title: De novo mutations in SIK1 cause a spectrum of developmental epilepsies.
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.
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Hansen
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Chelsi
authors.initials: C
authors.lastname: Snow
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Tuttle
authors.affiliation: Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Dalia H
authors.initials: DH
authors.lastname: Ghoneim
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Chun-Song
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Sonya A
authors.initials: SA
authors.lastname: Gunter
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO 63110, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Smyser
authors.affiliation: Department of Neurology, Washington University, St. Louis, MO 63110, USA.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.affiliation: Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University, St. Louis, MO 63110, USA.
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.affiliation: 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.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: LeBonheur Children's Hospital and the University of Tennessee, Memphis, TN 38103, USA.
authors.forename: James
authors.initials: J
authors.lastname: Wheless
authors.affiliation: 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.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Halterman
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Jansen
authors.affiliation: Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA; Departments of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Bryce M
authors.initials: BM
authors.lastname: Paschal
authors.affiliation: 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: alex_paciorkowski@urmc.rochester.edu.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
mesh_terms: D000367:Age Factors; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002648:Child; D017931:DNA Primers / Q000235:genetics; D004569:Electroencephalography; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D017346:Protein Serine-Threonine Kinases; C509080:SIK1 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases
references.citation: Epilepsia. 2001;42 Suppl 3:23-6
references.pmid: 11520318
references.citation: Epilepsia. 2008 Nov;49(11):1865-70
references.pmid: 18557779
references.citation: Brain Dev. 2002 Aug;24(5):266-8
references.pmid: 12142061
references.citation: J Biol Chem. 2002 Nov 1;277(44):42334-43
references.pmid: 12200423
references.citation: J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):397-400
references.pmid: 12943728
references.citation: Epilepsia. 2004 Nov;45(11):1416-28
references.pmid: 15509243
references.citation: Am J Hum Genet. 2004 Dec;75(6):1079-93
references.pmid: 15492925
references.citation: Brain Dev. 1987;9(4):371-6
references.pmid: 3434712
references.citation: Epilepsia. 1993;34 Suppl 7:S7-17
references.pmid: 8243377
references.citation: Epilepsia. 1995 Oct;36(10):1017-24
references.pmid: 7555952
references.citation: FEBS J. 2006 Jun;273(12):2730-48
references.pmid: 16817901
references.citation: Epilepsy Res. 2006 Aug;70 Suppl 1:S68-76
references.pmid: 16829044
references.citation: Epilepsy Res. 2006 Aug;70 Suppl 1:S58-67
references.pmid: 16829045
references.citation: Neurology. 2007 Jul 31;69(5):427-33
references.pmid: 17664401
references.citation: Nat Genet. 2008 Jun;40(6):782-8
references.pmid: 18469812
references.citation: Epilepsia. 2008 Jun;49(6):1027-37
references.pmid: 18266744
references.citation: Hum Mol Genet. 2008 Dec 1;17(23):3740-60
references.pmid: 18799476
references.citation: Brain Dev. 2002 Jan;24(1):13-23
references.pmid: 11751020
references.citation: J Neurosci. 2009 Feb 25;29(8):2334-43
references.pmid: 19244510
references.citation: Endocr J. 2009;56(1):121-30
references.pmid: 18946175
references.citation: Pediatr Neurol. 2009 Aug;41(2):111-3
references.pmid: 19589458
references.citation: J Med Genet. 2010 Jan;47(1):22-9
references.pmid: 19592390
references.citation: J Child Neurol. 2010 Apr;25(4):423-8
references.pmid: 19749181
references.citation: Epilepsia. 2010 Oct;51(10):2175-89
references.pmid: 20608959
references.citation: Epilepsia. 2010 Dec;51(12):2449-52
references.pmid: 21204804
references.citation: Synapse. 2012 Jan;66(1):61-70
references.pmid: 21954104
references.citation: Endocrinology. 2012 Jan;153(1):223-33
references.pmid: 22109884
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):117-22
references.pmid: 23256157
references.citation: PLoS One. 2013;8(1):e54545
references.pmid: 23349925
references.citation: Neurogenetics. 2013 May;14(2):99-111
references.pmid: 23389741
references.citation: PLoS Genet. 2013;9(8):e1003709
references.pmid: 23990802
references.citation: Cell. 2013 Aug 29;154(5):1100-11
references.pmid: 23993098
references.citation: Nature. 2013 Sep 12;501(7466):217-21
references.pmid: 23934111
references.citation: J Neurosci. 2012 Oct 10;32(41):14389-401
references.pmid: 23055509