title: Microtubule-associated defects caused by EFHC1 mutations in juvenile myoclonic epilepsy.
abstract: Juvenile myoclonic epilepsy (JME) is a common form of epilepsy with a substantial genetic basis to its etiology. While earlier studies have identified EFHC1 as a causative gene for JME, subsequent studies have suggested that ethnicity may play a role in determining expression of the JME phenotype among individuals carrying EFHC1 mutations. Here, we report on our studies on EFHC1 in JME patients from India. We examined the complete structure of the EFHC1 transcript from 480 JME patients and 700 control chromosomes by direct sequencing. Functional correlates of mutations were studied by immunolocalization experiments in cultured mammalian cells and protein homology modeling by in silico methods. Thirteen mutations, of which 11 were previously not known, were identified in 28 JME patients. These mutations accounted for about 6% of the patients examined. Functional studies suggest that these EFHC1 mutations result in microtubule-related abnormalities during cell division. In silico analysis for a subset of mutations suggests that they may affect EFHC1 protein domains, compromising its ability to interact with other proteins. Our observations strengthen the evidence supporting a role for EFHC1 in JME in a population ethnically and geographically distinct from the one in which the gene was initially identified, and broaden the extent of allelic heterogeneity in the gene.
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, Karnataka, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Raju
authors.affiliation: Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Satishchandra
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, Karnataka, India.
authors.forename: Sourav
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India.
authors.forename: Vishwanathan
authors.initials: V
authors.lastname: Iyer
authors.affiliation: Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India.
authors.forename: Sanjib
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, Karnataka, India.|Neuroscience Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore, Karnataka, India.
authors.forename: Anuranjan
authors.initials: A
authors.lastname: Anand
mesh_terms: D000293:Adolescent; D000328:Adult; D002135:Calcium-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002875:Chromosomes / Q000648:ultrastructure; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007194:India; D008297:Male; D009154:Mutation; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics*; D000072417:Protein Domains; D055815:Young Adult
chemical_list: D002135:Calcium-Binding Proteins; C489648:EFHC1 protein, human
keywords: EFHC1/myoclonin1; etiology; immunolocalization; in silico analysis; juvenile myoclonic epilepsy