Affinage

CDKL5

Cyclin-dependent kinase-like 5 · UniProt O76039

Length
960 aa
Mass
107.5 kDa
Annotated
2026-04-28
100 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CDKL5 is a brain-enriched serine/threonine kinase that controls dendritic morphogenesis, synaptic function, neuronal excitability, and survival by phosphorylating diverse substrates at a consensus RPX(S/T) motif. Its catalytic activity, regulated by autophosphorylation of a TEY activation-loop motif and by DYRK1A-mediated phosphorylation at Ser-308 controlling nuclear–cytoplasmic shuttling, targets microtubule regulators (MAP1S, EB2, ARHGEF2), synaptic proteins (amphiphysin 1, PSD-95-associated complexes, Cav2.3), transcriptional regulators (HDAC4, SMAD3, Elongin A), and centrosomal/polarity factors (CEP131, DLG5), thereby governing dendritic microtubule dynamics, synaptic vesicle endocytosis, NMDA receptor localization, and transcription-coupled DNA damage responses (PMID:30266824, PMID:30266825, PMID:23651931, PMID:27466189, PMID:34605059, PMID:38081835, PMID:36759195). Loss-of-function mutations cause CDKL5 deficiency disorder, an epileptic encephalopathy with neurodevelopmental deficits characterized by disrupted AKT/GSK-3β and mTOR signaling, NMDA receptor overaccumulation, and dendritic hypotrophy, phenotypes that are reversible upon postnatal gene restoration in mice (PMID:23236174, PMID:24952363, PMID:28688852, PMID:34651584). CDKL2 and ICK provide partially compensatory kinase activity toward CDKL5 substrates such as EB2 in vivo (PMID:38326557).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Establishing that CDKL5 is a functional kinase that autophosphorylates and interacts with MeCP2 placed CDKL5 into an active signaling pathway rather than being merely a disease-associated gene of unknown function.

    Evidence In vitro kinase assay and co-immunoprecipitation in mammalian cells

    PMID:15917271 PMID:16330482

    Open questions at the time
    • Whether MeCP2 is a direct physiological substrate remained disputed between the two 2005 studies
    • Endogenous substrates in neurons were unknown
    • Upstream regulators of CDKL5 kinase activity were undefined
  2. 2006 High

    Demonstrating that disease-causing mutations alter TEY activation-loop phosphorylation and that the C-terminal domain negatively regulates catalytic activity and nuclear localization established the first structure–function framework for CDKL5.

    Evidence Site-directed mutagenesis of patient mutations with in vitro kinase assays and subcellular fractionation

    PMID:16935860

    Open questions at the time
    • Crystal structure of the kinase domain was unavailable
    • The mechanism by which the C-terminal tail inhibits catalysis was undefined
    • Whether TEY phosphorylation is purely autophosphorylation or also mediated by upstream kinases was unresolved
  3. 2008 High

    Showing that CDKL5 actively shuttles between nucleus and cytoplasm, with disease-causing C-terminal truncations causing constitutive nuclear accumulation, revealed that mislocalization is a pathogenic mechanism.

    Evidence Immunostaining, subcellular fractionation, and nuclear export inhibition in cell lines

    PMID:18701457

    Open questions at the time
    • The nuclear export signal sequence was not precisely mapped
    • Functional consequences of nuclear-restricted CDKL5 in neurons were untested
  4. 2012 High

    Cdkl5 knockout mice displaying autistic-like behaviors and disrupted AKT-mTOR signaling established the first in vivo disease model and identified downstream pathway perturbations, while parallel work showed CDKL5 can arrest cell cycle and is transcriptionally repressed by MYCN.

