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: 8245109
• 负责人: JULIA N BAILEY
• 金额: $ 48.99万
• 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/8245109
• 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. PUBLIC HEALTH RELEVANCE: 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. To find a cure, we will define developmental Mendelian JME genes involved in neuronal genesis, migration and death, such as myoclonin with one EF hand calcium binding motif and the non-Mendelian risk alleles that contribute to complex genetics. Cures in JME can become a reality only by defining its many genes and then unravelling their epilepsy/disease causing mechanisms.

描述（由申请人提供）：对于美国约30万青少年肌阵挛性癫痫（JME）患者和全世界约500万至1000万青少年肌阵挛性癫痫患者，目前尚无治愈方法。因此，我们的总体目标是通过国际“GENESS”联盟加速发现JME的癫痫致病基因，其发病机制和治疗方法。这个财团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完成的。到目前为止，大多数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，凋亡和成神经细胞迁移的发育基因突变引起的，如具有EF手钙结合基序的基因，如Myoclonin 1/EFHC 1。为了验证JME的发育基因假说，本研究采用传统的连锁分析和全基因组扫描方法，对5个JME家系（003、0 J1、040、106和017）进行精细定位，确定了5个新的染色体位点，其候选基因主要是发育基因。达到LOD评分3.3的家族（0 J1、106和016）是“最高优先级”，并将首先在目标1中进行研究，因为我们使用LightScanner系统和测序在3或4代家族中搜索与受影响者分离的突变。我们将研究的候选发育基因的例子是EGLN 3，家族106中的凋亡基因，CREG 2，家族017中的干细胞增强子，家族003中的具有4个EF-手的Centrin 1，家族040中的GPRIN 2，神经突生长的诱导剂，以及28个CAE/JME家族的先证者中的Swiprosin（具有2个EF手的EFHD 2）。目的2（Yrs 2 -3）将使用与染色体6p 12-q14、14q11.2、2q11.2、18p11.23和10q11.2-21连锁的相同的STRP/SNP标记复制连锁，以筛选其他14个“DNA就绪”的JME大家族。然后，我们将使用构建的STS和tSNP单倍型筛选239个其他中等大小的“DNA就绪”家庭与JME，并寻找更多的重组。目标3（Yrs 3 -4）将对80个大中型“DNA就绪”JME家族的681个样本进行基因组扫描，其中Illumina人类连锁集（6095个SNP）已被CIDR（NIH国家人类基因组研究所）批准，并寻找更多导致癫痫的发育基因。目标4（1-5年）将从387个多代/多代和单代家庭收集DNA，并将其与已经收集的614个JME家庭和1000个对照相结合。我们将在第五年向CIDR（NIH国家人类基因组研究所）申请使用Illumina Human 1 M Bead芯片（包括1 M SNP和56 K CNV探针）对所有1000个JME家族/单例和1000个对照进行基因组扫描，用于连锁和连锁不平衡的联合分析。只有通过定义（1）高风险的主要JME基因并开发其敲除/敲入小鼠模型，以及（2）有助于其复杂遗传学的JME风险等位基因，才能解开发病机制，并希望治愈成为现实。 公共卫生关系：对于美国约30万青少年肌阵挛性癫痫（JME）患者和全世界约500万至1000万患有这种疾病的患者，没有治愈方法。为了找到治疗方法，我们将定义参与神经元发生，迁移和死亡的发育孟德尔JME基因，例如具有一个EF手钙结合基序的肌阵挛蛋白和有助于复杂遗传学的非孟德尔风险等位基因。JME的治愈只能通过定义其许多基因，然后解开其癫痫/疾病引起机制来实现。