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Toshimitsu Suzuki - One of the best experts on this subject based on the ideXlab platform.

  • epilepsy protein EFHC1 myoclonin1 is expressed in cells with motile cilia but not in neurons or mitotic apparatuses in brain
    Scientific Reports, 2020
    Co-Authors: Toshimitsu Suzuki, Ikuyo Inoue, Kazuhiro Yamakawa
    Abstract:

    EFHC1 gene encodes the myoclonin1 protein, also known as Rib72-1. Pathogenic variants in EFHC1 have been reported in patients with juvenile myoclonic epilepsy (JME). Although several studies of immunohistological investigations reproducibly showed that the myoclonin1 is expressed in cells with flagella and motile cilia such as sperm, trachea and ependymal cells lining the brain ventricles, whether myoclonin1 is also expressed in neurons still remains controversial. Here we investigated myoclonin1 expression using widely-used polyclonal (mRib72-pAb) and self-made monoclonal (6A3-mAb) anti-myoclonin1 antibodies together with EFHC1 homozygous knock-out (EFHC1-/-) mice. All of the western blot, immunocytochemical, and immunohistochemical analyses showed that mRib72-pAb crossreacts with several mouse proteins besides myoclonin1, while 6A3-mAb specifically recognized myoclonin1 and detected it only in cells with motile cilia but not in neurons. In dividing cells, mRib72-pAb signals were observed at the midbody (intercellular bridge) and mitotic spindle, but 6A3-mAb did not show any signals at these apparatuses. We further found that the complete elimination of myoclonin1 in EFHC1-/- mouse did not critically affect cell division and migration of neurons in cerebral cortex. These results indicate that myoclonin1 is not expressed in neurons, not a regulator of cell division or neuronal migration during cortical development, but expressed in choroid plexus and ependymal cells and suggest that EFHC1 mutation-dependent JME is a motile ciliopathy.

  • re evaluation of myoclonin1 immunosignals in neuron mitotic spindle and midbody nonspecific
    Epilepsy & Behavior, 2013
    Co-Authors: Kazuhiro Yamakawa, Toshimitsu Suzuki
    Abstract:

    Abstract Mutations in EFHC1 gene cause juvenile myoclonic epilepsy (JME). We previously showed that myoclonin1 protein encoded by EFHC1 is expressed in prenatal choroid plexus and postnatal ependymal cell cilia but may not be in neurons. However, another group reported that myoclonin1 is expressed in neurons and at mitotic spindle, and that the suppression of EFHC1 by RNAi caused disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. We re-investigated their results by using the same polyclonal antibody that they used, and found that the signals in neurons remained in EFHC1-deficient mouse, suggesting that the signals in neurons were nonspecific. Furthermore, EFHC1 (−/−) mouse did not show any abnormalities such as disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. Further investigations are required to clarify these discrepancies. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

  • The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death.
    Cell calcium, 2012
    Co-Authors: Masahiro Katano, Toshimitsu Suzuki, Kripamoy Aguan, Yuji Hara, Tomohiro Numata, Shigeki Kiyonaka, Shinichiro Yamamoto, Takafumi Miki, Seishiro Sawamura, Kazuhiro Yamakawa
    Abstract:

    The transient receptor potential M2 channel (TRPM2) is the Ca(2+)-permeable cation channel controlled by cellular redox status via β-NAD(+) and ADP-ribose (ADPR). TRPM2 activity has been reported to underlie susceptibility to cell death and biological processes such as inflammatory cell migration and insulin secretion. However, little is known about the intracellular mechanisms that regulate oxidative stress-induced cell death via TRPM2. We report here a molecular and functional interaction between the TRPM2 channel and EF-hand motif-containing protein EFHC1, whose mutation causes juvenile myoclonic epilepsy (JME) via mechanisms including neuronal apoptosis. In situ hybridization analysis demonstrates TRPM2 and EFHC1 are coexpressed in hippocampal neurons and ventricle cells, while immunoprecipitation analysis demonstrates physical interaction of the N- and C-terminal cytoplasmic regions of TRPM2 with the EFHC1 protein. Coexpression of EFHC1 significantly potentiates hydrogen peroxide (H(2)O(2))- and ADPR-induced Ca(2+) responses and cationic currents via recombinant TRPM2 in HEK293 cells. Furthermore, EFHC1 enhances TRPM2-conferred susceptibility of HEK293 cells to H(2)O(2)-induced cell death, which is reversed by JME mutations. These results reveal a positive regulatory action of EFHC1 on TRPM2 activity, suggesting that TRPM2 contributes to the expression of JME phenotypes by mediating disruptive effects of JME mutations of EFHC1 on biological processes including cell death.