    Evidence Cdkl5 KO mouse behavioral and kinome profiling; cell cycle analysis and ChIP in neuroblastoma cells

    PMID:22921766 PMID:23236174

    Open questions at the time
    • Whether AKT-mTOR disruption is a direct or indirect consequence of CDKL5 loss was unknown
    • Cell-type contributions to behavioral phenotypes were unresolved
  5. 2013 High

    Identification of amphiphysin 1 as a direct substrate (pSer-293) linking CDKL5 to synaptic vesicle endocytosis, and of the PSD-95 interaction linking CDKL5 to excitatory synapse targeting and dendritic spine formation, provided the first mechanistic connections between CDKL5 kinase activity and synaptic biology.

    Evidence LC-MS/MS substrate mapping, co-IP of CDKL5–PSD-95, RNAi-mediated loss-of-function with spine morphology readout

    PMID:23651931 PMID:23671101

    Open questions at the time
    • Whether amphiphysin 1 phosphorylation fully explains presynaptic defects was untested
    • The palmitoylation site on CDKL5 required for PSD-95 binding was not identified
  6. 2015 High

    Systematic mutagenesis defined the CDKL5 substrate consensus motif as RPX(S/T), and activity-dependent regulation of CDKL5 protein levels via PP1 dephosphorylation and proteasomal degradation was discovered, linking synaptic activity to kinase abundance.

    Evidence In vitro kinase assays with point-mutant substrates; pharmacological dissection of CDKL5 turnover in primary neurons

    PMID:25555910 PMID:25905439

    Open questions at the time
    • The specific phosphosites on CDKL5 targeted by PP1 for degradation were not mapped
    • In vivo relevance of activity-dependent CDKL5 degradation was not tested
  7. 2016 High

    Identification of HDAC4 and shootin1 as CDKL5 targets/interactors expanded the functional repertoire to include epigenetic regulation (HDAC4 cytoplasmic retention controlling MEF2A-dependent transcription) and neuronal polarization (axon specification via shootin1), while DYRK1A-mediated Ser-308 phosphorylation was found to control CDKL5 nuclear–cytoplasmic distribution.

    Evidence In vitro kinase assays, Cdkl5 KO mouse with HDAC4 inhibitor rescue, yeast two-hybrid and co-IP for shootin1, mutagenesis of Ser-308

    PMID:26849555 PMID:27466189 PMID:27840050

    Open questions at the time
    • The specific HDAC4 phosphosite(s) were not fully mapped
    • Shootin1 interaction was from a single lab and awaits independent confirmation
    • Whether DYRK1A regulation of CDKL5 localization occurs in vivo in neurons was untested
  8. 2017 High

    Cell-type-specific knockout studies demonstrated that CDKL5 loss in forebrain glutamatergic neurons causes hippocampal memory deficits, dendritic hypotrophy, and altered excitability, while molecular analysis revealed overaccumulation of GluN2B-NMDA receptors at postsynaptic densities as a key pathogenic mechanism.

    Evidence Glutamatergic-neuron conditional KO mice, electrophysiology, immunoelectron microscopy, GluN2B-selective antagonist rescue

    PMID:28674172 PMID:28688852

    Open questions at the time
    • Whether CDKL5 directly phosphorylates NMDA receptor subunits or acts indirectly was unknown
    • Contribution of GABAergic neuron CDKL5 loss was untested at this point
  9. 2018 High

    Chemical-genetic and quantitative phosphoproteomic screens converged on MAP1S, EB2, ARHGEF2, CEP131, and DLG5 as bona fide CDKL5 substrates, establishing that CDKL5 controls dendritic microtubule dynamics through MAP1S phosphorylation-dependent dissociation from microtubules.

    Evidence Analog-sensitive kinase allele, SILAC phosphoproteomics, phospho-specific antibodies, live EB3-GFP imaging in KO neurons

    PMID:30266824 PMID:30266825

    Open questions at the time
    • Functional roles of CEP131 and DLG5 phosphorylation were not characterized
    • Whether microtubule dynamics defects underlie spine morphology changes was not directly tested
  10. 2019 High

    GABAergic-neuron-specific CDKL5 loss was shown to cause autistic-like behaviors with excessive NMDA signaling, rescuable by low-dose NMDAR antagonism, while SMAD3 was identified as a CDKL5 substrate whose phosphorylation promotes neuronal survival via TGF-β signaling.

