Affinage

CDKL5

Cyclin-dependent kinase-like 5 · UniProt O76039

Audit flag: ungrounded claim
Length
960 aa
Mass
107.5 kDa
Annotated
2026-06-09
100 papers in source corpus 32 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKL5 is a brain-enriched serine/threonine kinase that governs neuronal maturation, synaptic function, and excitability through phosphorylation of an expanding set of cytoskeletal, synaptic, and nuclear substrates (PMID:20861382, PMID:30266824, PMID:38081835). Its catalytic activity is intrinsically autoinhibited by its C-terminal domain, which also controls nucleocytoplasmic distribution: C-terminal truncation enhances autophosphorylation and shifts the kinase between nucleus and cytoplasm, and DYRK1A-mediated phosphorylation at Ser-308 promotes cytoplasmic localization (PMID:16330482, PMID:18701457, PMID:27840050). CDKL5 recognizes substrates through an RPXS(A) consensus motif and phosphorylates the microtubule regulators MAP1S, EB2, and ARHGEF2 to control dendritic microtubule plus-end dynamics and cargo trafficking, the centrosomal protein CEP131, and DLG5 (PMID:25905439, PMID:30266824, PMID:30266925). In neurons it drives dendritic arborization and spine formation via a Rac1 complex and BDNF-dependent Rac1 activation, and via palmitoylation-dependent binding to PSD-95 that targets it to synapses (PMID:20861382, PMID:23671101). CDKL5 controls excitatory signaling by restraining postsynaptic GluN2B–SAP102 NMDA receptors and GluA2-containing AMPARs, and by phosphorylating the Cav2.3 (CACNA1E) calcium channel, such that its loss produces a partial channelopathy and hyperexcitability (PMID:28688852, PMID:29618004, PMID:38081835). Beyond development, CDKL5 phosphorylates SMAD3 to support neuronal survival, mediates synaptic vesicle endocytosis through its kinase domain, is recruited via poly(ADP-ribose) to transcription-coupled DNA damage sites where it phosphorylates Elongin A to enable transcriptional silencing, and phosphorylates p62 to initiate virophagy (PMID:30793413, PMID:34605059, PMID:36759195, PMID:37917202). CDKL5 also physically interacts with and is in a common pathway with MeCP2, which transcriptionally represses Cdkl5 by binding its methylated promoter, while MYCN represses CDKL5 in proliferating cells (PMID:15917271, PMID:20211261, PMID:22921766). Restoring CDKL5 after early development reverses behavioral and NMDA receptor signaling deficits, establishing an ongoing adult requirement (PMID:34651584).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Establishing CDKL5 as an active kinase physically and functionally linked to MeCP2 placed it within the Rett-spectrum disorder pathway and gave it a candidate substrate.

    Evidence Co-IP and in vitro kinase assays in brain and cell systems

    PMID:15499549 PMID:15917271

    Open questions at the time
    • A later study failed to confirm direct MeCP2 phosphorylation
    • Physiological consequences of MeCP2 phosphorylation not defined
  2. 2006 High

    Identifying C-terminal autoinhibition, TEY-motif autophosphorylation, and self-association defined how CDKL5 catalytic output and localization are intrinsically regulated.

    Evidence In vitro kinase assays, mutagenesis, Co-IP, and fractionation/immunofluorescence

    PMID:16330482 PMID:16935860

    Open questions at the time
    • Structural basis of autoinhibition unresolved
    • Trigger that relieves autoinhibition in vivo unknown
  3. 2008 High

    Demonstrating C-terminus-dependent nuclear export and developmental shuttling explained how Rett truncations cause aberrant nuclear accumulation.

    Evidence Brain immunostaining, fractionation, truncation constructs, nuclear export inhibition

    PMID:18701457 PMID:19740913

    Open questions at the time
    • Export receptor/NES not mapped
    • Functional role of nuclear speckle localization unclear
  4. 2010 High

    Showing CDKL5 forms a Rac1 complex required for BDNF-induced Rac1 activation and dendritic growth gave the kinase its first concrete neuronal morphogenesis role.

    Evidence RNAi, in utero electroporation, Co-IP, Rac1 activation assay, epistasis rescue

    PMID:20211261 PMID:20861382

    Open questions at the time
    • Direct Rac1 GEF/effector phosphorylated by CDKL5 not identified here
    • Whether Rac1 regulation requires kinase activity not fully resolved
  5. 2012 Medium

    Knockout kinome profiling and the MYCN repression axis connected CDKL5 loss to AKT-mTOR signaling and to control of neuronal proliferation/differentiation.

