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.
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.
| Bailey, Julia N; de Nijs, Laurence; Bai, Dongsheng et al. (2018) Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy. N Engl J Med 378:1018-1028 |
| Hernández-Vanegas, Laura E; Jara-Prado, Aurelio; Ochoa, Adriana et al. (2016) High-dose versus low-dose valproate for the treatment of juvenile myoclonic epilepsy: Going from low to high. Epilepsy Behav 61:34-40 |
| Friedrichs, Stefanie; Malzahn, Dörthe; Pugh, Elizabeth W et al. (2016) Filtering genetic variants and placing informative priors based on putative biological function. BMC Genet 17 Suppl 2:8 |
| Wight, Jenny E; Nguyen, Viet-Huong; Medina, Marco T et al. (2016) Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5-6.0 Hz polyspike waves. Mol Genet Genomic Med 4:197-210 |
| Jara-Prado, Aurelio; Ochoa, Adriana; Alonso, María Elisa et al. (2014) Late onset Lafora disease and novel EPM2A mutations: breaking paradigms. Epilepsy Res 108:1501-10 |
| Chen, Han; Malzahn, Dörthe; Balliu, Brunilda et al. (2014) Testing genetic association with rare and common variants in family data. Genet Epidemiol 38 Suppl 1:S37-43 |
| Delgado-Escueta, Antonio V; Koeleman, Bobby P C; Bailey, Julia N et al. (2013) The quest for juvenile myoclonic epilepsy genes. Epilepsy Behav 28 Suppl 1:S52-7 |
| Kasteleijn-Nolst Trenité, Dorothée G A; Schmitz, Bettina; Janz, Dieter et al. (2013) Consensus on diagnosis and management of JME: From founder's observations to current trends. Epilepsy Behav 28 Suppl 1:S87-90 |
| Machado-Salas, Jesús; Avila-Costa, María Rosa; Guevara, Patricia et al. (2012) Ontogeny of Lafora bodies and neurocytoskeleton changes in Laforin-deficient mice. Exp Neurol 236:131-40 |
| Tanaka, Miyabi; Bailey, Julia N; Bai, Dongsheng et al. (2012) Effects on promoter activity of common SNPs in 5' region of GABRB3 exon 1A. Epilepsia 53:1450-6 |
Showing the most recent 10 out of 17 publications