    Evidence GABAergic conditional KO and R59X knockin mice with NMDAR antagonist rescue; in vitro kinase assay for SMAD3 with TGF-β1 in vivo rescue in KO

    PMID:30793413 PMID:31201320

    Open questions at the time
    • The presynaptic versus postsynaptic locus of NMDAR dysregulation in GABAergic KO was unclear
    • SMAD3 as a substrate was from a single lab and the specific phosphosite was not fully characterized
  11. 2021 High

    CDKL5 was found to be recruited to transcription-coupled DNA damage sites via PAR binding, where it phosphorylates Elongin A to silence transcription at breaks, revealing an unexpected nuclear function beyond synaptic signaling; separately, temporal rescue experiments demonstrated that CDD phenotypes are reversible upon postnatal CDKL5 restoration.

    Evidence Live-cell DNA damage imaging, phosphoproteomics identifying Elongin A, PAR-binding assay; conditional temporal KO/rescue mice with behavioral and electrophysiological readouts

    PMID:34605059 PMID:34651584

    Open questions at the time
    • Whether transcription-coupled DNA damage repair contributes to CDD neuropathology is unknown
    • The degree of phenotypic rescue achievable in adult animals was not fully explored
  12. 2023 High

    Cav2.3 was identified as a physiological CDKL5 substrate whose phosphorylation accelerates channel inactivation; loss of this phosphorylation causes channel gain-of-function and neuronal hyperexcitability, directly connecting CDKL5 loss to ion channel dysfunction, while CDKL5 kinase activity was separately shown to be required for efficient synaptic vesicle endocytosis independent of amphiphysin 1 phosphorylation.

    Evidence SILAC phosphoproteomics, recombinant channel electrophysiology, Cav2.3 phosphomutant knockin mouse; Cdkl5 KO rat neurons with SV reporter and kinase-dead rescue

    PMID:36759195 PMID:38081835

    Open questions at the time
    • The specific CDKL5 substrate mediating synaptic vesicle endocytosis (if not amphiphysin 1) is unknown
    • Whether Cav2.3 phosphorylation loss accounts for seizure susceptibility in CDD patients is untested
  13. 2024 High

    Dual knockout experiments revealed that CDKL2 provides compensatory phosphorylation of CDKL5 substrates (notably EB2 at Ser-222) in vivo, establishing kinase redundancy that must be considered when interpreting single-KO phenotypes.

    Evidence Cell-type specific Cdkl5 KO with phospho-EB2 antibody; HEK293T kinase screen; Cdkl5/Cdkl2 dual KO mouse

    PMID:38326557

    Open questions at the time
    • The full set of substrates shared between CDKL5 and CDKL2 is undefined
    • Whether CDKL2 compensation is neuroprotective or masks disease severity in CDD is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of CDKL5 substrate recognition, the identity of the presynaptic substrate(s) required for synaptic vesicle endocytosis, whether transcription-coupled DNA damage repair contributes to CDD neuropathology, and the extent to which CDKL2/ICK compensation modulates disease severity.
  • No crystal or cryo-EM structure of full-length CDKL5 with substrate or regulatory domains
  • Presynaptic CDKL5 substrate for SV endocytosis remains unidentified
  • Contribution of nuclear DNA damage response function to neurological phenotypes is untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016740 transferase activity 6
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-112316 Neuronal System 7 R-HSA-162582 Signal Transduction 3 R-HSA-1266738 Developmental Biology 2 R-HSA-73894 DNA Repair 1
Partners
AMPHDLG4DYRK1AHDAC4IQGAP1MAP1SMAPRE2MECP2