    Evidence Cdkl5 KO mouse kinome profiling, behavior; neuroblastoma overexpression, ChIP, reporter assays

    PMID:22921766 PMID:23236174

    Open questions at the time
    • Direct CDKL5 substrates in the AKT-mTOR cascade not identified
    • Mechanism linking kinase activity to cell-cycle arrest unknown
  6. 2013 High

    Identifying palmitoylation-dependent PSD-95 binding as the synaptic targeting mechanism explained how pathogenic C-terminal truncations impair spine formation.

    Evidence Co-IP, palmitoylation manipulation, RNAi spine phenotype, pathogenic mutant analysis

    PMID:23671101

    Open questions at the time
    • Whether PSD-95 is a CDKL5 substrate not established
    • Kinase targets at the synapse not defined here
  7. 2015 High

    Defining the RPXSX substrate consensus through amphiphysin 1 phosphorylation provided the rule for predicting and validating CDKL5 substrates.

    Evidence In vitro kinase assays with Amph1/Amph2 mutants and motif mutagenesis

    PMID:25905439

    Open questions at the time
    • Physiological role of Amph1-Ser293 phosphorylation later questioned
    • Cellular context of phosphorylation not addressed
  8. 2016 Medium

    DYRK1A phosphorylation at Ser-308 and shootin1 interaction extended CDKL5 regulation to upstream control of localization and to axon specification.

    Evidence Co-IP, in vitro kinase assay, phosphomimetic mutants; yeast two-hybrid, RNAi epistasis in neurons

    PMID:26849555 PMID:27840050

    Open questions at the time
    • Whether shootin1 is a direct CDKL5 substrate not firmly established
    • In vivo significance of Ser-308 phosphorylation untested
  9. 2017 High

    Showing CDKL5 restrains postsynaptic GluN2B-SAP102 NMDA receptors and functions at the centrosome/midbody revealed both synaptic excitability control and a mitotic role.

    Evidence KO mouse PSD fractionation, immunoEM, patch clamp, pharmacological rescue; RNAi and H2B-S14D rescue in mitotic cells

    PMID:28688852 PMID:28740074

    Open questions at the time
    • Direct NMDA receptor substrate not identified
    • Relationship between mitotic and neuronal functions unclear
  10. 2018 High

    Unbiased chemical-genetic and phosphoproteomic substrate identification established MAP1S, EB2, ARHGEF2, CEP131, and DLG5 as physiological substrates linking CDKL5 to microtubule dynamics and cargo trafficking.

    Evidence Analog-sensitive kinase, SILAC phosphoproteomics, phospho-antibodies, KO mice, live EB3 imaging, rescue

    PMID:29618004 PMID:30266824 PMID:30266925

    Open questions at the time
    • How substrate phosphorylation maps onto disease phenotypes incompletely defined
    • AMPAR GluA2 regulation mechanism partly correlative
  11. 2019 High

    SMAD3 phosphorylation and GABAergic-specific loss-of-function linked CDKL5 to neuronal survival and to NMDA-receptor-dependent autistic-like behaviors amenable to pharmacological rescue.

    Evidence In vitro kinase assay, KO neuron survival, TGF-β1 rescue; GABAergic conditional and R59X knockin mice with NMDAR antagonist rescue

    PMID:30793413 PMID:31201320

    Open questions at the time
    • Direct SMAD3 phospho-site not detailed in narrative-relevant terms
    • Cell-type-specific substrate basis of behavior unresolved
  12. 2020 High

    Discovery of CDKL5 as a stress-responsive pro-death kinase phosphorylating SOX9 in renal epithelium revealed a function outside the nervous system.

    Evidence Kinome RNAi screen, RTEC conditional KO, SOX9 kinase assay, pharmacological inhibition, AKI mouse models

    PMID:32317630

    Open questions at the time
    • Whether SOX9 regulation occurs in neurons unknown
    • Tissue-specific determinants of CDKL5 pro-death versus pro-survival roles unclear
  13. 2021 High

    Identifying transcription-coupled, PAR-dependent recruitment to DNA damage sites with Elongin A phosphorylation, plus demonstrating an adult requirement, redefined CDKL5 as both a genome-protective nuclear kinase and a persistently required regulator.

