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FLASH GENE
Symbol CDKL5 contributors: mct/npt - updated : 28-01-2017
HGNC name cyclin-dependent kinase-like 5
HGNC id 11411
Corresponding disease
EIEE2 epileptic encephalopathy, early infantile, 2
ISSX infantile spasms syndrome with hypsarrhythmia
Location Xp22.13      Physical location : 18.443.724 - 18.671.747
Synonym name serine/threonine kinase 9
Synonym symbol(s) STK9
EC.number 2.7.11.22
DNA
TYPE functioning gene
SPECIAL FEATURE overlapping, gene in gene, opposite orientation
STRUCTURE 228.02 kb     21 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
Binding site
text structure
  • exons 17 to 20 in 3'overlapping with exon 6, 5, 4 and exon 3 of RS1
  • MYCN acts as a direct repressor of the CDKL5 promoter
    • MAPPING cloned Y linked N status provisional
    Map pter - DXS418 - SCML1 - DXS7994 - DXS7995 - DXS7997 - DXS7998 - DXS257 - DXS6762 - SCML2 - DXS7999 - DXS6763 - CDKL5 - DXS8000 - DXS6760 - RS1 RS1 - DXS7176 - DXS8001 - PPEF1 - DXS999 - DXS7161 - DXS443 - qter
    Authors Montini (98,99)
    RNA
    TRANSCRIPTS type messenger
    text
  • identification of a novel exon, which is referred to as exon 16b, within the cyclin-dependent kinase (CDK)-like 5 (CDKL5) gene that is implicated in the X-linked infantile spasm syndrome and the early-onset seizure variant of Rett syndrome (PMID: 21124335)
    • identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    21 - 3434 115 1030 in a variety of tissues 2012 21748340
    both isoforms differ in the 5prime untranslated exons
    22 - 3430 115 1030 in testis only 2012 21748340
    both isoforms differ in the 5prime untranslated exons
    - - - 107 - in brain and all other tissues 2012 21748340
  • including a novel exon (16b)
  • alternative C-terminus that terminates in intron 18
  • major CDKL5 transcript
    		•
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Lymphoid/Immunethymus   highly
    Nervousbrain   highly
    Reproductivefemale systemovary   
     male systemtestis  highly
     male systemprostate   
    Respiratorylung    
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervouscentral   
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text placenta, neural cells, neocortex, hippocampus
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • N-terminal catalytic domain highly homologous to members of the mitogen-activated protein (MAP) kinase and cyclin-dependent (CDK) kinase families
  • a TXY sequence, activation motif of classic MAP kinases
  • C-terminal domain, which is frequently deleted in pathogenic mutations, is involved in an active nuclear export mechanism modulating the subcellular distribution of the kinase
    • HOMOLOGY
    interspecies homolog to murine Stk9
    homolog to C.elegans zk254.4
    Homologene
    FAMILY
  • protein kinase superfamily
  • CMGC Ser/Thr protein kinase family
  • CDC2/CDKX subfamily
    • CATEGORY enzyme , receptor membrane serine/threonine kinase
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    text
  • CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the C-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions
  • shuttles between the two main cellular compartments and the relative concentrations in each compartment seem to vary in different brain areas and during development
  • localizes to specific nuclear foci referred to as nuclear speckles in both cell lines and tissue (Nemos 2009)
  • localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments
    • basic FUNCTION
  • having protein kinase, ATP binding activities
  • involved in protein amino acid phosphorylation
  • autophosphorylates (can self-associate and mediate the phosphorylation of its own TEY [Thr-Glu-Tyr] motif)and mediating the phosphorylation of the methyl-CpG-binding protein 2 (MECP2)
  • shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export
  • regulates the dynamic behaviour of nuclear speckles, and controls nuclear speckle morphology probably by regulating the phosphorylation state of splicing regulatory proteins (Ricciardi 2009)
  • involved indirectly in pre-mRNA processing, by controlling splicing factor dynamics (Ricciardi 2009)
  • functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation
  • localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity
  • critical role of the palmitoylation-dependent CDKL5-DLG4 interaction in localizing CDKL5 to synapses for normal spine development
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with MECP2 (could dephosphorylate MECP2, and form a protein complex, the catalytic activity of CDKL5 mediating the phosphorylation of MECP2)
  • subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-D-aspartate receptors and suggest regulation of CDKL5 by cell death pathways
  • MYCN acts as a direct repressor of the CDKL5 promoter
  • CDKL5 binds and phosphorylates the cell adhesion molecule LRRC4C (this phosphorylation event ensures a stable association between LRRC4C and DLG4)
  • AMPH is the cytoplasmic substrate for CDKL5 and its phosphorylation may play crucial roles in the neuronal development
  • binds to the scaffolding protein postsynaptic density DLG4, and this binding promotes the targeting of CDKL5 to excitatory synapses
  • CDKL5 regulates microtubule dynamics via phosphorylation of MAP1S
    • cell & other
    REGULATION
    activated by phosphorylation on tyrosine and threonine
    inhibited by by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology
    ASSOCIATED DISORDERS
    corresponding disease(s) ISSX , EIEE2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    leading to severe neurodevelopmental disorders
    constitutional       loss of function
    absence or reduction of CDKL5 kinase functions have a greater impact on the nervous system than a gain of activity
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS