De novo mutations in SIK1 cause a spectrum of developmental epilepsies

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, William B. Dobyns, James Wheless, Marc W. Halterman, Laura A. Jansen, Bryce M. Paschal, Alex R. Paciorkowski

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)682-690
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - Apr 2 2015
Externally publishedYes

Bibliographical note

Funding Information:
The authors would like to thank the families of our research subjects. Research reported in this work was supported by the NIH, National Institute of Neurologic Disorders and Stroke under award numbers K02NS072162 (to L.A.J.), R01NS046616 (to W.B.D.), R01NS076617 (to M.W.H.), and K08NS078054 (to A.R.P.), and the National Institute on Aging R01AG040162 (to B.M.P.). We would like to acknowledge the University of Rochester Genomics Research Center for sequencing support, and the University of Rochester Center for Integrated Research Computing for providing high-performance computing resources. We wish to thank Dr. Timothy McKinsey (University of Colorado, Denver) for HDAC5 constructs.

Publisher Copyright:
© 2015 The American Society of Human Genetics.


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