    Evidence Nuclear phosphoproteomics, PAR binding, DNA damage recruitment imaging, kinase-dead analysis; temporal KO/rescue mice with behavior and electrophysiology; cell-type KO seizure models

    PMID:33400301 PMID:34605059 PMID:34651584

    Open questions at the time
    • How nuclear DNA-damage role relates to synaptic functions unknown
    • Glutamatergic versus GABAergic substrate differences not molecularly resolved
  14. 2023 High

    Establishing Cav2.3 as a direct substrate and the kinase domain alone as sufficient for synaptic vesicle endocytosis tied CDKL5 to neuronal excitability as a partial channelopathy and to presynaptic membrane trafficking.

    Evidence SILAC phosphoproteomics, recombinant electrophysiology, phosphomutant knockin mice; SV reporter assays with kinase-dead and domain constructs

    PMID:36759195 PMID:38081835

    Open questions at the time
    • Endocytosis substrate distinct from amphiphysin 1 not identified
    • Contribution of Cav2.3 to overall CDD phenotype quantitatively undefined
  15. 2024 High

    Defining p62 phosphorylation in virophagy and CDKL2 compensation of EB2 phosphorylation expanded CDKL5 function to selective autophagy and revealed kinase redundancy in vivo.

    Evidence Co-IP, p62 mutant kinase assays, neurotropic virus KO mice; cell-type KO with phospho-antibody, in vitro kinase screen, dual Cdkl5/Cdkl2 KO mice

    PMID:37917202 PMID:38326557

    Open questions at the time
    • Extent of CDKL2 compensation across substrates unknown
    • Whether virophagy defect contributes to CDD pathology untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CDKL5's many substrates and subcellular roles are coordinately deployed across cell types and developmental stages to produce its disease phenotype remains unresolved.
  • No structural model of CDKL5 substrate engagement or autoinhibition
  • Hierarchy and relative phenotypic weight of substrates undefined
  • Mechanisms governing spatial partitioning between nuclear and synaptic functions unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 5 GO:0140657 ATP-dependent activity 3
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3 GO:0005886 plasma membrane 2 GO:0005654 nucleoplasm 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-73894 DNA Repair 1 R-HSA-9612973 Autophagy 1
Partners
DLG4DYRK1AEB2MECP2RAC1SHTN1SQSTM1

