De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies
| Autor: | Marwan Shinawi, James W. Wheless, Adam Spencer, Jeanne N. Hansen, Chun Song Yang, Laura A. Jansen, Dalia Ghoneim, Alex R. Paciorkowski, Emily Tuttle, Chelsi J. Snow, William B. Dobyns, Christopher D. Smyser, Christina A. Gurnett, Sonya A. Gunter, Bryce M. Paschal, Marc W. Halterman |
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| Rok vydání: | 2015 |
| Předmět: |
Ohtahara syndrome
Molecular Sequence Data Protein Serine-Threonine Kinases Biology medicine.disease_cause Bioinformatics Polymerase Chain Reaction Histone Deacetylases Epilepsy 03 medical and health sciences 0302 clinical medicine Report medicine Genetics Humans Genetics(clinical) Kinase activity Autistic Disorder Phosphorylation Early myoclonic encephalopathy Child Cellular localization Genetics (clinical) De novo mutations DNA Primers 030304 developmental biology Mutation 0303 health sciences Base Sequence Age Factors Infant Newborn Infant Electroencephalography medicine.disease Immunohistochemistry Magnetic Resonance Imaging Human genetics 3. Good health Protein kinase domain Autism Erratum Spasms Infantile 030217 neurology & neurosurgery |
| Zdroj: | The American Journal of Human Genetics. 96(4):682-690 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2015.02.013 |
| Popis: | Developmental epilepsies are age-dependent seizure disorders for which genetic causes have been increasingly identified. Here we report six unrelated individuals with mutations in salt-inducible kinase 1 (SIK1) in a series of 101 persons with early myoclonic encephalopathy, Ohtahara syndrome, and infantile spasms. Individuals with SIK1 mutations had short survival in cases with neonatal epilepsy onset, and an autism plus developmental syndrome after infantile spasms in others. All six mutations occurred outside the kinase domain of SIK1 and each of the mutants displayed autophosphorylation and kinase activity toward HDAC5. Three mutations generated truncated forms of SIK1 that were resistant to degradation and also showed changes in sub-cellular localization compared to wild-type SIK1. We also report the human neuropathologic examination of SIK1-related developmental epilepsy, with normal neuronal morphology and lamination but abnormal SIK1 protein cellular localization. Therefore, these results expand the genetic etiologies of developmental epilepsies by demonstrating SIK1 mutations as a cause of severe developmental epilepsy. |
| Databáze: | OpenAIRE |
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