Microtubule-associated defects caused by <i>EFHC1</i>
 mutations in juvenile myoclonic epilepsy

Raju, Praveen Kumar; Satishchandra, Parthasarathy; Nayak, Sourav; Iyer, Vishwanathan; Sinha, Sanjib; Anand, Anuranjan

doi:10.1002/humu.23221

Cited by 9 publications

(9 citation statements)

References 46 publications

(49 reference statements)

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“…Later on, new heterozygous mutations in EFHC1 were described in other Mexican, Honduras, and Japanese families but also in 3 unrelated Italian families and in 5 patients from Austria (Stogmann et al, 2006; Annesi et al, 2007; Medina et al, 2008; Jara-Prado et al, 2012). Recently two studies performed in India described 5 missense mutations in six independent families and 13 mutations in 28 patients (Raju et al, 2017; Thounaojam et al, 2017). While pathogenic variants of EFHC1 are present in 3% of Japanese JME patients, in 7 to 9% in JME patients from Mexico and Honduras and in 5% of JME patients from India, pathogenic variants of EFHC1 may be extremely rare in JME patients from Germany while possibly absent in the Dutch, Swedish, and United Kingdom populations.…”

Section: Genes Associated With Jme and Their Cellular Rolementioning

confidence: 99%

“…On the other hand, both the human and the drosophila ortholog of EFHC1 interact directly with tubulin and associate with the mitotic spindles. Moreover, either the overexpression of pathological mutants or of truncated forms, or the knockdown using RNAi, all produced abnormal mitotic spindles in HEK cells (de Nijs et al, 2009; Rossetto et al, 2011; de nijs et al, 2012; Raju et al, 2017).…”

Section: Genes Associated With Jme and Their Cellular Rolementioning

confidence: 99%

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Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Gilsoul

Grisar

Delgado‐Escueta

et al. 2019

Front. Cell. Neurosci.

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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.

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Section: Genes Associated With Jme and Their Cellular Rolementioning

confidence: 99%

Section: Genes Associated With Jme and Their Cellular Rolementioning

confidence: 99%

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Gilsoul

Grisar

Delgado‐Escueta

et al. 2019

Front. Cell. Neurosci.

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“…It was suggested that the structural change in thalamocortical networks was associated with increased risk of JME (14). Therefore, the etiopathogenesis of JME focuses on genes that regulate microtubular dynamics that confirm neuronal migration and neuronal binding (5). EFHC1 is a new microtubule-associated protein that is very important in regulating neuronal migration during cell division and development.…”

Section: Discussionmentioning

confidence: 99%

“…Myoclonin 1 is synthesized in the cortex, hippocampus, and cerebellum of the adolescent and adult mouse brain (4). Myoclonin 1 was shown to be a protein associated with microtubule proteins, which have a structural role in cell division, and to cause microtubule-related anomalies in cell division in the presence of pathogenic variations (5). It is also known to play a role in cell division and neuronal migration during cortical development (6).…”

Section: Introductionmentioning

confidence: 99%

Susceptibility to Juvenile Myoclonic Epilepsy Associated with the EFHC1 Gene: First Case Report in Turkey

Şirinocak¹,

Salman²,

Kesim³

et al. 2019

tnd

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Juvenile myoclonic epilepsy (JME), characterized by predominating myoclonic seizures, is one of the most common forms of genetic generalized epilepsy. Genetic studies in JME reported susceptibility associated with EFHC1 gene. A 26-year-old male patient was admitted to our epilepsy outpatient clinic unit with one generalized tonic-clonic seizure and with previous myoclonic seizures started at the age of 17 years described as jerky movements. His neurologic examination and neuroimaging studies were normal. The family history was unremarkable. His electroencephalography was recorded under treatment and showed short-lasting paroxysms consisting of 6-7 Hz generalized slow waves and superimposed sharp contoured waves, slightly prominent over the posterior halves of the hemispheres, interpreted as generalized paroxysmal abnormality. After performing whole exom sequencing and investigating epilepsy-related genes, a heterozygous missense variant was found in EFHC1 gene causing amino acid change [rs137852776: NM_018100.4: c.685T>C;p 15 (Phe229Leu)]. His seizures are still under control with valproate 1000 mg/d. Variants in EFHC1 gene are the most commonly observed genetic abnormalities in patients with familial JME in different countries. Our study reported a EFHC1 gene variation in a patient typical JME for the first time in our country. Our finding is important for future clinical studies and genetic counseling in JME.

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“…Juvenile myoclonic epilepsy is a common form of GGEs, with a substantial genetic basis, including mutations in CACNB4, CASR, GABRA1, GABRD, and EFHC1. 30,31 Despite heritability estimates of up to 70%, genetic factors predisposing to JME are still mostly unknown due to their complex genetic predisposition and extensive genetic heterogeneity. Up to now, there have been no reports on the association between HCN2 variants and the susceptibility to JME.…”

Section: Discussionmentioning

confidence: 99%

Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

Yang

et al. 2017

Clin Exp Pharma Physio

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Epilepsy is a common complex neurological disorder, and some forms are resistant to drug treatment. The HCN1/HCN2 genes encode hyperpolarization-activated cyclic nucleotide-gated channels, which play important roles in the electrophysiology of neurons. We investigated the association between HCN1/HCN2 variants and drug resistance or the risk of genetic generalized epilepsies (GGEs). We used matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to assess nine variants of HCN1/HCN2 in 284 healthy participants and 483 GGEs (279 drug-responsive, 204 drug-resistant). Frequencies of HCN2 rs7255568 and rs3752158 G alleles differed in GGEs and in controls (P = .039, P = .027, respectively). The frequency of HCN2 haplotype (CAC) was higher in patients than controls (P = .046). The frequency of the HCN1 rs10462087 CC+CT genotype was lower in patients with childhood absence epilepsy (CAE) than controls (P = .047). Rs7255568 was associated with the risk of CAE (P = .028) and juvenile myoclonic epilepsy (JME) (P = .02). Rs3752158 was associated with the risk of generalized tonic-clonic seizures, JME, and febrile seizures (all P < .05). The frequency of the HCN2 haplotype (CAC) was higher in patients with JME (P = .015) and in those with febrile seizures (P = .024) than in controls. No significant association was found between HCN1/HCN2 alleles, genotypes or haplotypes, and drug resistance in patients. After Bonferroni's multiple comparisons correction, only the HCN2 rs3752158 C allele and GC+CC genotype frequencies in patients with JME were higher than those in controls (19.2% vs 11.6%, odds ratio (OR) = 1.71, 95% CI = 1.18-2.32), P = .004 < 0.05/9; 36% vs 22.2%, OR = 1.62(1.18-2.23), P = .003 < 0.05/9). Our study suggests that HCN2 rs3752158 is involved in the susceptibility to JME.

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Microtubule-associated defects caused by EFHC1 mutations in juvenile myoclonic epilepsy

Cited by 9 publications

References 46 publications

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Subtle Brain Developmental Abnormalities in the Pathogenesis of Juvenile Myoclonic Epilepsy

Susceptibility to Juvenile Myoclonic Epilepsy Associated with the EFHC1 Gene: First Case Report in Turkey

Case‐control pharmacogenetic study of HCN1/HCN2 variants and genetic generalized epilepsies

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