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CDKL5 physically interacts with MeCP2 both in vivo and in vitro, and CDKL5 kinase activity mediates phosphorylation of MeCP2 as well as autophosphorylation, placing the two proteins in a common molecular pathway. Co-immunoprecipitation (in vivo), in vitro kinase assay, immunostaining Human molecular genetics High 15917271
2005 CDKL5 is a nuclear protein expressed in neurons during neural maturation and synaptogenesis, and its subcellular localization overlaps with MeCP2 in the nervous system. Immunostaining, Western blotting, fractionation Human molecular genetics Medium 15917271
2005 Disease-causing missense mutations in the CDKL5 kinase domain, affecting highly conserved amino acids, impair catalytic activity as assessed by autophosphorylation, indicating that kinase inactivation underlies pathogenesis. In vitro autophosphorylation kinase assay with patient-derived mutant forms of CDKL5 American journal of human genetics Medium 15499549
2005 CDKL5 is primarily localized in the nucleus; removal of the C-terminal domain increases expression, enhances autophosphorylation activity, and causes perinuclear (cytoplasmic) localization, demonstrating that the C-terminus negatively regulates kinase activity and controls nuclear localization. Transfection of C-terminal deletion constructs, subcellular fractionation, in vitro kinase assay Human molecular genetics Medium 16330482
2005 CDKL5 detected binding to MeCP2 but not to ARX; neither MeCP2 nor ARX was confirmed as a direct phosphorylation substrate by CDKL5 in this study (negative finding for direct MeCP2 phosphorylation). Co-immunoprecipitation, in vitro kinase assay Human molecular genetics Low 16330482
2006 Disease-causing CDKL5 mutations show both impaired and increased catalytic activity relative to wild-type; wild-type CDKL5 autophosphorylates its TEY motif and phosphorylates MeCP2 in vitro; CDKL5 can self-associate (homo-oligomerize); the C-terminus negatively regulates catalytic activity and is required for proper sub-nuclear localization. In vitro kinase assay, TEY phosphorylation analysis, co-immunoprecipitation for self-association, subcellular localization by immunofluorescence The Journal of biological chemistry High 16935860
2008 CDKL5 subcellular distribution is regulated by its C-terminal tail: the C-terminus is required for cytoplasmic localization via active nuclear export, while Rett-syndrome truncations of the C-terminus cause constitutive nuclear accumulation. CDKL5 shuttles between nucleus and cytoplasm during neuronal development. Immunostaining of brain sections, subcellular fractionation, C-terminal deletion/truncation constructs, nuclear export inhibition The Journal of biological chemistry High 18701457
2009 CDKL5 localizes to nuclear speckles (pre-mRNA splicing factor storage/modification sites), regulates their morphology in a kinase-activity-dependent manner, and influences alternative splicing activity. Immunofluorescence co-localization with speckle markers, CDKL5 overexpression/knockdown, minigene splicing assay Human molecular genetics Medium 19740913
2010 Cdkl5 is a MeCP2-repressed target gene: increased MeCP2 levels repress Cdkl5 expression, Cdkl5 promoter methylation increases upon MeCP2 upregulation, and MeCP2 binds the methylated Cdkl5 promoter; siRNA knockdown of MeCP2 or inhibition of DNA methyltransferases induces Cdkl5 expression. MeCP2 overexpression/siRNA knockdown, DNA methylation analysis, chromatin immunoprecipitation (ChIP), quantitative PCR Neurobiology of disease Medium 20211261
2010 CDKL5 regulates neuronal morphogenesis via Rac1 signaling: CDKL5 colocalizes and forms a protein complex with Rac1 in neurons and fibroblasts; CDKL5 knockdown inhibits neurite growth and dendritic arborization; overexpression of Rac1 rescues dendritic defects from CDKL5 knockdown; dominant-negative Rac1 abolishes the growth-promoting effect of CDKL5; CDKL5 is required for BDNF-induced Rac1 activation. RNAi knockdown, overexpression, in utero electroporation, Co-immunoprecipitation, Rac1 activation assay, BDNF stimulation The Journal of neuroscience High 20861382
2011 Extrasynaptic NMDA receptor activation induces nuclear-to-cytoplasmic translocation of endogenous CDKL5 in hippocampal neurons followed by proteasomal degradation; CDKL5 does not constitutively shuttle between nucleus and cytoplasm in post-mitotic neurons unlike in proliferating cells. Immunofluorescence in primary hippocampal neurons, glutamate/NMDA stimulation, proteasome inhibitor treatment, subcellular fractionation The Journal of biological chemistry Medium 21832092
2012 CDKL5 loss-of-function in mice disrupts multiple signal transduction pathways including the AKT-mTOR cascade, as revealed by kinome profiling, and leads to autistic-like behavioral deficits. Cdkl5 knockout mouse, kinome profiling, behavioral analysis Proceedings of the National Academy of Sciences of the United States of America Medium 23236174
2012 CDKL5 overexpression in neuroblastoma cells causes G0/G1 cell cycle arrest and promotes differentiation; MYCN acts as a direct transcriptional repressor of the CDKL5 promoter, establishing a MYCN–CDKL5 axis governing neuronal proliferation and differentiation. Overexpression in neuroblastoma cells, flow cytometry, ChIP, promoter reporter assays, MYCN knockdown Biochimica et biophysica acta Medium 22921766