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CDKL5 is a functional kinase capable of autophosphorylation and phosphorylation of MeCP2 in vitro; CDKL5 and MeCP2 interact both in vivo and in vitro, placing them in a common molecular pathway. In vitro kinase assay, co-immunoprecipitation (in vivo and in vitro binding) Human molecular genetics High 15917271
2006 Disease-causing mutations in CDKL5 alter catalytic activity (both impaired and increased) and impair phosphorylation of its TEY activation-loop motif; the C-terminal domain negatively regulates catalytic activity and is required for proper sub-nuclear localization; CDKL5 can self-associate and mediates autophosphorylation of its own TEY motif. In vitro kinase assay, site-directed mutagenesis, subcellular fractionation/localization studies The Journal of biological chemistry High 16935860
2005 CDKL5 kinase activity is required for its function; disease-associated mutations cause loss of kinase autophosphorylation activity; the C-terminal domain regulates CDKL5 expression and autophosphorylation and determines perinuclear localization when removed; MeCP2 binds CDKL5 but is not a direct substrate. In vitro kinase assay (autophosphorylation), immunoprecipitation, subcellular localization studies Human molecular genetics High 16330482
2008 CDKL5 shuttles between cytoplasm and nucleus; the C-terminal tail localizes the protein to the cytoplasm via active nuclear export; disease-causing C-terminal truncations result in constitutive nuclear localization, suggesting gain-of-function in the nuclear compartment. Immunostaining, Western blotting, subcellular fractionation, nuclear export inhibition experiments The Journal of biological chemistry High 18701457
2013 CDKL5 binds the scaffolding protein PSD-95 in a palmitoylation-dependent manner, and this interaction promotes targeting of CDKL5 to excitatory synapses; pathogenic C-terminal truncations diminish CDKL5-PSD-95 binding and synaptic accumulation; loss of CDKL5 or disruption of the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. Co-immunoprecipitation, RNAi knockdown, live imaging, spine morphology analysis Proceedings of the National Academy of Sciences of the United States of America High 23671101
2013 Amphiphysin 1 (Amph1) is an endogenous cytoplasmic substrate of CDKL5; CDKL5 phosphorylates Amph1 at Ser-293; phosphorylation at this site reduces Amph1 affinity for endophilin, a protein involved in synaptic vesicle endocytosis; disease-causing missense mutations in the CDKL5 catalytic domain impair kinase activity toward Amph1. In vitro kinase assay, LC-MS/MS substrate identification, co-immunoprecipitation, mutagenesis Archives of biochemistry and biophysics High 23651931
2016 HDAC4 is a direct phosphorylation target of CDKL5; CDKL5-dependent phosphorylation promotes HDAC4 cytoplasmic retention; in Cdkl5 KO mice, hypophosphorylated HDAC4 translocates to the nucleus, binds chromatin and MEF2A transcription factor, leading to reduced histone 3 acetylation and altered neuronal gene expression. In vitro kinase assay, immunofluorescence, Cdkl5 KO mouse model, HDAC4 inhibitor rescue Human molecular genetics High 27466189
2012 Loss of CDKL5 in mice disrupts multiple signal transduction pathways including the AKT-mTOR cascade, as revealed by kinome profiling; Cdkl5 KO mice show autistic-like social deficits, motor impairment, and fear memory impairment. Cdkl5 KO mouse model, kinome profiling, behavioral assays Proceedings of the National Academy of Sciences of the United States of America High 23236174
2014 Loss of CDKL5 impairs hippocampal neurogenesis: increases proliferation of neural precursors, increases apoptosis of postmitotic granule neuron precursors, reduces total granule cell number, and causes severe dendritic hypotrophy; these defects are associated with impaired AKT/GSK-3β signaling. Cdkl5 KO mouse model, immunostaining, Western blotting, hippocampus-dependent memory assays Neurobiology of disease High 24952363
2018 Using chemical genetics, CDKL5 was found to phosphorylate three microtubule-associated proteins: MAP1S, EB2, and ARHGEF2 at defined sites; substrate phosphorylations are reduced in CDKL5 KO mouse neurons; CDKL5 regulates dendritic microtubule dynamics via phosphorylation of MAP1S, which promotes MAP1S dissociation from microtubules; anterograde cargo trafficking is compromised in CDKL5 KO dendrites. Chemical genetics (analog-sensitive kinase), phosphoproteomics, shRNA rescue, live imaging of EB3-GFP microtubule dynamics in KO neurons The EMBO journal High 30266824