  • dna variants in coding region of EFHC1 snps do not associate with juvenile myoclonic epilepsy
    Epilepsia, 2009
    Co-Authors: Dongsheng Bai, Toshimitsu Suzuki, Marco T. Medina, Julia N Bailey, Maria Elisa Alonso, Reyna M Duron, Iris E Martinezjuarez, Jesus Machadosalas, Ricardo Ramosramirez, Miyabi Tanaka
    Abstract:

    Juvenile myoclonic epilepsy (JME) is the most common cause of primary grand mal seizures and accounts for at least 3 to 12% of all epilepsies. JME can be inherited as a Mendelian autosomal dominant or autosomal recessive trait or as a non-Mendelian complex genetic trait. Three mutation-harboring Mendelian genes for JME have been reported. Mutations in α1 subunit of γ-aminobutyric acid receptor subtype A on chromosome 5q34 segregated with nine affected individuals of a three-generation French Canadian family with JME (Cossette et al., 2002). Mutations in a chloride-channel gene, CLCN2 on chromosome 3q26 segregated with five affected members of a three-generation German family with JME (Haug et al., 2003). Our group first mapped a JME locus in chromosome 6p12 (Liu et al., 1995, 1996; Serratosa et al., 1996; Bai et al., 2002) and identified a mutation-harboring Mendelian gene that encodes a protein with one EF-hand motif. Hence, we called the gene EFHC1. We reported one doubly heterozygous and three heterozygous missense mutations segregated in 21 clinical and electroencephalography (EEG) affected members of six unrelated two- to four-generation JME Hispanic families from California (U.S.A.) and Mexico (Suzuki et al., 2004). The 6p12 JME locus was again mapped independently by two separate groups; first, by a genome-wide linkage study of JME families from various countries of Europe (Hempelmann et al., 2006) and second by a chromosome 6p12 replication genetic linkage study in a smaller cohort of 18 Dutch families (Pinto et al., 2004). Similar and novel missense mutations in EFHC1 were reported in Caucasian JME patients from Tennessee (U.S.A.), Italy, and Austria (Ma et al., 2006; Stogmann et al., 2006; Annesi et al., 2007). Therefore the causality of the gene in a Mendelian JME has been established, but the influence of common functional single nucleotide polymorphisms (SNPs) in JME with complex genetics has not been established. Pinto et al. (2006) reported three SNPs of EFHC1 that were not associated with JME in a case-control study of 112 unrelated patients and 180 controls. In our present study, we chose the most common four coding SNPs of EFHC1 and performed both case-control and family-based association studies to determine if they contribute to the complex genetics of JME.

  • EFHC1 deficiency causes spontaneous myoclonus and increased seizure susceptibility
    Human Molecular Genetics, 2009
    Co-Authors: Toshimitsu Suzuki, Ikuyo Inoue, Hiroyuki Miyamoto, Takashi Nakahari, Takahiro Suemoto, Bin Jiang, Yuki Hirota, Shigeyoshi Itohara, Takaomi C Saido, Tadaharu Tsumoto
    Abstract:

    : Mutations in EFHC1 gene have been previously reported in patients with epilepsies, including those with juvenile myoclonic epilepsy. Myoclonin1, also known as mRib72-1, is encoded by the mouse EFHC1 gene. Myoclonin1 is dominantly expressed in embryonic choroid plexus, post-natal ependymal cilia, tracheal cilia and sperm flagella. In this study, we generated viable EFHC1-deficient mice. Most of the mice were normal in outward appearance, and both sexes were found to be fertile. However, the ventricles of the brains were significantly enlarged in the null mutants, but not in the heterozygotes. Although the ciliary structure was found intact, the ciliary beating frequency was significantly reduced in null mutants. In adult stages, both the heterozygous and null mutants developed frequent spontaneous myoclonus. Furthermore, the threshold of seizures induced by pentylenetetrazol was significantly reduced in both heterozygous and null mutants. These observations seem to further suggest that decrease or loss of function of myoclonin1 may be the molecular basis for epilepsies caused by EFHC1 mutations.

A V Delgadoescueta - One of the best experts on this subject based on the ideXlab platform.

  • 0045 mutations of myoclonin1 EFHC1 disrupt radial and tangential migrations during brain development
    Epilepsy & Behavior, 2013
    Co-Authors: Thierry Grisar, Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Bernard Coumans, Bernard Lakaye
    Abstract:

    many of the milder forms of epilepsy, the genetic contribution is made up of many factors that each contributes little to the disease risk. This is called multifactorial inheritance. Juvenile myoclonic epilepsy (JME) is thought to be inherited in amultifactorial mode. So, while genetic factors are largely to blame for the condition, we encountermany sporadic cases, in addition to families with multiple affected members with JME and families with both JME and other forms of epilepsy. Genetic research is aimed at finding genetic factors that contribute to disease risk. If the genetic factor has a large effect, genetic testing can be used for diagnosis and prognosis and, maybe, for treatment. In multifactorial disorders, such as JME, the aims are more fundamental: understanding the biology of the disorder by placing the genes that contribute in a network that makes sense. The quality of the research into multifactorial traits depends on many factors: first, a correct diagnosis; next, knowledge of ethnicity of the patients and the healthy people we used to compare them with; and, finally, the quality of the lab work and the statistical analysis. In this talk, I will discuss what is known about the multifactorial genetics of JME and what is done to move forward. I will dedicate time to the question as to why knowledge of ethnicity is important in this type of studies.

