Discovering More Juvenile Myoclonic Epilepsy Genes by a Consortium

一个联盟发现更多青少年肌阵挛性癫痫基因

• 批准号: 8438430
• 负责人: JULIA N BAILEY
• 金额: $ 46.37万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438430
• 关键词: 10p13; 10q11.2; 14q11.2; 18p; 1p36; 1p36.12; 1q23.3; 6p12; Affect; Alleles; Apoptosis; Candidate Disease Gene; Carpet; Cessation of life; Chromosome Mapping; Chromosomes; Complex; Copy Number Polymorphism; Custom; DNA; Developing Countries; Development; Developmental Gene; Disease; EF Hand Motifs; EF-Hand Domain; Enhancers; Epilepsy; Family; Family member; Future; Generations; Genes; Genetic; Genetic Recombination; Genome Scan; Haplotypes; Human; Human Genetics; Interleukin-1 Receptors; International; Ions; Joints; Juvenile Myoclonic Epilepsy; Knock-out; Link; Linkage Disequilibrium; MAP4K4 gene; Maps; Methods; Microsatellite Repeats; Mutation; National Human Genome Research Institute; Neurites; Neurons; Persons; Population Control; Recruitment Activity; Risk; Sampling; Scanning; Site; Societies; Stem cells; System; Testing; Time; Trimethoprim-Sulfamethoxazole; United States National Institutes of Health; comparative genomic hybridization; design; genetic linkage analysis; genetic resource; genome wide association study; high risk; member; migration; mouse model; neuroblast; neurogenesis; proband; public health relevance

DESCRIPTION (provided by applicant): For about 300,000 people in the USA with Juvenile Myoclonic Epilepsy (JME) and about 5 to 10 million persons, worldwide, with this disease, there is no cure. Thus, our general purpose is to accelerate discovery of epilepsy causing genes for JME, their pathogenetic mechanisms and cures through an international "GENESS" consortium. This consortium includes various sites in the developing world which provide human genetic resources, such as many large families, that far surpass what can be accomplished in Western societies like the USA. To the present time, most common genetic epilepsies are thought to be due to ion- channelopathies. Here we hypothesize that common epilepsies, such as JME, are caused by mutations in developmental genes that are involved in neurogenesis, apoptosis and neuroblast migration, such as genes with EF hand calcium binding motif like Myoclonin1/EFHC1. To test the hypothesis of developmental genes causing JME in preliminary studies, we used traditional linkage analysis and genome-wide scanning, then fine mapping in five large JME families (003, 0J1, 040, 106 and 017) and defined five new putative chromosome loci whose candidate genes are mainly developmental genes. Families (0J1, 106 and 016) which reached LOD score of 3.3 are "highest priority" and will be studied first in Aim 1 as we search for mutations that segregate with affecteds in 3 or 4 generations families using LightScanner system and sequencing. Examples of candidate developmental genes we will study are EGLN3, an apoptosis gene in Family 106, CREG2, an enhancer of stem cells, in Family 017, Centrin1 with 4 EF-hands in Family 003,GPRIN2, an inducer of neurite outgrowth, in Family 040 and Swiprosin (EFHD2 with 2 EF hands) in probands of 28 CAE/JME families. Aim 2 (Yrs2-3) will replicate linkage using the same STRPs/SNPs markers linked to chromosomes 6p12-q14, 14q11.2, 2q11.2, 18p11.23 and 10q11.2-21 to screen 14 other large 'DNA ready' JME families. We will then use constructed STS and tSNP haplotypes to screen 239 other medium-size 'DNA ready' families with JME and look for more recombinations. Aim 3 (Yrs3-4)will genome scan 681 samples of 80 large and medium-sized 'DNA-ready' JME families with Illumina Human Linkage set (6095 SNPs) already approved by CIDR (NIH National Human Genome Research Institute) and look for more epilepsy causing developmental genes. Aim 4 (Yrs 1-5) will collect DNA from 387 more multiplex/multigenerational and simplex families, and combine them with the already-collected 614 JME families and 1000 controls. We will apply to CIDR (NIH National Human Genome Research Institute) to genome scan all 1000 JME families/singletons and 1000 controls using the Illumina Human 1 M Bead chip (includes 1 M SNPs and 56K CNV probes) for joint analysis of linkage and linkage disequilibrium in Year 5. Only by defining (1) high-risk major JME genes and developing their knockout/knockin mice models, and (2) JME risk alleles that contribute to their complex genetics can pathogenetic mechanisms be unraveled and hopes for cures become a reality.

描述(由申请人提供)：美国约30万青少年肌阵挛癫痫(JME)患者和全球约500万至1000万青少年肌阵挛癫痫患者无法治愈。因此，我们的总体目标是通过一个国际“GENESS”联盟加速发现JME的癫痫致病基因、致病机制和治疗方法。这个联盟包括发展中国家的各种地点，这些地点提供人类遗传资源，例如许多大家庭，远远超过美国等西方社会所能实现的成就。到目前为止，最常见的遗传性癫痫被认为是由于离子通道病。在这里，我们假设常见的癫痫，如JME，是由参与神经发生、细胞凋亡和神经母细胞迁移的发育基因突变引起的，例如带有EF手钙结合基序的基因，如Myoclonin1/EFHC1。为了在初步研究中验证JME的发育基因假说，我们采用了传统的连锁分析和全基因组扫描，然后对5个JME大家系(003、0J1、040、106和017)进行了精细定位，确定了5个新的可能的染色体基因座，它们的候选基因主要是发育基因。LOD评分达到3.3的家系(0J1、106和016)是“最优先的”，将首先在目标1中进行研究，因为我们使用LightScanner系统和测序在3代或4代家系中寻找与患者分离的突变。我们将要研究的候选发育基因包括106家族中的凋亡基因EGLN3,017家族中的干细胞增强子CREG2,003家族中具有4个EF-Hand的Centrin1,040家族中的轴突生长诱导者GPRIN2，以及28个CAE/JME家族的先证者中的Swiprosin(EFHD2，2个EF-Hand)。AIM 2(Yrs2-3)将利用与染色体6p12-q14、14q11.2、2q11.2、18p11.23和10q11.2-21连锁的相同的STRPs/SNPs标记来复制连锁，以筛选其他14个‘DNA Ready’JME大家族。然后，我们将使用构建的STS和tSNP单倍型用JME筛选其他239个中等大小的‘DNA Ready’家族，并寻找更多的重组。Aim 3(Yrs3-4)将对80个具有Illumina Human Linkage Set(6095个SNPs)的大中型“DNA-Ready”JME家族的681个样本进行基因组扫描，并寻找更多导致癫痫的发育基因。目标4(1-5岁)将从387个多基因/多代和单纯型家系中收集DNA，并将它们与已经收集的614个JME家系和1000个对照相结合。我们将应用美国国立卫生研究院(NIH)人类基因组研究所(CIDR)使用Illumina Human 1M Bead芯片(包括1M SNPs和56K CNV探针)对所有1000个JME家系/单身个体和1000名对照进行基因组扫描，以在第五年联合分析连锁和连锁不平衡。只有确定(1)高危主要JME基因并建立其敲除/敲除小鼠模型，以及(2)与其复杂遗传学有关的JME危险等位基因，才能揭示其发病机制，并有望成为现实。