2013 CDKL5 binds directly to the scaffolding protein PSD-95 in a palmitoylation-dependent manner, and this interaction is required for synaptic targeting of CDKL5; pathogenic C-terminal truncation mutations reduce CDKL5–PSD-95 binding and synaptic accumulation; loss of CDKL5 or disruption of CDKL5–PSD-95 interaction inhibits dendritic spine formation and growth. Co-immunoprecipitation, palmitoylation manipulation, RNAi knockdown, overexpression, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 23671101
2014 CDKL5 loss impairs AKT/GSK-3β signaling, reduces survival of newborn neurons, decreases total granule cell number in hippocampal dentate gyrus, and causes dendritic hypotrophy of newly generated granule cells. Cdkl5 knockout mouse, Western blotting for AKT/GSK-3β pathway, immunohistochemistry, BrdU labeling, behavioral testing Neurobiology of disease Medium 24952363
2014 Loss of CDKL5 in cortical neurons reduces dendritic arborization; conditional knockout in excitatory versus inhibitory forebrain neurons maps behavioral phenotypes to separable cell types; Akt/rpS6 signaling is altered in CDKL5-deficient neurons. Conditional Cre-loxP knockout mice (excitatory and inhibitory neuron-specific), morphological analysis, EEG, behavioral testing, Western blotting PloS one Medium 24838000
2015 CDKL5 phosphorylates amphiphysin 1 (Amph1) at Ser-293, and substrate recognition requires an arginine at the P-3 position and a proline at P-2 (consensus RPXSX); the Amph2 CLAP domain contributes to efficient phosphorylation. In vitro kinase assay with Amph1/Amph2 mutants, site-directed mutagenesis, phosphorylation mapping Biochemistry High 25905439
2016 CDKL5 interacts with and is phosphorylated at Ser-308 by DYRK1A; DYRK1A-mediated phosphorylation of CDKL5 at Ser-308 increases its cytoplasmic localization; phosphomimetic S308D mutation shifts CDKL5 to the cytosol while S308A keeps it nuclear. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, immunofluorescence Biochemical and biophysical research communications Medium 27840050
2016 CDKL5 interacts with shootin1 (a determinant of axon formation) in vivo; both proteins colocalize at the distal tip of outgrowing axons; CDKL5 loss disrupts neuronal polarization; CDKL5 overexpression generates supernumerary axons in a shootin1-dependent manner; shootin1 phosphorylation is reduced in CDKL5-silenced neurons. Yeast two-hybrid screening, Co-immunoprecipitation, immunofluorescence, RNAi knockdown, overexpression in hippocampal neurons PloS one Medium 26849555
2017 CDKL5 deficiency in the hippocampus causes postsynaptic overaccumulation of GluN2B and SAP102, increased NMDA/AMPA ratio and prolonged NMDA-EPSC decay time; ifenprodil (GluN2B-selective antagonist) abrogates NMDA-induced hyperexcitability, indicating CDKL5 controls postsynaptic localization of the GluN2B–SAP102 complex. Cdkl5 knockout mouse, subcellular fractionation of PSD, immunoelectron microscopy, whole-cell patch clamp, pharmacological rescue Neurobiology of disease High 28688852
2017 CDKL5 localizes to the centrosome and midbody in proliferating cells; its depletion by RNAi causes multipolar spindle formation and cytokinesis failure; CDKL5-depleted midbodies lack HIPK2 and H2B-S14 phosphorylation; expression of phosphomimetic H2B-S14D rescues spindle multipolarity. Immunofluorescence, RNAi knockdown, rescue with H2B-S14D phosphomimetic, microscopy of mitotic cells Scientific reports Medium 28740074
2018 Using chemical genetics (analog-sensitive kinase approach), CDKL5 was found to directly phosphorylate three microtubule-associated proteins — MAP1S, EB2, and ARHGEF2 — at defined sites; phosphorylation of these substrates is reduced in CDKL5 knockout mice (confirming physiological relevance); CDKL5 phosphorylation of MAP1S promotes its dissociation from microtubules; loss of CDKL5 leads to longer EB3-labelled dendritic microtubule plus-end growth, rescued by MAP1S shRNA; anterograde cargo trafficking is impaired in CDKL5 KO dendrites. Chemical genetics (analog-sensitive kinase), mass spectrometry, phospho-specific antibodies, CDKL5 KO mice, live imaging of EB3, shRNA knockdown, cargo trafficking assay The EMBO journal High 30266824
2018 Quantitative phosphoproteomic screen identified MAP1S (pSer900), CEP131 (pSer35), and DLG5 as cellular substrates of CDKL5; the phospho-acceptor motif is RPXSA; pathogenic CDKL5 mutations cause major reduction of kinase activity in vitro and in cells. Quantitative phosphoproteomics (SILAC), phospho-specific antibodies, in vitro kinase assay with patient-derived mutants The EMBO journal High 30266925
2018 Cdkl5 deficiency in primary hippocampal neurons causes reduced GluA2 subunit expression, hyper-phosphorylation of GluA2-Ser880, increased GluA2 ubiquitination, and a shift to GluA2-lacking calcium-permeable AMPARs at the synapse. RNAi knockdown in neurons, Western blotting, immunoprecipitation, surface AMPAR immunofluorescence Human molecular genetics Medium 29618004