  • the quest for juvenile myoclonic epilepsy genes
    Epilepsy & Behavior, 2013
    Co-Authors: Marco T. Medina, Julia N Bailey, A V Delgadoescueta, Bobby P C Koeleman, Reyna M Duron
    Abstract:

    Abstract Introduced into a specific population, a juvenile myoclonic epilepsy (JME) mutation generates linkage disequilibrium (LD). Linkage disequilibrium is strongest when the JME mutation is of recent origin, still “hitchhiking” alleles surrounding it, as a haplotype into the next thousands of generations. Recombinations decay LD over tens of thousands of generations causing JME alleles to produce smaller genetic displacements, requiring other genes or environment to produce an epilepsy phenotype. Family-based linkage analysis captures rare epilepsy alleles and their “hitchhiking” haplotypes, transmitted as Mendelian traits, supporting the common disease/multiple rare allele model. Genome-wide association studies identify JME alleles whose linkage disequilibrium has decayed through thousands of generations and are sorting out the common disease/common allele versus rare allele models. Five Mendelian JME genes have been identified, namely, CACNB4 , CASR , GABRa1 , GABRD , and Myoclonin1/EFHC1. Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

  • novel myoclonin1 EFHC1 mutations in mexican patients with juvenile myoclonic epilepsy
    Seizure-european Journal of Epilepsy, 2012
    Co-Authors: Aurelio Jaraprado, Marco T. Medina, Julia N Bailey, A V Delgadoescueta, Iris E Martinezjuarez, Adriana Ochoa, Victor M Gonzalez, Maria Del Carmen Fernandezgonzalezaragon, Minerva Lopezruiz, Maria Elisa Alonso
    Abstract:

    Abstract Purpose The purpose of this study was to identify the prevalence of mutations in the Myoclonin1 / EFHC1 gene in Mexican patients with juvenile myoclonic epilepsy (JME). Method We studied forty-one patients at the National Institute of Neurology and Neurosurgery in Mexico City and 100 healthy controls. DNA was extracted from the peripheral venous blood of all participants. The exons of EFHC1 were then amplified and sequenced. Results We found three new putative mutations, all of which were heterozygous missense mutations located in exon 3. The first identified mutation, 352C>T, produces a R118C change in the protein and cosegregated in the patient's affected father and brother. The second identified mutation, 544C>T, produces a R182L change in the protein and was found in the patient's asymptomatic father. The third identified mutation, 458>A, produces a R153Q change in the protein and was also found in the patient's father. These mutations were not found in controls. Conclusions The frequency of Myoclonin1 / EFHC1 mutations in our sample is 7.3%. Thus, we conclude that mutations in the Myoclonin1 / EFHC1 gene are an important cause of JME in Mexican patients.

  • mutations of EFHC1 linked to juvenile myoclonic epilepsy disrupt radial and tangential migrations during brain development
    Human Molecular Genetics, 2012
    Co-Authors: Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Thierry Grisar, Bernard Coumans, Bernard Lakaye
    Abstract:

    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 microtubule-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 the 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.

  • myoclonin1 EFHC1 in cell division neuroblast migration synapse dendrite formation in juvenile myoclonic epilepsy
    2012
    Co-Authors: Thierry Grisar, Laurence De Nijs, Bernard Lakaye, Joseph J Loturco, Andrea Daga, A V Delgadoescueta
    Abstract:

    This chapter presents recent works on Myocloni1/ EFHC1 a protein encoded by an epilepsy causing gene of juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic or genetic generalized epilepsies. Myoclonin 1/EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. This effect was a result of cortical progenitors failing to exit the cell cycle. On the other hand, defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Mutant analysis of DEFHC1 lossand gain-of-function alleles in vivo in Drosophila revealed a number of neuronal defects, including abnormal synaptic development characterized by extensive satellite bouton formation, increased frequency of spontaneous neurotransmitter release, and aberrations in dendritic arbour morphogenesis. Thus, Myoclonin 1/ EFHC1 is a regulator of cell division and neuronal migration during cortical development synaptic bouton and dendritic morphogenesis. Disruption of these properties lead to JME, being now therefore considered as a developmental disease. Juvenile myoclonic epilepsy (JME) is the most frequent form of idiopathic/genetic generalized epilepsy. It accounts for 2–12 % of all epilepsies. JME symptoms of myoclonias and tonicclonic convulsions appear in adolescence in an otherwise normal person with normal neurological and cognitive functions (Delgado-Escueta and Bacsal, 1984)1. Five percent of these patients, five percent of their affected family members and eight percent of a 252 patient Corresponding author : Prof Thierry GRISAR, MD,PhD, University of Liege, GIGA Neuroscience Blvd de l’Hopital 1, 4000 Liege BELGIUM e-mail : tgrisar@ulg.ac.be. Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies cohort followed for over 20 years only have seizures when triggered by external factors such as alcohol use, fatigue, menstruation and sleep deprivation. To understand the disease mechanisms underlying the stages of susceptibility and epileptogenesis in JME, many have tried to define its complex heritability and identify the genes corresponding to the fifteen chromosomal loci so far linked to the disease2 (see also chapter ...in this book). In 2004, Suzuki et al. identified several heterozygous missense mutations in a gene called EFHC1 3 in different unrelated families with JME probands. Since then, heterozygous non sense, deletion frame shifts and novel missense mutations have been identified in various populations of Italy, Austria and Chile 4–7 .Nine percent of sporadic JME cases detected in families consecutively seen in epilepsy clinics of Mexico and Honduras and 3 % of clinic patients from Japan carry mutations in EFHC1. This represents the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group 7. The gene encodes a 75-kDa protein with three DM10 domains of unknown function and a single EF-hand motif, a Ca2+-binding domain. The transcript is observed in many cell type of human tissue including brain (in particular in ependymal or periventricular cells) but also best expressed in dividing cells with highest levels in lung and testis 3. It was first proposed that EFHC1 was “pro-apoptotic” when overexpression in hippocampal neurons in vitro induced apoptotic cell death. This effect was significantly reduced by any of the five mutations associated with JME. Patch-clamp analysis of BHK (Baby Hamster Kidney) cells transfected with Cav2.3 VDCC (voltage-dependent calcium channel) and EFHC1 showed significantly increased R-type Ca2+ currents. So, the pro-apoptotic effect of EFHC1 was assigned to this enhancing effect on Ca2+ through Cav2.3 VDCC 3. In 2005, another research group pointed out that EFHC1 is orthologous to Rib72, an axonemal protein of Chlamydomonas reinhardtii. They demonstrated that EFHC1 is abundantly expressed in mouse tissues that have motile cilia or flagella, including the brain, and suggested that it plays a role in the intrinsic properties of these organelles 8. One of our laboratories previously reported that the subcellular distribution of EFHC1 in different cell lines varied during the cell cycle. In interphase cells, the protein is present in the cytoplasm and nucleus, except nucleoli and is particularly concentrated at the centrosome. During mitosis, EFHC1 is localized at spindle poles of the mitotic spindle and also at the midbody during cytokinesis 9. These results suggest that EFHC1 could play an important role during cell division and in particular during brain development since mRNA expression is higher at embryonic stages as compared to adult 10. More recently, we demonstrated that EFHC1 is a microtubule-associated protein (MAP) playing a key role in neuronal migration 11. In this chapter we review these putative roles of Myoclonin 1 / EFHC1 or during brain development and during adulthood. We posit an hypothesis that JME is a developmental disease involving neuronal migration and synaptic bouton and dendritic morphogenesis. EFHC1/MYOCLONIN1, A PROTEIN OF UNKNOWN FUNCTION Myoclonin 1 /EFHC1 gene is located on chromosome 6 (6p11–12) between markers D6S1960 and D6S11024, spans 72 kb and contains 11 exons. This gene encodes a protein of 640 amino acids. A domain search identified three tandemly repeated so called DM10 domains, a motif with unknown function. This protein also contains a single EF-hand, a well known Ca2+binding motif, from which it was named EFHC1 for EF-hand Containing 1 (Figure 1). This motif is located at the C-terminus between amino acid 578 and 606 and encoded by a nucleotide sequence present in exon 10. Page 2 Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies Figure 1. Schematic representation of the EFHC1/Myoclonin1 gene, the long and short forms of the EFHC1 protein and the different mutations found co segregated with the JME phenotype The transcript undergo alternative splicing in exon 4, resulting in a C-terminally truncated protein, eliminating the EF-hand domain and two DM10 sequences. This last short form therefore only contains 278 amino acids, the first 240 being common with the entire molecule.

Bernard Lakaye - One of the best experts on this subject based on the ideXlab platform.

  • Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy.
    Frontiers in cellular neuroscience, 2019
    Co-Authors: Maxime Gilsoul, Laurence De Nijs, Thierry Grisar, Antonio V. Delgado-escueta, Bernard Lakaye
    Abstract:

    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 during development. These alterations may explain "microdysgenesis" neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.

  • 0045 mutations of myoclonin1 EFHC1 disrupt radial and tangential migrations during brain development
    Epilepsy & Behavior, 2013
    Co-Authors: Thierry Grisar, Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Bernard Coumans, Bernard Lakaye
    Abstract:

    many of the milder forms of epilepsy, the genetic contribution is made up of many factors that each contributes little to the disease risk. This is called multifactorial inheritance. Juvenile myoclonic epilepsy (JME) is thought to be inherited in amultifactorial mode. So, while genetic factors are largely to blame for the condition, we encountermany sporadic cases, in addition to families with multiple affected members with JME and families with both JME and other forms of epilepsy. Genetic research is aimed at finding genetic factors that contribute to disease risk. If the genetic factor has a large effect, genetic testing can be used for diagnosis and prognosis and, maybe, for treatment. In multifactorial disorders, such as JME, the aims are more fundamental: understanding the biology of the disorder by placing the genes that contribute in a network that makes sense. The quality of the research into multifactorial traits depends on many factors: first, a correct diagnosis; next, knowledge of ethnicity of the patients and the healthy people we used to compare them with; and, finally, the quality of the lab work and the statistical analysis. In this talk, I will discuss what is known about the multifactorial genetics of JME and what is done to move forward. I will dedicate time to the question as to why knowledge of ethnicity is important in this type of studies.

  • Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or Myoclonin1.
    Epilepsy & Behavior, 2013
    Co-Authors: Laurence De Nijs, Nathalie Wolkoff, Thierry Grisar, Bernard Lakaye
    Abstract:

    Abstract Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

  • mutations of EFHC1 linked to juvenile myoclonic epilepsy disrupt radial and tangential migrations during brain development
    Human Molecular Genetics, 2012
    Co-Authors: Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Thierry Grisar, Bernard Coumans, Bernard Lakaye
    Abstract:

    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 microtubule-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 the 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.

  • myoclonin1 EFHC1 in cell division neuroblast migration synapse dendrite formation in juvenile myoclonic epilepsy
    2012
    Co-Authors: Thierry Grisar, Laurence De Nijs, Bernard Lakaye, Joseph J Loturco, Andrea Daga, A V Delgadoescueta
    Abstract:

    This chapter presents recent works on Myocloni1/ EFHC1 a protein encoded by an epilepsy causing gene of juvenile myoclonic epilepsy (JME), one of the most frequent forms of idiopathic or genetic generalized epilepsies. Myoclonin 1/EFHC1 is a microtubule-associated protein involved in the regulation of cell division. In vitro, EFHC1 loss of function disrupted mitotic spindle organization, impaired M phase progression, induced microtubule bundling and increased apoptosis. EFHC1 impairment in the rat developing neocortex by ex vivo and in utero electroporation caused a marked disruption of radial migration. This effect was a result of cortical progenitors failing to exit the cell cycle. On the other hand, defects in the radial glia scaffold organization and in the locomotion of postmitotic neurons. Mutant analysis of DEFHC1 lossand gain-of-function alleles in vivo in Drosophila revealed a number of neuronal defects, including abnormal synaptic development characterized by extensive satellite bouton formation, increased frequency of spontaneous neurotransmitter release, and aberrations in dendritic arbour morphogenesis. Thus, Myoclonin 1/ EFHC1 is a regulator of cell division and neuronal migration during cortical development synaptic bouton and dendritic morphogenesis. Disruption of these properties lead to JME, being now therefore considered as a developmental disease. Juvenile myoclonic epilepsy (JME) is the most frequent form of idiopathic/genetic generalized epilepsy. It accounts for 2–12 % of all epilepsies. JME symptoms of myoclonias and tonicclonic convulsions appear in adolescence in an otherwise normal person with normal neurological and cognitive functions (Delgado-Escueta and Bacsal, 1984)1. Five percent of these patients, five percent of their affected family members and eight percent of a 252 patient Corresponding author : Prof Thierry GRISAR, MD,PhD, University of Liege, GIGA Neuroscience Blvd de l’Hopital 1, 4000 Liege BELGIUM e-mail : tgrisar@ulg.ac.be. Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies cohort followed for over 20 years only have seizures when triggered by external factors such as alcohol use, fatigue, menstruation and sleep deprivation. To understand the disease mechanisms underlying the stages of susceptibility and epileptogenesis in JME, many have tried to define its complex heritability and identify the genes corresponding to the fifteen chromosomal loci so far linked to the disease2 (see also chapter ...in this book). In 2004, Suzuki et al. identified several heterozygous missense mutations in a gene called EFHC1 3 in different unrelated families with JME probands. Since then, heterozygous non sense, deletion frame shifts and novel missense mutations have been identified in various populations of Italy, Austria and Chile 4–7 .Nine percent of sporadic JME cases detected in families consecutively seen in epilepsy clinics of Mexico and Honduras and 3 % of clinic patients from Japan carry mutations in EFHC1. This represents the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group 7. The gene encodes a 75-kDa protein with three DM10 domains of unknown function and a single EF-hand motif, a Ca2+-binding domain. The transcript is observed in many cell type of human tissue including brain (in particular in ependymal or periventricular cells) but also best expressed in dividing cells with highest levels in lung and testis 3. It was first proposed that EFHC1 was “pro-apoptotic” when overexpression in hippocampal neurons in vitro induced apoptotic cell death. This effect was significantly reduced by any of the five mutations associated with JME. Patch-clamp analysis of BHK (Baby Hamster Kidney) cells transfected with Cav2.3 VDCC (voltage-dependent calcium channel) and EFHC1 showed significantly increased R-type Ca2+ currents. So, the pro-apoptotic effect of EFHC1 was assigned to this enhancing effect on Ca2+ through Cav2.3 VDCC 3. In 2005, another research group pointed out that EFHC1 is orthologous to Rib72, an axonemal protein of Chlamydomonas reinhardtii. They demonstrated that EFHC1 is abundantly expressed in mouse tissues that have motile cilia or flagella, including the brain, and suggested that it plays a role in the intrinsic properties of these organelles 8. One of our laboratories previously reported that the subcellular distribution of EFHC1 in different cell lines varied during the cell cycle. In interphase cells, the protein is present in the cytoplasm and nucleus, except nucleoli and is particularly concentrated at the centrosome. During mitosis, EFHC1 is localized at spindle poles of the mitotic spindle and also at the midbody during cytokinesis 9. These results suggest that EFHC1 could play an important role during cell division and in particular during brain development since mRNA expression is higher at embryonic stages as compared to adult 10. More recently, we demonstrated that EFHC1 is a microtubule-associated protein (MAP) playing a key role in neuronal migration 11. In this chapter we review these putative roles of Myoclonin 1 / EFHC1 or during brain development and during adulthood. We posit an hypothesis that JME is a developmental disease involving neuronal migration and synaptic bouton and dendritic morphogenesis. EFHC1/MYOCLONIN1, A PROTEIN OF UNKNOWN FUNCTION Myoclonin 1 /EFHC1 gene is located on chromosome 6 (6p11–12) between markers D6S1960 and D6S11024, spans 72 kb and contains 11 exons. This gene encodes a protein of 640 amino acids. A domain search identified three tandemly repeated so called DM10 domains, a motif with unknown function. This protein also contains a single EF-hand, a well known Ca2+binding motif, from which it was named EFHC1 for EF-hand Containing 1 (Figure 1). This motif is located at the C-terminus between amino acid 578 and 606 and encoded by a nucleotide sequence present in exon 10. Page 2 Myoclonin1/EFHC1 in cell division, neuroblast migration, synapse/dendrite formation in juvenile myoclonic epilepsy Japer's Basic M ecanism s of he Eppsies Japer's Basic M ecanism s of he Eppsies Figure 1. Schematic representation of the EFHC1/Myoclonin1 gene, the long and short forms of the EFHC1 protein and the different mutations found co segregated with the JME phenotype The transcript undergo alternative splicing in exon 4, resulting in a C-terminally truncated protein, eliminating the EF-hand domain and two DM10 sequences. This last short form therefore only contains 278 amino acids, the first 240 being common with the entire molecule.

