Evidence map›Paper›PMID 39136782›Full record

ArticleCellular and molecular life sciences : CMLS2024

Novel CDKL5 targets identified in human iPSC-derived neurons.

Sean Massey, Ching-Seng Ang, Nadia M Davidson, Anita Quigley, Ben Rollo, Alexander R Harris, Robert M I Kapsa, John Christodoulou, Nicole J Van Bergen

Erratum issuedAbstract read
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In one paragraph

Article in Cellular and molecular life sciences : CMLS, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Sean MasseyBrain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, 3052, Australia.
Ching-Seng AngThe Bio21 Institute of Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, VIC, Australia.
Nadia M DavidsonMurdoch Children's Research Institute, Royal Children's Hospital, Melbourne, 3052, Australia.
Anita QuigleyElectrical and Biomedical Engineering, School of Engineering, RMIT University, Melbourne, VIC, Australia.
Ben RolloDepartment of Neuroscience, Central Clinical School, Monash University, Melbourne, Australia.
Alexander R HarrisDepartment of Biomedical Engineering, University of Melbourne, Melbourne, 3010, Australia.
Robert M I KapsaElectrical and Biomedical Engineering, School of Engineering, RMIT University, Melbourne, VIC, Australia.
John Christodoulou *Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, 3052, Australia.
Nicole J Van Bergen *Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, 3052, Australia. N.van@unimelb.edu.au.ORCID http://orcid.org/0000-0002-6768-3665

Funding

Minority Investigator Recruitment,Retention &CareersR13AG020106 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI JACKSON, JAMES S · 2001 to 2001
$35k
Foundation for Children 2018-16Loulou Foundation CDKL5 Forum Junior FellowshipMedical Research Future Funds (MRFF) Stem Cell Therapies Mission MRF2007465Murdoch Children's Research Institute Genomic Medicine Research GrantMurdoch Children's Research Institute Genomics MedicineMurdoch Children's Research Institute Near Miss grantMurdoch Children's Research Institute Strategic Pilot Project in Stem CellNovo Nordisk Foundation reNEW Center for Stem Cell Medicine NNF21CC0073729Orphan Disease Center of the University of Pennsylvania MDBR-20-106-CDKL5Royal Children's Hospital Foundation The Chair in Genomic MedicineState Government of Victoria Operational Infrastructure Support ProgramVeski Near Miss Pilot Award
6 · The paper itself

Abstract

CDKL5 Deficiency Disorder (CDD) is a debilitating epileptic encephalopathy disorder affecting young children with no effective treatments. CDD is caused by pathogenic variants in Cyclin-Dependent Kinase-Like 5 (CDKL5), a protein kinase that regulates key phosphorylation events in neurons. For therapeutic intervention, it is essential to understand molecular pathways and phosphorylation targets of CDKL5. Using an unbiased phosphoproteomic approach we identified novel targets of CDKL5, including GTF2I, PPP1R35, GATAD2A and ZNF219 in human iPSC-derived neuronal cells. The phosphoserine residue in the target proteins lies in the CDKL5 consensus motif. We validated direct phosphorylation of GTF2I and PPP1R35 by CDKL5 using complementary approaches. GTF2I controls axon guidance, cell cycle and neurodevelopment by regulating expression of neuronal genes. PPP1R35 is critical for centriole elongation and cilia morphology, processes that are impaired in CDD. PPP1R35 interacts with CEP131, a known CDKL5 phospho-target. GATAD2A and ZNF219 belong to the Nucleosome Remodelling Deacetylase (NuRD) complex, which regulates neuronal activity-dependent genes and synaptic connectivity. In-depth knowledge of molecular pathways regulated by CDKL5 will allow a better understanding of druggable disease pathways to fast-track therapeutic development.

Indexed as

Epileptic SyndromesInduced Pluripotent Stem CellsNeuronsProtein Serine-Threonine KinasesSpasms, InfantileHumansPhosphorylationCDKL5 protein, humanProtein Serine-Threonine KinasesCDKL5 deficiency disorderGTF2IKinaseNeurodevelopmental disorderPhosphoproteomicsPhosphorylationPPP1R35

Identifiers

PMID39136782
PMCPMC11335273

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.