2018 Quantitative phosphoproteomic screening identified MAP1S (pSer900), CEP131 (pSer35), and DLG5 as cellular CDKL5 substrates; the consensus phosphorylation motif for CDKL5 is RPXSA; pathogenic CDKL5 mutations cause major reduction in CDKL5 activity both in vitro and in cells. Quantitative phosphoproteomics, phospho-specific antibodies, in vitro kinase assays with disease mutants The EMBO journal High 30266825
2017 CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors and SAP102 in hippocampal CA1; Cdkl5 KO mice show increased NMDA/AMPA ratio and prolonged NMDA-EPSC decay; GluN2B and SAP102 are overaccumulated in the postsynaptic density of Cdkl5 KO mice; GluN2B-selective antagonist ifenprodil abrogates NMDA-induced hyperexcitability. Cdkl5 KO mouse, electrophysiology (patch-clamp), subcellular fractionation, immunoelectron microscopy Neurobiology of disease High 28688852
2017 Loss of CDKL5 specifically in forebrain glutamatergic neurons impairs hippocampal-dependent memory; CDKL5-deficient pyramidal neurons show decreased dendritic complexity, increased mEPSC and mIPSC frequency, and hyperexcitability in dendritic domains constrained by elevated inhibition. Conditional KO mouse (glutamatergic neuron-specific), behavioral assays, patch-clamp electrophysiology, voltage-sensitive dye imaging The Journal of neuroscience High 28674172
2016 CDKL5 interacts with shootin1, a brain-specific determinant of axon formation; CDKL5 and shootin1 co-localize at the distal tip of outgrowing axons; CDKL5 overexpression causes supernumerary axons while silencing disrupts neuronal polarization; shootin1 phosphorylation is reduced in CDKL5-silenced neurons; the two proteins act in a common pathway for axon specification. Yeast two-hybrid, co-immunoprecipitation, live imaging, RNAi silencing, overexpression in primary hippocampal neurons PloS one Medium 26849555
2017 CDKL5 interacts with IQGAP1; loss of CDKL5 impairs cell migration and IQGAP1 localization at the leading edge; CDKL5 is required for IQGAP1 to form a functional complex with Rac1 and CLIP170 (microtubule plus-end tracking protein), thereby regulating microtubule dynamics. Co-immunoprecipitation, cell migration assay, immunofluorescence localization, rescue with pregnenolone Human molecular genetics Medium 28641386
2015 Neuronal depolarization induces rapid increase in CDKL5 levels via extrasomatic synthesis; in mature neurons, NMDA receptor stimulation induces protein phosphatase 1-dependent dephosphorylation of CDKL5 that is required for its proteasome-dependent degradation, providing activity-dependent control of CDKL5 levels. Primary neuron cultures, pharmacological inhibitors, metabolic labeling, proteasome inhibition The Journal of biological chemistry Medium 25555910
2016 DYRK1A binds to and phosphorylates CDKL5 at Ser-308 (near the nuclear localization signal); phosphorylation at Ser-308 promotes cytosolic localization of CDKL5; the phosphomimetic S308D mutation shifts CDKL5 to cytoplasm while S308A remains nuclear. Co-immunoprecipitation, site-directed mutagenesis, subcellular localization experiments in Neuro2a cells Biochemical and biophysical research communications Medium 27840050
2010 CDKL5 (Cdkl5) is a MeCP2-repressed target gene; increased MeCP2 levels repress Cdkl5 expression in rat brain; Cdkl5 is regulated by DNA methylation, as DNMT inhibitors or MeCP2 knockdown induce its expression; cocaine increases Cdkl5 gene methylation and MeCP2 binding to the Cdkl5 locus in striatum. siRNA knockdown, MeCP2 overexpression, DNMT inhibitor treatment, ChIP, in vivo cocaine model Neurobiology of disease Medium 20211261
2019 Selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes accompanied by excessive glutamatergic transmission and increased postsynaptic NMDA receptor levels; acute low-dose NMDAR inhibition ameliorates autistic-like behaviors in GABAergic CDKL5 KO mice and in a CDD-associated R59X knockin mouse. GABAergic-neuron-specific conditional KO mouse, R59X knockin mouse, behavioral assays, electrophysiology, receptor level measurements Nature communications High 31201320
