Mutations in EFHC1 cause juvenile myoclonic epilepsy

Suzuki, Toshimitsu; Delgado‐Escueta, Antonio V.; Aguan, Kripamoy; Alonso, María Elisa; Jun, Shi; Hara, Yuji; Nishida, Motohiro; Numata, Tomohiro; Medina, Marco T.; Takeuchi, T.; Morita, Ryoji; Bai, Dongsheng; Ganesh, Subramaniam; Sugimoto, Yukihiko; Inazawa, Johji; Bailey, Julia N.; Ochoa, Adriana; Jara‐Prado, Aurelio; Rasmussen, Astrid; Ramos-Peek, Jaime; Córdova, Sergio; Rubio-Donnadieu, Francisco; Inoue, Yushi; Ōsawa, Makiko; Kaneko, Sunao; Oguni, Hirokazu; Mori, Yasuo; Yamakawa, Kazuhiro

doi:10.1038/ng1393

Cited by 334 publications

(361 citation statements)

References 26 publications

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“…Consequently, voltage-gated and ligand-gated ion channels are the preeminent targets for AEDs. Indeed, when linkage studies have identified genes of unknown function as candidate epilepsy genes, the gene products have often turned out to be ion channel subunits or proteins associated in some way with ion channels (see discussion of EFHC1 34 and LGI1 35 in the sections on voltage-gated calcium and potassium channels, respectively).…”

Section: New Approaches To Identify Aed Molecular Targetsmentioning

confidence: 99%

“…89 Five mutations in EFHC1, a gene encoding a protein with an EF-hand motif, have been found in families with juvenile myoclonic epilepsy (JME). 34 This protein associates with the R-type Ca 2ϩ channel Ca v 2.3. EFHC1 increases R-type Ca 2ϩ currents, but this activity is lost when the protein bears the mutations associated with JME.…”

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

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Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: New Approaches To Identify Aed Molecular Targetsmentioning

confidence: 99%

Section: Voltage-gated Calcium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…Moreover, inherited grand mal or tonicclonic seizures can result from JME [Janz, 1959]. A recent report suggested that JME may be caused by mutations in the EFHC1 gene [Suzuki et al, 2004]. Here I will discuss the evidence supporting a role for Efhc1 in JME and detail recent analyses [Ikeda et al, 2005] that demonstrate that this protein is the mammalian orthologue of Chlamydomonas Rib72 and as such is likely an integral axonemal component [Patel-King et al, 2002;Ikeda et al, 2003] located within the protofilament ribbons [Ikeda et al, 2003] and, potentially, is also present in basal bodies/centrioles [Hinchcliffe and Linck, 1998;Keller et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

“…Northern analysis of murine tissues demonstrated that Efhc1 expression was vastly upregulated in testis and was also prominent in lung and oviduct [Suzuki et al, 2004;Ikeda et al, 2005], which both contain large numbers of ciliated cells. In comparison, expression levels in other murine tissues including brain, heart, kidney, and spleen were low.…”

Section: Introductionmentioning

confidence: 99%

Axonemal protofilament ribbons, DM10 domains, and the link to juvenile myoclonic epilepsy

King

2006

Cell Motil. Cytoskeleton

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Juvenile myoclonic epilepsy (JME) is a common neurological disorder that results in short uncontrolled muscle contractions and sometimes more severe seizures. Genetic studies have suggested that JME may be caused by mutations in EFHC1. The Efhc1 protein consists of three DM10 domains and a C-terminal region containing a potential Ca 2þ -binding motif. In Chlamydomonas, a protein (Rib72) of almost identical domain structure is a component of the protofilament ribbons within the doublet microtubules of the flagellar axoneme. Here I discuss recent work that supports assignment of human Efhc1 as a ciliary component and the resulting implications for the mechanism of disease causation. Cell Motil.

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“…1991; Suzuki et al. 2004). Ultimately, further genetic, informatics and molecular experimental studies identified mutations in Myoclonin1 /EFHC1 in 6p12 as disease causing in JME (Suzuki et al.…”

Section: Introductionmentioning

confidence: 99%

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

Wight

Nguyen

Medina³

et al. 2016

Molec Gen & Gen Med

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Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic persons with normal EEGs. Two‐point parametric linkage analyses were performed with 5185 single‐nucleotide polymorphisms on individual pedigrees and pooled pedigrees using four diagnostic models based on epilepsy/EEG diagnoses. Haplotype analyses of the entire genome were also performed for each individual. In pedigree 1, haplotyping identified a 34 cM region in 2q21.2–q31.1 cosegregating with all affected members, an area close to 2q14.3 identified by linkage (Z max = 1.77; pedigree 1). In pedigree 2, linkage and haplotyping identified a 44 cM cosegregating region in 13q13.3–q31.2 (Z max = 3.50 at 13q31.1; pooled pedigrees). In pedigree 3, haplotyping identified a 6 cM cosegregating region in 17q12. Possible cosegregation was also identified in 13q14.2 and 1q32 in pedigree 3, although this could not be definitively confirmed due to the presence of uninformative markers in key individuals. Differing chromosome regions identified in specific JME subsyndromes may contain separate JME disease‐causing genes, favoring the concept of JME as several distinct diseases. Whole‐exome sequencing will likely identify a CAE/JME gene in 2q21.2–2q31.1, a JME/pA gene in 13q13.3–q31.2, and a cJME gene in 17q12.

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Mutations in EFHC1 cause juvenile myoclonic epilepsy

Cited by 334 publications

References 26 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Axonemal protofilament ribbons, DM10 domains, and the link to juvenile myoclonic epilepsy

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves

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