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Cell Press, American Journal of Human Genetics, 4(96), p. 682-690, 2015

DOI: 10.1016/j.ajhg.2015.02.013

Cell Press, American Journal of Human Genetics, 6(96), p. 1009

DOI: 10.1016/j.ajhg.2015.05.003

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De Novo Mutations in SIK1 Cause a Spectrum of Developmental Epilepsies

Journal article published in 2015 by Jeanne Hansen, Chelsi Snow, Emily Tuttle, Dalia H. Ghoneim, Chun-Song Yang, Adam Spencer, Sonya A. Gunter, Christopher D. Smyser, Christina A. Gurnett, Marwan Shinawi ORCID, William B. Dobyns, James Wheless, Marc W. Halterman, Laura A. Jansen, Bryce M. Paschal and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.