2019 SMAD3 is a direct phosphorylation target of CDKL5; CDKL5-dependent phosphorylation stabilizes SMAD3 protein; CDKL5-deficient neurons show reduced SMAD3 signaling and are more vulnerable to excitotoxic stimuli; TGF-β1 treatment normalizes defective neuronal survival in Cdkl5 KO neurons and prevents NMDA-induced cell death in vivo. In vitro kinase assay, Western blotting in KO neurons, TGF-β1 rescue experiments in vitro and in vivo Brain pathology Medium 30793413
2019 Selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice with excessive glutamatergic transmission, hyperexcitability, and increased postsynaptic NMDA receptors; acute low-dose NMDA receptor inhibition ameliorates autistic-like behaviors in GABAergic-specific and R59X knockin CDKL5 mice. Conditional GABAergic-specific Cre-lox KO, behavioral testing, electrophysiology, pharmacological rescue with NMDAR antagonist, knockin mouse model Nature communications High 31201320
2020 CDKL5 is a stress-responsive kinase in renal tubular epithelial cells that promotes cell death through phosphorylation-dependent suppression of the pro-survival transcription factor SOX9; genetic or pharmacological Cdkl5 inhibition protects against nephrotoxic and ischemia-associated acute kidney injury in mouse models. Kinome-wide RNAi screen, conditional Cdkl5 gene ablation in RTECs, kinase assay with SOX9, pharmacological inhibition (AST-487), mouse AKI models Nature communications High 32317630
2021 CDKL5 is recruited to sites of DNA damage in actively transcribed regions; a nuclear phosphoproteomic screen identified Elongin A (ELOA) as a CDKL5 substrate phosphorylated on a CDKL5 consensus motif; CDKL5 recruitment and ELOA phosphorylation require active transcription and poly(ADP-ribose) (PAR) synthesis, to which CDKL5 can bind; CDKL5 kinase activity is essential for transcriptional silencing at sites of DNA double-strand breaks. Quantitative nuclear phosphoproteomics, PAR binding assay, recruitment to DNA damage sites by imaging, transcription inhibition experiments, kinase-dead mutant analysis The EMBO journal High 34605059
2021 Postdevelopmental (adult-stage) loss of CDKL5 disrupts behavioral domains, hippocampal circuit communication, and dendritic spine morphology; restoration of Cdkl5 expression after early brain development ameliorates CDD-related behavioral impairments and aberrant NMDA receptor signaling, demonstrating that CDKL5 function is required beyond early development. Temporal conditional knockout and rescue mouse models (inducible Cre), behavioral testing, electrophysiology, dendritic spine morphology analysis The Journal of clinical investigation High 34651584
2021 CDKL5 deficiency in glutamatergic (Emx1- or CamK2α-Cre) but not GABAergic neurons generates high-frequency spontaneous recurrent seizures, accompanied by hippocampal mossy fiber sprouting and increased excitatory synaptic activity (higher frequency but unchanged amplitude of sEPSCs and mEPSCs in dentate granule cells). Cell-type-specific conditional KO (Emx1-Cre, CamK2α-Cre, GAD-Cre), in vivo EEG/video, Timm staining for mossy fiber sprouting, whole-cell patch clamp Epilepsia High 33400301
2023 CDKL5 directly phosphorylates the voltage-gated calcium channel Cav2.3 (CACNA1E); loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, increasing neuronal excitability; CDD is therefore partly a channelopathy sharing mechanistic features with CACNA1E gain-of-function DEE69. SILAC phosphoproteomic screen, recombinant channel electrophysiology, Cav2.3 phosphomutant knockin mice, CDKL5 KO mice, neuronal excitability recordings Nature communications High 38081835
2023 CDKL5 is selectively required for efficient synaptic vesicle (SV) endocytosis in hippocampal neurons; the isolated CDKL5 kinase domain fully restores SV endocytosis kinetics in KO neurons; kinase-inactive CDKL5 mutations fail to rescue endocytosis; phosphorylation of amphiphysin 1 by CDKL5 is not required for SV endocytosis (negative finding for Amph1 as presynaptic effector of endocytosis). Cdkl5 knockout rat hippocampal neurons, genetically encoded SV reporter, kinase-dead and domain-deletion constructs, rescue experiments The Journal of neuroscience High 36759195
2024 CDKL5 and EB2 phosphorylation (pS222) are prominent in excitatory and inhibitory neurons but absent in astrocytes; ~15–20% residual EB2 pS222 persists in neuronal CDKL5 KO, regulated by NMDA and PP1/PP2A; CDKL2 and ICK can phosphorylate EB2-S222 in vitro; dual Cdkl5/Cdkl2 KO mice confirm that CDKL2 compensates CDKL5 substrate phosphorylation in vivo. Cell-type-specific conditional KO mice, phospho-specific antibody for EB2 pS222, kinase screen in HEK293T cells, dual KO mice Molecular psychiatry Medium 38326557
2024 CDKL5 directly binds the selective autophagy receptor p62 and phosphorylates p62 at T269/S272; CDKL5-mediated p62 phosphorylation promotes large p62 inclusion body formation that captures viral capsids, initiating virophagy; CDKL5 deficiency reduces clearance of Sindbis virus capsid aggregates and increases neuronal cell death after neurotropic virus infection. Co-immunoprecipitation, in vitro kinase assay with p62 mutants, Cdkl5 KO mice infected with neurotropic viruses, imaging of p62 inclusion bodies The Journal of clinical investigation High 37917202

