Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy

peer reviewe

Importin-8 Modulates Division of Apical Progenitors, Dendritogenesis and Tangential Migration During Development of Mouse Cortex

The building of the brain is a multistep process that requires the coordinate expression of thousands of genes and an intense nucleocytoplasmic transport of RNA and proteins. This transport is mediated by karyopherins that comprise importins and exportins. Here, we investigated the role of the ß-importin, importin-8 (IPO8) during mouse cerebral corticogenesis as several of its cargoes have been shown to be essential during this process. First, we showed that Ipo8 mRNA is expressed in mouse brain at various embryonic ages with a clear signal in the sub-ventricular/ventricular zone (SVZ/VZ), the cerebral cortical plate (CP) and the ganglionic eminences. We found that acute knockdown of IPO8 in cortical progenitors reduced both their proliferation and cell cycle exit leading to the increase in apical progenitor pool without influencing the number of basal progenitors (BPs). Projection neurons ultimately reached their appropriate cerebral cortical layer, but their dendritogenesis was specifically affected, resulting in neurons with reduced dendrite complexity. IPO8 knockdown also slowed the migration of cortical interneurons. Together, our data demonstrate that IPO8 contribute to the coordination of several critical steps of cerebral cortex development. These results suggest that the impairment of IPO8 function might be associated with some diseases of neuronal migration defects

Childhood Absence Epilepsy with Tonic-Clonic Seizures and Electroencephalogram 3–4-Hz Spike and Multispike–Slow Wave Complexes: Linkage to Chromosome 8q24

SummaryChildhood absence epilepsy (CAE), a common form of idiopathic generalized epilepsy, accounts for 5%–15% of childhood epilepsies. To map the chromosomal locus of persisting CAE, we studied the clinical and electroencephalographic traits of 78 members of a five-generation family from Bombay, India. The model-free affected–pedigree member method was used during initial screening with chromosome 6p, 8q, and 1p microsatellites, and only individuals with absence seizures and/or electroencephalogram 3–4-Hz spike– and multispike–slow wave complexes were considered to be affected. Significant P values of .00000–.02 for several markers on 8q were obtained. Two-point linkage analysis, assuming autosomal dominant inheritance with 50% penetrance, yielded a maximum LOD score (Zmax) of 3.6 for D8S502. No other locus in the genome achieved a significant Zmax. For five smaller multiplex families, summed Zmax was 2.4 for D8S537 and 1.7 for D8S1761. Haplotypes composed of the same 8q24 microsatellites segregated with affected members of the large family from India and with all five smaller families. Recombinations positioned the CAE gene in a 3.2-cM interval

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic

Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study

The role of intestinal cell kinase in interneurons, a protein mutated in Juvenile Myoclonic Epilepsy

Intestinal cell kinase (ICK) is a serine/threonine kinase for which homozygous mutations have been associated with two neolethals syndrome (ECO & SRP) characterized by anomalies involving the endocrine, cerebral, and skeletal systems. More recently, novel heterozygous mutations (Fig.1) have been associated with juvenile myoclonic epilepsy (JME). Using ex-vivo electroporation, it has been demonstrated that pathogenic mutations affect the physiology of neural progenitor (mitosis, cell cycle & apoptosis) and radial migration in mouse neocortex. Considering epilepsy as an imbalance between excitation and inhibition, it appeared us interesting to complete the study with the effect of JME mutations on inhibitory side and so to determine the role of ICK in interneurons (INs)

Isolation and characterization of mouse homologue for the human epilepsy gene, EPM2A

Mutations in the novel gene,EPM2A,have been shown recently to cause the progressive myoclonus epilepsy of Lafora type. EPM2Ais predicted to encode a putative protein-tyrosine phosphatase but its specific role in normal brain function and in the Lafora disease is not known. As a first step towards understanding the cellular function of EPM2A in an animal model, we have isolated cDNA clones for mouse EPM2A and analyzed its expression. Sequence analyses of the mouse cDNA clones revealed a complete ORF that supports the 5′ coding sequence predicted for human EPM2A from the genomic sequence. When compared toEPM2A,the mouse homologue, named Epm2a, shows 86% identity at the nucleotide level and 88% identity and 93% similarity at the amino acid level. Similar to the human counterpart, Epm2a showed ubiquitous expression in Northern with a major transcript size of 3.5 kb. We have mapped the Epm2a to the proximal region of mouse chromosome 10 which is the syntenic region for human chromosome band, 6q24. Our results suggest that EPM2A is highly conserved in mammals and might have a conserved function

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Juvenile myoclonic epilepsy (JME), a lifelong disorder that starts during adolescence, is the most common of genetic generalized epilepsy syndromes. JME is characterized by awakening myoclonic jerks and myoclonic-tonic-clonic (m-t-c) grand mal convulsions. Unfortunately, one third of JME patients have drug refractory m-t-c convulsions and these recur in 70-80% who attempt to stop antiepileptic drugs (AEDs). Behavioral studies documented impulsivity, but also impairment of executive functions relying on organization and feedback, which points to prefrontal lobe dysfunction. Quantitative voxel-based morphometry (VBM) revealed abnormalities of gray matter (GM) volumes in cortical (frontal and parietal) and subcortical structures (thalamus, putamen, and hippocampus). Proton magnetic resonance spectroscopy (MRS) found evidence of dysfunction of thalamic neurons. White matter (WM) integrity was disrupted in corpus callosum and frontal WM tracts. Magnetic resonance imaging (MRI) further unveiled anomalies in both GM and WM structures that were already present at the time of seizure onset. Aberrant growth trajectories of brain development occurred during the first 2 years of JME diagnosis. Because of genetic origin, disease causing variants were sought, first by positional cloning, and most recently, by next generation sequencing. To date, only six genes harboring pathogenic variants (GABRA1, GABRD, EFHC1, BRD2, CASR, and ICK) with Mendelian and complex inheritance and covering a limited proportion of the world population, are considered as major susceptibility alleles for JME. Evidence on the cellular role, developmental and cell-type expression profiles of these six diverse JME genes, point to their pathogenic variants driving the first steps of brain development when cell division, expansion, axial, and tangential migration of progenitor cells (including interneuron cortical progenitors) sculpture subtle alterations in brain networks and microcircuits Frontiers during development. These alterations may explain "microdysgenesis" neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.</p

"Jasper's Basic Mechanisms of the Epilepsies" Workshop.

In 1969, H.H. Jasper, A.A. Ward, and A. Pope and the Public Health Service Advisory Committee on the Epilepsies of the National Institutes of Health (NIH) published the first edition on Basic Mechanisms of the Epilepsies (BME). Since then, basic and clinical researchers in epilepsy have gathered together each decade to assess where epilepsy research has been, what it has accomplished, and where it should go. In 1999, the third edition of BME was named in honor of H.H. Jasper. Projected for publication in 2011, the fourth edition of Jasper's BME will (1) synthesize the role of interactions between neurons, synapses, and glia in the initiation, spread, and arrest of seizures; (2) examine the molecular, cellular, and network plasticity mechanisms that subserve excitability, seizure susceptibility, and ultimately epileptogenesis; (3) provide a framework for expanding the genome of rare mendelian epilepsies and understanding the complex heredity responsible for common epilepsies; (4) explore cellular mechanisms of the two main groups of presently known Mendelian epilepsy genes, namely ion channelopathies and developmental epilepsy genes; and (5) for the first time, describe the current efforts to translate the discoveries in epilepsy disease mechanisms into molecular and cellular therapeutic strategies in order to repair and cure the epilepsies. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at). © 2010 International League Against Epilepsy

EFHC1, a protein mutated in Juvenile Myoclonic Epilepsy, interacts with TTLL6 and modulates the level of tubulin polyglutamylation

EFHC1 is the most frequently mutated gene in Juvenile Myoclonic Epilepsy (JME) and encodes for a Microtubule Associated Protein (MAP) of unknown function. Interestingly, in ependymal cells of EFHC1 null-mutant (EFHC1-KO) mouse, a specific decrease of cilia beating is observed. Polyglutamylation is a crucial post-translational modification of tubulin (PMT) which plays a role in centriole stability, mitosis but also axoneme/cilia motility. In ependymal cells, beating behavior is due to the activity of the Tubulin Tyrosin Ligase like 6 (TTLL6). Taken together, these results suggest an interaction between EFHC1 and TLL6

Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development

g.oxfordjournals.org/ D ow nloaded from 2 Heterozygous mutations in Myoclonin1/EFHC1 cause juvenile myoclonic epilepsy (JME), the most common form of genetic generalized epilepsies, while homozygous F229L mutation is associated with primary intractable epilepsy in infancy. Heterozygous mutations in adolescent JME patients produce subtle malformations of cortical and subcortical architecture whereas homozygous F229L mutation in infancy induces severe brain pathology and death. However, the underlying pathological mechanisms for these observations remain unknown. We had previously demonstrated that EFHC1 is a microtubules-associated protein (MAP) involved in cell division and radial migration during cerebral corticogenesis. Here, we show that JME-mutations, including F229L, do not alter the ability of EFHC1 to colocalize with the centrosome and the mitotic spindle but act in a dominant-negative manner to impair mitotic spindle organization. We also found that mutants EFHC1 expression disrupted radial and tangential migration by affecting morphology of radial glia and migrating neurons. These results show how Myoclonin1/EFHC1 mutations disrupt brain development and potentially produce structural brain abnormalities on which epileptogenesis is established