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Research progress on the pathogenesis of CDKL5 pathogenic variants and related encephalopathy

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Abstract

Cyclin-dependent kinase-like 5 (CDKL5) is a gene encoding a serine/threonine kinase that possesses an N-terminal catalytic domain and a large C-terminal domain and is located on the short arm of the X-chromosome at position 22 (Xp22). CDKL5 regulates neuronal migration, axonal growth, dendritic morphogenesis, and synaptic development and affects synaptic function. Pathogenic variants include deletions, truncations, splice variants, and missense variants. The specificity of CDKL5 is mainly determined by the shared sequence of amino acid residues, which is the phosphorylation site of the target protein with the motif Arg-Pro-X-Ser/Thr-Ala/Pro/Gly/Ser (R-P-X-[S/T]-[A/G/P/S]). Developmental encephalopathy caused by pathogenic variants of CDKL5 has a variety of nervous system symptoms, such as epilepsy, hypotonia, growth retardation, dyskinesia, cortical visual impairment, sleep disorders, and other clinical symptoms. This review summarizes the mechanism of CDKL5-induced allogeneic lesions in the nervous system and the clinical manifestations of related encephalopathy.

   Conclusion: This review clarifies CDKL5's participation in neurodevelopmental diseases as well as its crucial function in dividing cells, cultured neurons, knockout mice, and human iPSC-derived neurons. CDKL5 variants help identify clinical diagnostic biomarkers. Although a few direct substrates of CDKL5 have been identified, more must be found in order to fully comprehend the signaling pathways connected to CDKL5 in the brain and the mechanisms that underlie its activities.

What is Known:

• The CDKL5 gene has multiple functions and mainly causes disease by affecting neuronal migration, axon growth, dendritic morphogenesis, and synaptic development. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense mutations only occur in the kinase domain or have an impact on splicing sites.

• Developmental encephalopathy caused by pathogenic variants of CDKL5 has a variety of nervous system symptoms, such as epilepsy, hypotonia, growth retardation, dyskinesia, cortical visual impairment, sleep disorders and other clinical symptoms. The CDKL5 deficiency disorder is being recognized as a severe developmental epileptic encephalopathy with early infancy start.

What is New:

• Chemical genetic identification of CDKL5 substrates reveals its role in neuronal microtubule dynamics. Various MT-binding proteins have been identified as interactors of CDKL5. MTs are dynamic structures that are crucial for the migration, polarity, and shape of neurons.

• Neurons in CDKL5 knockout neurons were kept alive by TGF-β1 restoration of SMAD3 signaling, providing evidence for a potential new therapeutic target for CDD. CDKL5 kinase activity is essential for the transcriptional silencing of genes induced by DNA double-strand breaks, CDKL5 may play a key role in the identification of DNA damage in neurons, and the discovery in understanding the molecular basis of CDKL5-related diseases is of great significance.

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Abbreviations

BAX:

Bcl2-associated X

BDNF:

Brain-derived neurotrophic factor

CDD:

CDKL5 deficiency

CDKL5:

Cyclin-dependent kinase-like 5

CEP131:

Centrosomal protein 131

CLIP170:

Cytoplasmic linker protein 170

ELOA:

Elongin A

GEFs:

Guanine nucleotide exchange factors

iPSCs:

Induced pluripotent stem cells

MAP1S:

Microtubule-associated protein 1S

MTs:

Microtubules

NGL-1 :

Netrin G1 ligand

NMDA:

N-methyl-D-aspartate

PSD:

Postsynaptic density

PSD-95:

Postsynaptic density-95

Rac1:

Ras-related C3 botulinum toxin substrate 1

RNAi:

RNA interference

SMAD:

Small mothers against decapentaplegic

SMAD3:

Small mothers against decapentaplegic 3

TGF-β:

Transforming growth factor-β

TIPS:

Terminal tracer proteins

TrkB:

Tyrosine receptor kinase B

Xp22:

X-chromosome at position 22

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Funding

This work was supported by the Gansu Provincial Science and Technology Plan Project (21YF1FA171), the Lanzhou Science and Technology Plan Project (2018–1-111), the Second Hospital of Lanzhou University “Cuiying Technological Innovation” Program (CY2019-MS13), and the 2017 Lanzhou University Second Hospital “Cuiying Graduate Instructor” Training Program (201701).

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  1. Department of Neurology, Lanzhou University Second Hospital, Lanzhou, 730000, China

    Xuyan Sun & Tiancheng Wang

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All authors contributed to the study conception and design. Tiancheng Wang is responsible for the feasibility analysis, quality control, proofreading, supervision and management of the article. Xuyan Sun put forward the idea of the article, literature retrieval and collection, paper writing, and revision.

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Correspondence to Tiancheng Wang.

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Sun, X., Wang, T. Research progress on the pathogenesis of CDKL5 pathogenic variants and related encephalopathy. Eur J Pediatr 182, 3049–3056 (2023). https://doi.org/10.1007/s00431-023-05006-z

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