2. Academic Validation
  3. De novo mutations in SIK1 cause a spectrum of developmental epilepsies

De novo mutations in SIK1 cause a spectrum of developmental epilepsies

  • Am J Hum Genet. 2015 Apr 2;96(4):682-90. doi: 10.1016/j.ajhg.2015.02.013.
Jeanne Hansen 1,  Chelsi Snow 2,  Emily Tuttle 1,  Dalia H Ghoneim 1,  Chun-Song Yang 2,  Adam Spencer 2,  Sonya A Gunter 3,  Christopher D Smyser 4,  Christina A Gurnett 4,  Marwan Shinawi 5,  William B Dobyns 6,  James Wheless 7,  Marc W Halterman 8,  Laura A Jansen 3,  Bryce M Paschal 9,  Alex R Paciorkowski 10
Affiliations

Affiliations

  • 1 Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 2 Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
  • 3 Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
  • 4 Department of Neurology, Washington University, St. Louis, MO 63110, USA.
  • 5 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, St. Louis, MO 63110, USA.
  • 6 Department of Neurology and Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Research Institute, Seattle, WA 98105, USA.
  • 7 LeBonheur Children's Hospital and the University of Tennessee, Memphis, TN 38103, USA.
  • 8 Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
  • 9 Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA; Departments of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
  • 10 Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA; Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA. Electronic address: [email protected].
PMID: 25839329 DOI: 10.1016/j.ajhg.2015.02.013
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.

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