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CDKL5

From Wikipedia, the free encyclopedia

CDKL5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDKL5, EIEE2, ISSX, STK9, CFAP247, cyclin dependent kinase like 5, DEE2
External IDsOMIM: 300203; MGI: 1278336; HomoloGene: 55719; GeneCards: CDKL5; OMA:CDKL5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6792

382253

Ensembl

ENSG00000008086

ENSMUSG00000031292

UniProt

O76039

Q3UTQ8

RefSeq (mRNA)

NM_001037343
NM_003159
NM_001323289

NM_001024624

RefSeq (protein)

NP_001032420
NP_001310218
NP_003150

NP_001019795

Location (UCSC)Chr X: 18.43 – 18.65 MbChr X: 159.55 – 159.78 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase that in humans is encoded by the CDKL5 gene. It is critically involved in early brain development and function, particularly in neuronal maturation and synaptic regulation. Mutations in CDKL5 are associated with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition that manifests with early-onset epilepsy, developmental delay, and motor and cognitive impairment. CDKL5 is closely related to the cyclin-dependent kinase family and has been implicated in disorders such as Rett syndrome and other epileptic encephalopathies.

Gene

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The CDKL5 gene is located on the X chromosome at locus Xp22.[5][6][7] It undergoes alternative splicing to produce multiple transcript variants.[5][7][8][9] Pathogenic variants in CDKL5 can result in either loss of function or altered subcellular localization of the protein, which contributes to disease pathology.[10][11][7][6] The gene is expressed predominantly in the brain and is particularly active during early developmental stages.[12][13][14]

Structure

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CDKL5 encodes a serine/threonine kinase with a highly conserved catalytic domain similar to cyclin-dependent kinases (CDKs), though it functions independently of cyclins.[5][15] The C-terminal region of the protein plays a critical role in its subcellular localization and regulation.[13][14] During neuronal development, CDKL5 localizes to both the nucleus and cytoplasm, with nuclear localization being essential for its role in gene regulation and splicing.[15][16][5]

Function

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CDKL5 plays a central role in neuronal function by regulating signal transduction pathways that influence dendritic spine morphology, synaptogenesis, and neuronal survival.[17][5][18] It is involved in the phosphorylation of target proteins that modulate neuronal activity and gene expression.[17][19][20] CDKL5 has also been shown to interact with nuclear speckles and influence RNA splicing machinery, which may underlie some of its neurodevelopmental functions.[15][17]

Clinical significance

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Mutations in CDKL5 cause CDKL5 deficiency disorder (CDD), an X-linked dominant condition characterized by early-onset epileptic seizures, severe intellectual disability, and motor dysfunction.[21][22] CDD is considered distinct from classic Rett syndrome, although overlapping features have been noted, especially in female patients.[21] Clinical presentations of CDKL5 mutations can vary widely, and cases have been reported in both males and females.[23][24] Genetic testing for CDKL5 is recommended in infants presenting with epileptic encephalopathy of unknown origin.[25][13] Research is ongoing into potential therapies, including gene therapy[26][23] and molecular modulation of downstream targets.[5][17]