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Human molecular genetics 255 15917271
2004 Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. American journal of human genetics 244 15499549
2012 The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. European journal of human genetics : EJHG 227 22872100
2005 CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms. Journal of medical genetics 185 15689447
2012 Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice. Proceedings of the National Academy of Sciences of the United States of America 180 23236174
2008 CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail. The Journal of biological chemistry 172 18701457
2014 Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PloS one 156 24838000
2010 CDKL5, a protein associated with rett syndrome, regulates neuronal morphogenesis via Rac1 signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 154 20861382
2005 Early onset seizures and Rett-like features associated with mutations in CDKL5. European journal of human genetics : EJHG 134 16015284
2006 Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation. The Journal of biological chemistry 132 16935860
2019 CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia 127 31313283
2012 Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia 120 22998673
2014 Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling. Neurobiology of disease 111 24952363
2016 Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome. Orphanet journal of rare diseases 110 27080038
2005 CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. Human molecular genetics 104 16330482
2017 CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiology of disease 102 28688852
2013 Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development. Proceedings of the National Academy of Sciences of the United States of America 96 23671101
2012 What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural plasticity 88 22779007
2016 Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 86 27770071
2010 CDKL5 is a brain MeCP2 target gene regulated by DNA methylation. Neurobiology of disease 84 20211261
2009 Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature. Clinical genetics 84 19793311
2016 Functional abilities in children and adults with the CDKL5 disorder. American journal of medical genetics. Part A 79 27528505
2018 Molecular and Synaptic Bases of CDKL5 Disorder. Developmental neurobiology 77 30246934
2011 iPS cells to model CDKL5-related disorders. European journal of human genetics : EJHG 73 21750574
2018 Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics. The EMBO journal 72 30266824
2020 CDKL5 Deficiency Disorder-A Complex Epileptic Encephalopathy. Brain sciences 71 32079229
2013 CDKL5 regulates flagellar length and localizes to the base of the flagella in Chlamydomonas. Molecular biology of the cell 69 23283985
2018 Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase. The EMBO journal 67 30266825
2019 Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder. Nature communications 62 31201320
2017 CDKL5 variants: Improving our understanding of a rare neurologic disorder. Neurology. Genetics 62 29264392
2011 CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life. Developmental medicine and child neurology 62 21309761
2011 CDKL5 alterations lead to early epileptic encephalopathy in both genders. Epilepsia 61 21770923
2016 Characterisation of CDKL5 Transcript Isoforms in Human and Mouse. PloS one 60 27315173
2019 Severity Assessment in CDKL5 Deficiency Disorder. Pediatric neurology 59 31147226
2015 Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs. Oxidative medicine and cellular longevity 59 26236424
2019 AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 30952813
2018 CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder. Human molecular genetics 57 29474534
2009 Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 57 19241098
2021 Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits. The Journal of clinical investigation 53 34651584
2020 A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury. Nature communications 53 32317630
2009 CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery. Human molecular genetics 53 19740913
2018 Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder. Neural plasticity 50 29977282
2012 Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. American journal of medical genetics. Part A 50 22678952
2016 CDKL5 and Shootin1 Interact and Concur in Regulating Neuronal Polarization. PloS one 41 26849555
2014 Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications. European journal of human genetics : EJHG 41 25315662
2012 CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells. Biochimica et biophysica acta 40 22921766
2010 Epilepsy caused by CDKL5 mutations. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 40 20493745
2022 CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development. Biochemical Society transactions 38 35997111
2006 Seizures and electroencephalographic findings in CDKL5 mutations: case report and review. Brain & development 38 17049193
2019 Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic. International journal of molecular sciences 37 31618813
2014 Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC medical genetics 37 24564546
2006 MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. Journal of human genetics 37 17089071
2021 CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures. Epilepsia 36 33400301
2020 Artificial escape from XCI by DNA methylation editing of the CDKL5 gene. Nucleic acids research 36 31925439
2017 CDKL5 deficiency entails sleep apneas in mice. Journal of sleep research 35 28230307