Laurence De Nijs - One of the best experts on this subject based on the ideXlab platform.

  • Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy.
    Frontiers in cellular neuroscience, 2019
    Co-Authors: Maxime Gilsoul, Laurence De Nijs, Thierry Grisar, Antonio V. Delgado-escueta, Bernard Lakaye
    Abstract:

    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 during development. These alterations may explain "microdysgenesis" neuropathology, impulsivity, executive dysfunctions, EEG polyspike waves, and awakening m-t-c convulsions observed in JME patients.

  • EFHC1 variants in juvenile myoclonic epilepsy reanalysis according to nhgri and acmg guidelines for assigning disease causality
    Genetics in Medicine, 2017
    Co-Authors: Julia N Bailey, Marco T. Medina, Laurence De Nijs, Reyna M Duron, Christopher Patterson, Viethuong V Nguyen, Miyabi Tanaka, Aurelio Jaraprado
    Abstract:

    EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case–control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether EFHC1−/− KO mice recapitulate CTC convulsions and “microdysgenesis” neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. Nine variants were classified as “pathogenic,” 14 as “likely pathogenic,” 9 as “benign,” and 2 as “likely benign.” Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non–ion channel microtubule–associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and “microdysgenesis” neuropathology of JME. Genet Med 19 2, 144–156.

  • 0045 mutations of myoclonin1 EFHC1 disrupt radial and tangential migrations during brain development
    Epilepsy & Behavior, 2013
    Co-Authors: Thierry Grisar, Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Bernard Coumans, Bernard Lakaye
    Abstract:

    many of the milder forms of epilepsy, the genetic contribution is made up of many factors that each contributes little to the disease risk. This is called multifactorial inheritance. Juvenile myoclonic epilepsy (JME) is thought to be inherited in amultifactorial mode. So, while genetic factors are largely to blame for the condition, we encountermany sporadic cases, in addition to families with multiple affected members with JME and families with both JME and other forms of epilepsy. Genetic research is aimed at finding genetic factors that contribute to disease risk. If the genetic factor has a large effect, genetic testing can be used for diagnosis and prognosis and, maybe, for treatment. In multifactorial disorders, such as JME, the aims are more fundamental: understanding the biology of the disorder by placing the genes that contribute in a network that makes sense. The quality of the research into multifactorial traits depends on many factors: first, a correct diagnosis; next, knowledge of ethnicity of the patients and the healthy people we used to compare them with; and, finally, the quality of the lab work and the statistical analysis. In this talk, I will discuss what is known about the multifactorial genetics of JME and what is done to move forward. I will dedicate time to the question as to why knowledge of ethnicity is important in this type of studies.

  • Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or Myoclonin1.
    Epilepsy & Behavior, 2013
    Co-Authors: Laurence De Nijs, Nathalie Wolkoff, Thierry Grisar, Bernard Lakaye
    Abstract:

    Abstract Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

  • mutations of EFHC1 linked to juvenile myoclonic epilepsy disrupt radial and tangential migrations during brain development
    Human Molecular Genetics, 2012
    Co-Authors: Laurence De Nijs, A V Delgadoescueta, Nathalie Wolkoff, Thierry Grisar, Bernard Coumans, Bernard Lakaye
    Abstract:

    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 microtubule-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 the 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.

