于BXD家族菌株中，该家族菌株 使BXD系列成为识别CM修饰剂的极佳平台。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 背景修饰Mypn突变对CM表型的影响。这项提议是首批 多学科合作努力确定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的修饰物 与Mypn相互作用并导致CM变异的基因。