2021 CDKL5 is recruited to sites of DNA damage in actively transcribed nuclear regions; a phosphoproteomic screen identified Elongin A (ELOA) as a nuclear CDKL5 substrate phosphorylated at a CDKL5 consensus motif; recruitment of CDKL5 and ELOA requires active transcription and poly(ADP-ribose) (PAR) synthesis; CDKL5 can bind PAR; CDKL5 kinase activity is essential for transcriptional silencing induced by DNA double-strand breaks. Live-cell imaging of DNA damage recruitment, quantitative phosphoproteomics, PAR binding assay, kinase-inactive mutant analysis The EMBO journal High 34605059
2019 SMAD3 is a direct phosphorylation target of CDKL5; CDKL5-dependent phosphorylation promotes SMAD3 protein stability; restoration of SMAD3 signaling via TGF-β1 normalizes defective neuronal survival and maturation in Cdkl5 KO neurons and prevents NMDA-induced hippocampal cell death in vivo. In vitro kinase assay, Cdkl5 KO mouse model, TGF-β1 in vivo treatment, immunostaining Brain pathology Medium 30793413
2020 CDKL5 phosphorylates SOX9, suppressing its pro-survival transcriptional activity in renal tubular epithelial cells; Cdkl5 genetic or pharmacological inhibition mitigates nephrotoxic and ischemia-associated acute kidney injury in mouse models. Kinome RNAi screen, kinase assay (activation-specific antibodies), RTEC-specific Cdkl5 KO mouse, small molecule inhibitor (AST-487) Nature communications High 32317630
2012 CDKL5 overexpression arrests the cell cycle at G0/G1 and induces cellular differentiation in neuroblastoma cells; CDKL5 expression is directly repressed by MYCN transcription factor, which binds the CDKL5 promoter. Cell cycle analysis (flow cytometry), differentiation assays, ChIP, promoter reporter assays, MYCN overexpression/knockdown Biochimica et biophysica acta Medium 22921766
2023 CDKL5 phosphorylates the voltage-gated Ca2+ channel Cav2.3 (encoded by CACNA1E) as a physiological substrate in mice and humans; loss of Cav2.3 phosphorylation leads to channel gain-of-function via slower inactivation and enhanced cholinergic stimulation, resulting in increased neuronal excitability; Cav2.3 phosphomutant mice recapitulate aspects of CDD. SILAC-based phosphoproteomic screen, recombinant channel electrophysiology, Cav2.3 phosphomutant mouse model, interdisciplinary phenotyping Nature communications High 38081835
2023 CDKL5 kinase activity is required for efficient synaptic vesicle (SV) endocytosis in central nerve terminals; kinase-inactive CDKL5 mutations fail to restore SV endocytosis in Cdkl5 KO rat neurons; the isolated CDKL5 kinase domain is sufficient to rescue SV endocytosis; amphiphysin 1 phosphorylation is not required for this presynaptic role. Cdkl5 KO rat primary hippocampal neurons, genetically encoded SV reporter, kinase-inactive mutant rescue, isolated kinase domain rescue The Journal of neuroscience High 36759195
2015 CDKL5 substrate recognition requires an arginyl residue at the P-3 position and a prolyl residue at P-2 relative to the phospho-acceptor serine; the consensus motif is RPXSX; the CLAP domain structure of amphiphysin 1 is also required for efficient phosphorylation. In vitro kinase assay with point-mutant and deletion-mutant substrates (Amph1 and Amph2) Biochemistry High 25905439
2021 Postdevelopmental loss of CDKL5 disrupts hippocampal circuit communication, dendritic spine morphology, and multiple behavioral domains; restoration of Cdkl5 expression after early development ameliorates CDD-related behavioral impairments and aberrant NMDA receptor signaling, demonstrating reversibility of CDKL5 deficiency phenotypes. Conditional temporal Cdkl5 KO and rescue mouse models, behavioral assays, electrophysiology, spine morphology analysis The Journal of clinical investigation High 34651584
2024 CDKL5 and EB2 phospho-Ser222 (a CDKL5 substrate) are expressed in excitatory and inhibitory neurons but not astrocytes; approximately 15-20% of EB2 pS222 remains in Cdkl5 KO brains, attributable to a compensating kinase activity; CDKL2 and ICK can phosphorylate EB2 S222; dual Cdkl5/Cdkl2 KO mice demonstrate that CDKL2 phosphorylates CDKL5 substrates in vivo. Conditional Cdkl5 KO mice (excitatory, inhibitory, astrocyte-specific), phospho-specific antibody for EB2 pS222, kinase screen in HEK293T cells, dual KO mouse Molecular psychiatry High 38326557