Reyna M Duron - One of the best experts on this subject based on the ideXlab platform.

  • EFHC1 variants in juvenile myoclonic epilepsy reanalysis according to nhgri and acmg guidelines for assigning disease causality
    Genetics in Medicine, 2017
    Co-Authors: Julia N Bailey, Marco T. Medina, Laurence De Nijs, Reyna M Duron, Christopher Patterson, Viethuong V Nguyen, Miyabi Tanaka, Aurelio Jaraprado
    Abstract:

    EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case–control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether EFHC1−/− KO mice recapitulate CTC convulsions and “microdysgenesis” neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. Nine variants were classified as “pathogenic,” 14 as “likely pathogenic,” 9 as “benign,” and 2 as “likely benign.” Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non–ion channel microtubule–associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and “microdysgenesis” neuropathology of JME. Genet Med 19 2, 144–156.

  • absence seizures in juvenile myoclonic epilepsy whole exome sequencing results and subsyndromes p2 008
    Neurology, 2016
    Co-Authors: Marco T. Medina, Reyna M Duron, Iris E Martinezjuarez, Aurelio Jaraprado, Adriana Ochoa, Minerva Lopezruiz, Yolli Molina, Laura Maria De Figueiredo Ferreira Guilhoto, Elsa Yacubian
    Abstract:

    OBJECTIVE To refine classification of Juvenile Myoclonic Epilepsy (JME) subsyndromes in 298 cases according to age at onset of absence seizures (ABS) and results of whole exome sequencing (WES). BACKGROUND The 2011 Avignon Workshop established the diagnostic criteria for JME as onset of awakening myoclonias and EEG 4-6Hz polyspike waves between 10-25 years of age. However, ABS with/without eyelid myoclonia (EM), astatic drop, and photosensitivity confound JME nosology. DESIGN/METHODS JME cases were regrouped according to age onset of ABS: early childhood (1-5 yr) [eCA/JME], childhood (6-11y) [CA/JME], adolescence [adolABS/JME] (12-21y), and JME with ABS in adulthood (22y+). WES of 12 large JME families followed linkage and haplotype analysis. Discovered epilepsy genes were then screened in the 298 cases. RESULTS Out of 298, 134 probands (45[percnt]) had classic JME (cJME), 60 (20[percnt]) had CA/JME, 70 (23[percnt]) had adolABS/JME, 20 (7[percnt]) had eCA/JME, 9 (3[percnt]) had astatic seizures with JME, and only 5 (2[percnt]) had adulthood ABS/JME. EFHC1 variants were genetically implicated in cJME (16 cases) and CA/JME (1 case), ICK variants in cJME (7 probands) and adolABS/JME (1 proband). IPO8 variants in photosensitive CA with/without EM evolving to JME (6 probands), JME with adolABS (2 probands), JME with absence and astatic seizures (1 proband), and JME with adult onset ABS (1 proband), and 7 cases of childhood ABS only from another cohort. PROSER1 variants were implicated adolABS/JME (6 probands) and one case with cJME. MYOFERLIN variant was implicated in a proband with photosensitive eCA/ JME. CONCLUSIONS EFHC1 and ICK variants are most common in cJME, while IPO8 and MYOFERLIN variants predominate in JME with eCA, adolABS, CA/JME and adult onset ABS. PROSER1 variants associated with pyknoleptic adolABS/JME. Finding variants of genes mean JME subsyndromes are true entities and separate diseases. Study supported by NIH R01NS055057, VACO Merit Review Grant, CIDR. Disclosure: Dr. Duron has nothing to disclose. Dr. Medina has nothing to disclose. Dr. Martinez-Juarez has received personal compensation for activities with commercial entities as a consultant. Dr. Jara-Prado has nothing to disclose. Dr. Ochoa has nothing to disclose. Dr. Lopez-Ruiz has nothing to disclose. Dr. Molina has nothing to disclose. Dr. Guilhoto has nothing to disclose. Dr. Yacubian has nothing to disclose. Dr. Wight has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Lin has nothing to disclose. Dr. Bai has nothing to disclose. Dr. Tanaka has nothing to disclose. Dr. Patterson has nothing to disclose. Dr. Alonso has nothing to disclose. Dr. Bailey has nothing to disclose. Dr. Delgado-Escueta has nothing to disclose.