2016 CDKL5 knockout leads to altered inhibitory transmission in the cerebellum of adult mice. Genes, brain, and behavior 35 27108663
2005 Myoclonic encephalopathy in the CDKL5 gene mutation. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 33 16326141
2022 CDKL5 Deficiency Disorder-Related Epilepsy: A Review of Current and Emerging Treatment. CNS drugs 31 35633486
2021 CDKL5 kinase controls transcription-coupled responses to DNA damage. The EMBO journal 30 34605059
2020 Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder. Neural plasticity 30 32587608
2020 Exploring genotype-phenotype relationships in the CDKL5 deficiency disorder using an international dataset. Clinical genetics 30 33047306
2018 Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder. Neuropharmacology 30 30326240
2017 CDKL5 localizes at the centrosome and midbody and is required for faithful cell division. Scientific reports 29 28740074
2011 Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation. The Journal of biological chemistry 29 21832092
2021 Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Annals of clinical and translational neurology 28 33538404
2021 CDKL5 deficiency disorder in males: Five new variants and review of the literature. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 28 33989939
2019 CDKL5 deficiency predisposes neurons to cell death through the deregulation of SMAD3 signaling. Brain pathology (Zurich, Switzerland) 28 30793413
2018 The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5. Human molecular genetics 28 29618004
2021 CDKL5 Deficiency Augments Inhibitory Input into the Dentate Gyrus That Can Be Reversed by Deep Brain Stimulation. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 34544833
2019 Phenotypic manifestations between male and female children with CDKL5 mutations. Brain & development 27 31122804
2010 Cyclin-dependent kinase-like 5 (CDKL5) mutation screening in Rett syndrome and related disorders. Twin research and human genetics : the official journal of the International Society for Twin Studies 27 20397747
2021 Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement. Journal of child neurology 26 34547934
2012 Variant of Rett syndrome and CDKL5 gene: clinical and autonomic description of 10 cases. Neuropediatrics 26 22430159
2021 Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants. Brain & development 24 33436160
2020 Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons. Molecular neurobiology 23 32002787
2019 Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. International journal of molecular sciences 23 31450582
2023 Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. Nature communications 22 38081835
2019 Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder? International journal of molecular sciences 21 31438497
2016 Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A). Biochemical and biophysical research communications 21 27840050
2014 Optimizing the molecular diagnosis of CDKL5 gene-related epileptic encephalopathy in boys. Epilepsia 21 25266480
2020 Involvement of the CDKL5-SOX9 signaling axis in rhabdomyolysis-associated acute kidney injury. American journal of physiology. Renal physiology 20 33044867
2019 Aminoglycoside drugs induce efficient read-through of CDKL5 nonsense mutations, slightly restoring its kinase activity. RNA biology 20 31232219
2023 Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE). Epilepsy & behavior : E&B 19 37011526
2022 Touchscreen cognitive deficits, hyperexcitability and hyperactivity in males and females using two models of Cdkl5 deficiency. Human molecular genetics 19 35445702
2024 Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular psychiatry 18 38326557
2023 Epilepsy-Related CDKL5 Deficiency Slows Synaptic Vesicle Endocytosis in Central Nerve Terminals. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 36759195
2022 Neuronal hyperexcitability and ion channel dysfunction in CDKL5-deficiency patient iPSC-derived cortical organoids. Neurobiology of disease 18 36202289
2018 Neuron-Type Specific Loss of CDKL5 Leads to Alterations in mTOR Signaling and Synaptic Markers. Molecular neurobiology 18 30288694
2015 Critical Determinants of Substrate Recognition by Cyclin-Dependent Kinase-like 5 (CDKL5). Biochemistry 18 25905439
2023 CDKL5 deficiency disorder: progressive brain atrophy may be part of the syndrome. Cerebral cortex (New York, N.Y. : 1991) 17 37429835
2022 Cortical Visual Impairment in CDKL5 Deficiency Disorder. Frontiers in neurology 17 35153983
2022 Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 17 36109452
2021 Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder. International journal of molecular sciences 17 34073043
2024 CDKL5 regulates p62-mediated selective autophagy and confers protection against neurotropic viruses. The Journal of clinical investigation 16 37917202
2017 Molecular and genetic insights into an infantile epileptic encephalopathy - CDKL5 disorder. Frontiers in biology 16 28580010
2021 A GABAB receptor antagonist rescues functional and structural impairments in the perirhinal cortex of a mouse model of CDKL5 deficiency disorder. Neurobiology of disease 15 33621640
2021 Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder. Neurobiology of disease 15 33905871
2016 Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 15 27900411
2013 Mutations in the C-terminus of CDKL5: proceed with caution. European journal of human genetics : EJHG 15 23756444
2022 Cdkl5 mutant zebrafish shows skeletal and neuronal alterations mimicking human CDKL5 deficiency disorder. Scientific reports 14 35665761

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