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. American journal of human genetics 382 15492925
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 254 15917271
2008 Key clinical features to identify girls with CDKL5 mutations. Brain : a journal of neurology 224 18790821
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 176 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 170 18701457
2014 Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PloS one 153 24838000
2008 The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 150 18266744
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 131 16935860
2019 CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia 125 31313283
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 109 27080038
2005 CDKL5/Stk9 kinase inactivation is associated with neuronal developmental disorders. Human molecular genetics 102 16330482
2017 CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility. Neurobiology of disease 101 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 95 23671101
2012 What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural plasticity 86 22779007
2016 Seizure variables and their relationship to genotype and functional abilities in the CDKL5 disorder. Neurology 85 27770071
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
2010 CDKL5 is a brain MeCP2 target gene regulated by DNA methylation. Neurobiology of disease 83 20211261
2015 There is variability in the attainment of developmental milestones in the CDKL5 disorder. Journal of neurodevelopmental disorders 82 25657822
2016 HDAC4: a key factor underlying brain developmental alterations in CDKL5 disorder. Human molecular genetics 81 27466189
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
2017 Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 77 28674172
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
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 65 30266825
2019 Altered NMDAR signaling underlies autistic-like features in mouse models of CDKL5 deficiency disorder. Nature communications 60 31201320
2016 Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex. Frontiers in cellular neuroscience 60 27965538
2014 GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS cells. European journal of human genetics : EJHG 60 24916645
2016 Characterisation of CDKL5 Transcript Isoforms in Human and Mouse. PloS one 59 27315173
2015 Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder. Neurobiology of disease 59 26143616
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 Severity Assessment in CDKL5 Deficiency Disorder. Pediatric neurology 58 31147226
2013 Identification of amphiphysin 1 as an endogenous substrate for CDKL5, a protein kinase associated with X-linked neurodevelopmental disorder. Archives of biochemistry and biophysics 58 23651931
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
2009 Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes. Neurogenetics 57 19241098
2018 CDKL5 protein substitution therapy rescues neurological phenotypes of a mouse model of CDKL5 disorder. Human molecular genetics 55 29474534
2020 A kinome-wide screen identifies a CDKL5-SOX9 regulatory axis in epithelial cell death and kidney injury. Nature communications 53 32317630
2021 Temporal manipulation of Cdkl5 reveals essential postdevelopmental functions and reversible CDKL5 deficiency disorder-related deficits. The Journal of clinical investigation 52 34651584
2012 Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships. American journal of medical genetics. Part A 50 22678952
2018 Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder. Neural plasticity 46 29977282
2011 A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Human genetics 44 21748340
2020 Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder. Epilepsy research 41 33341033
2016 CDKL5 and Shootin1 Interact and Concur in Regulating Neuronal Polarization. PloS one 41 26849555
2016 Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clinical genetics 41 27062609
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
2006 Seizures and electroencephalographic findings in CDKL5 mutations: case report and review. Brain & development 38 17049193
2022 CDKL5 deficiency disorder: molecular insights and mechanisms of pathogenicity to fast-track therapeutic development. Biochemical Society transactions 37 35997111