  • the quest for juvenile myoclonic epilepsy genes
    Epilepsy & Behavior, 2013
    Co-Authors: Marco T. Medina, Julia N Bailey, A V Delgadoescueta, Bobby P C Koeleman, Reyna M Duron
    Abstract:

    Abstract Introduced into a specific population, a juvenile myoclonic epilepsy (JME) mutation generates linkage disequilibrium (LD). Linkage disequilibrium is strongest when the JME mutation is of recent origin, still “hitchhiking” alleles surrounding it, as a haplotype into the next thousands of generations. Recombinations decay LD over tens of thousands of generations causing JME alleles to produce smaller genetic displacements, requiring other genes or environment to produce an epilepsy phenotype. Family-based linkage analysis captures rare epilepsy alleles and their “hitchhiking” haplotypes, transmitted as Mendelian traits, supporting the common disease/multiple rare allele model. Genome-wide association studies identify JME alleles whose linkage disequilibrium has decayed through thousands of generations and are sorting out the common disease/common allele versus rare allele models. Five Mendelian JME genes have been identified, namely, CACNB4 , CASR , GABRa1 , GABRD , and Myoclonin1/EFHC1. Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to JME. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?

  • dna variants in coding region of EFHC1 snps do not associate with juvenile myoclonic epilepsy
    Epilepsia, 2009
    Co-Authors: Dongsheng Bai, Toshimitsu Suzuki, Marco T. Medina, Julia N Bailey, Maria Elisa Alonso, Reyna M Duron, Iris E Martinezjuarez, Jesus Machadosalas, Ricardo Ramosramirez, Miyabi Tanaka
    Abstract:

    Juvenile myoclonic epilepsy (JME) is the most common cause of primary grand mal seizures and accounts for at least 3 to 12% of all epilepsies. JME can be inherited as a Mendelian autosomal dominant or autosomal recessive trait or as a non-Mendelian complex genetic trait. Three mutation-harboring Mendelian genes for JME have been reported. Mutations in α1 subunit of γ-aminobutyric acid receptor subtype A on chromosome 5q34 segregated with nine affected individuals of a three-generation French Canadian family with JME (Cossette et al., 2002). Mutations in a chloride-channel gene, CLCN2 on chromosome 3q26 segregated with five affected members of a three-generation German family with JME (Haug et al., 2003). Our group first mapped a JME locus in chromosome 6p12 (Liu et al., 1995, 1996; Serratosa et al., 1996; Bai et al., 2002) and identified a mutation-harboring Mendelian gene that encodes a protein with one EF-hand motif. Hence, we called the gene EFHC1. We reported one doubly heterozygous and three heterozygous missense mutations segregated in 21 clinical and electroencephalography (EEG) affected members of six unrelated two- to four-generation JME Hispanic families from California (U.S.A.) and Mexico (Suzuki et al., 2004). The 6p12 JME locus was again mapped independently by two separate groups; first, by a genome-wide linkage study of JME families from various countries of Europe (Hempelmann et al., 2006) and second by a chromosome 6p12 replication genetic linkage study in a smaller cohort of 18 Dutch families (Pinto et al., 2004). Similar and novel missense mutations in EFHC1 were reported in Caucasian JME patients from Tennessee (U.S.A.), Italy, and Austria (Ma et al., 2006; Stogmann et al., 2006; Annesi et al., 2007). Therefore the causality of the gene in a Mendelian JME has been established, but the influence of common functional single nucleotide polymorphisms (SNPs) in JME with complex genetics has not been established. Pinto et al. (2006) reported three SNPs of EFHC1 that were not associated with JME in a case-control study of 112 unrelated patients and 180 controls. In our present study, we chose the most common four coding SNPs of EFHC1 and performed both case-control and family-based association studies to determine if they contribute to the complex genetics of JME.

  • novel mutations in myoclonin1 EFHC1 in sporadic and familial juvenile myoclonic epilepsy
    Neurology, 2008
    Co-Authors: M T Medina, Toshimitsu Suzuki, Julia N Bailey, Dongsheng Bai, Maria Elisa Alonso, Reyna M Duron, Iris E Martinezjuarez, Y Inoue, I Yoshimura, Sunao Kaneko
    Abstract:

    Background: Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in 20% of Hispanic families with JME. Objective: To examine what percentage of consecutive JME clinic cases have mutations in Myoclonin1/EFHC1 . Methods: We screened 44 consecutive patients from Mexico and Honduras and 67 patients from Japan using heteroduplex analysis and direct sequencing. Results: We found five novel mutations in transcripts A and B of Myoclonin1/EFHC1 . Two novel heterozygous missense mutations (c.755C>A and c.1523C>G) in transcript A occurred in both a singleton from Mexico and another singleton from Japan. A deletion/frameshift (C.789del.AV264fsx280) in transcript B was present in a mother and daughter from Mexico. A nonsense mutation (c.829C>T) in transcript B segregated in four clinically and seven epileptiform-EEG affected members of a large Honduran family. The same nonsense mutation (c.829C>T) occurred as a de novo mutation in a sporadic case. Finally, we found a three-base deletion (−364○%–362del.GAT) in the promoter region in a family from Japan. Conclusion: Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Honduras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1 . These results represent the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group. GLOSSARY: CAE = childhood absence epilepsy; FS = febrile seizures in infancy/childhood; GM = grand mal tonic clonic seizure; JME = Juvenile myoclonic epilepsy; PSW = 3–6 Hz polyspike and slow wave complexes; SW = single spike and slow wave complex.