De novo mutations in SIK1 dysregulate HDAC5-MEF2C activity and cause Ohtahara syndrome and infantile spasms. J. N. Hansen1, C. Snow2, E. Tuttle1, D. Ghoneim1, C. Smyser3, C. A. Gurnett3, M. Shinawi4, W. B. Dobyns5, J. Wheless6, M. W. Halterman1,7, L. A. Jansen8, B. M. Paschal2,9, A. R. Paciorkowski1,7,10 1) Center for Neural Development and Disease, University of Rochester, Rochester, NY; 2) Center for Cell Signaling, University of Virginia, Charlottesville, VA; 3) Department of Neurology, Washington University, St. Louis, MO; 4) Department of Pediatrics, Division of Genomic Medicine, Washington University, St. Louis, MO; 5) Department of Neurology and Division of Genetic Medicine, Department of Pediatrics, University of Washington and Center for Integrative Brain Research, Seattle Research Institute, Seattle, WA; 6) LeBonheur Children's Hospital and the University of Tennessee, Memphis, TN; 7) Department of Neurology, University of Rochester Medical Center, Rochester, NY; 8) Department of Neurology, University of Virginia, Charlottesville, VA; 9) Departments of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA; 10) Departments of Pediatrics and Biomedical Genetics, University of Rochester Medical Center, Rochester, NY.

   Ohtahara syndrome and infantile spasms are severe childhood epilepsies for which genetic causes have been increasingly identified, including mutations in the forebrain transcription factors ARX, FOXG1 and MEF2C. Here we report 3 individuals with Ohtahara syndrome and 3 individuals with infantile spasms with de novo mutations in the salt-inducible-kinase SIK1 that dysregulate downstream HDAC5 and MEF2C activity. A subset of SIK1 mutants are expressed at higher levels than wild-type SIK1 and are also more resistant to proteasomal degradation. Downstream signaling of SIK1 is also disrupted by these mutations, with SIK1 mutants exhibiting reduced MEF2C transcriptional activity and/or increased HDAC5 phosphorylation in vitro. These observations suggest that SIK1 mutations causing Ohtahara syndrome and infantile spasms are likely gain-of-function mutations. This report is the first example of a human disease associated with SIK1 mutations, and a novel cause of developmental epilepsy associated with dysregulation of the forebrain transcription factor MEF2C.

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