2014 Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC medical genetics 37 24564546
2021 Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder. Journal of neuroinflammation 36 34238328
2020 Artificial escape from XCI by DNA methylation editing of the CDKL5 gene. Nucleic acids research 36 31925439
2019 Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic. International journal of molecular sciences 36 31618813
2007 Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature. Epilepsy & behavior : E&B 34 18063413
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
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
2015 Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5. The Journal of biological chemistry 30 25555910
2020 Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder. Neural plasticity 29 32587608
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
2021 Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death. Aging and disease 28 34094641
2021 CDKL5 kinase controls transcription-coupled responses to DNA damage. The EMBO journal 28 34605059
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
2017 The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex. Human molecular genetics 28 28641386
2019 Phenotypic manifestations between male and female children with CDKL5 mutations. Brain & development 27 31122804
2021 Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Annals of clinical and translational neurology 26 33538404
2021 Cerebral Visual Impairment in CDKL5 Deficiency Disorder Correlates With Developmental Achievement. Journal of child neurology 26 34547934
2022 International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder. Frontiers in neurology 25 35795799
2021 Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants. Brain & development 24 33436160
2020 The green tea polyphenol epigallocatechin-3-gallate (EGCG) restores CDKL5-dependent synaptic defects in vitro and in vivo. Neurobiology of disease 23 32032735
2019 Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy. International journal of molecular sciences 23 31450582
2020 Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons. Molecular neurobiology 22 32002787
2011 Clinical phenotype of 5 females with a CDKL5 mutation. Journal of child neurology 22 21765152
2019 Microtubules: A Key to Understand and Correct Neuronal Defects in CDKL5 Deficiency Disorder? International journal of molecular sciences 21 31438497
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
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 20 27840050
2015 Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder. Free radical biology & medicine 20 26006105
2023 Epilepsy-linked kinase CDKL5 phosphorylates voltage-gated calcium channel Cav2.3, altering inactivation kinetics and neuronal excitability. Nature communications 19 38081835
2015 Somatic mosaicism of a CDKL5 mutation identified by next-generation sequencing. Brain & development 19 25819767
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 Touchscreen cognitive deficits, hyperexcitability and hyperactivity in males and females using two models of Cdkl5 deficiency. Human molecular genetics 18 35445702
2018 Neuron-Type Specific Loss of CDKL5 Leads to Alterations in mTOR Signaling and Synaptic Markers. Molecular neurobiology 18 30288694
2018 A framework for understanding quality of life domains in individuals with the CDKL5 deficiency disorder. American journal of medical genetics. Part A 18 30561084
2024 Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Molecular psychiatry 17 38326557
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 17 37011526
2022 Neuronal hyperexcitability and ion channel dysfunction in CDKL5-deficiency patient iPSC-derived cortical organoids. Neurobiology of disease 17 36202289
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
2015 Critical Determinants of Substrate Recognition by Cyclin-Dependent Kinase-like 5 (CDKL5). Biochemistry 17 25905439
2005 Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2. American journal of medical genetics. Part A 17 16086395
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2017 Molecular and genetic insights into an infantile epileptic encephalopathy - CDKL5 disorder. Frontiers in biology 16 28580010