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000008086 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031292 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e f Kittelberger R, Reichel MP, Joyce MA, Staak C (October 1997). "Serological crossreactivity between Brucella abortus and Yersinia enterocolitica 0:9. III. Specificity of the in vitro antigen-specific gamma interferon test for bovine brucellosis diagnosis in experimentally Yersinia enterocolitica 0:9-infected cattle". Veterinary Microbiology. 57 (4): 361–371. doi:10.1016/s0378-1135(97)00110-7. PMID 9444073.
  6. ^ a b Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, et al. (April 2010). "Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy". Epilepsia. 51 (4): 647–654. doi:10.1111/j.1528-1167.2009.02308.x. PMID 19780792.{{cite journal}}: CS1 maint: overridden setting (link)
  7. ^ a b c Balestra D, Giorgio D, Bizzotto M, Fazzari M, Ben Zeev B, Pinotti M, et al. (August 2019). "Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy". International Journal of Molecular Sciences. 20 (17): 4130. doi:10.3390/ijms20174130. hdl:2434/738478. PMID 31450582.{{cite journal}}: CS1 maint: overridden setting (link)
  8. ^ Wu YT, Adnan A (August 2018). "Damage and Failure of Axonal Microtubule under Extreme High Strain Rate: An In-Silico Molecular Dynamics Study". Scientific Reports. 8 (1): 12260. Bibcode:2018NatSR...812260W. doi:10.1038/s41598-018-29804-w. PMC 6095851. PMID 30115936.
  9. ^ Kessous R, Aricha-Tamir B, Sheizaf B, Shteiner N, Moran-Gilad J, Weintraub AY (October 2013). "Clinical and microbiological characteristics of Bartholin gland abscesses". Obstetrics and Gynecology. 122 (4): 794–799. doi:10.1097/AOG.0b013e3182a5f0de. PMID 24084536.
  10. ^ Skarsgard ED, Meuli M, VanderWall KJ, Bealer JF, Adzick NS, Harrison MR (October 1996). "Fetal endoscopic tracheal occlusion ('Fetendo-PLUG') for congenital diaphragmatic hernia". Journal of Pediatric Surgery. 31 (10): 1335–1338. doi:10.1016/s0022-3468(96)90823-4. PMID 8906656.
  11. ^ Oi A, Katayama S, Hatano N, Sugiyama Y, Kameshita I, Sueyoshi N (January 2017). "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. 482 (2): 239–245. doi:10.1016/j.bbrc.2016.11.048. PMID 27840050.
  12. ^ Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, et al. (October 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. 283 (44): 30101–30111. doi:10.1074/jbc.M804613200. hdl:2434/816769. PMID 18701457.
  13. ^ a b c Liao W, Lee KZ (November 2023). "CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome". Human Molecular Genetics. 32 (23): 3276–3298. doi:10.1093/hmg/ddad149. PMID 37688574.
  14. ^ a b Tassinari M, Uguagliati B, Trazzi S, Cerchier CB, Cavina OV, Mottolese N, et al. (June 2023). "Early-onset brain alterations during postnatal development in a mouse model of CDKL5 deficiency disorder". Neurobiology of Disease. 182: 106146. doi:10.1016/j.nbd.2023.106146. hdl:11585/928833. PMID 37164289.{{cite journal}}: CS1 maint: overridden setting (link)
  15. ^ a b c Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V (December 2009). "CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery". Human Molecular Genetics. 18 (23): 4590–4602. doi:10.1093/hmg/ddp426. hdl:2434/657521. PMID 19740913.
  16. ^ Baum RP, Hertel A, Lorenz M, Schwarz A, Encke A, Hör G (May 1989). "99Tcm-labelled anti-CEA monoclonal antibody for tumour immunoscintigraphy: first clinical results". Nuclear Medicine Communications. 10 (5): 345–352. doi:10.1097/00006231-198905000-00005. PMID 2662074.
  17. ^ a b c d Massey S, Ang CS, Davidson NM, Quigley A, Rollo B, Harris AR, et al. (August 2024). "Novel CDKL5 targets identified in human iPSC-derived neurons". Cellular and Molecular Life Sciences. 81 (1): 347. doi:10.1007/s00018-024-05389-8. PMC 11335273. PMID 39136782.{{cite journal}}: CS1 maint: overridden setting (link)
  18. ^ Nguyen LB, Salen G, Shefer S, Bullock J, Chen T, Tint GS, et al. (July 1994). "Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis". Metabolism. 43 (7): 855–859. doi:10.1016/0026-0495(94)90266-6. PMID 8028508.{{cite journal}}: CS1 maint: overridden setting (link)
  19. ^ Rimmer A (June 2018). "Overseas doctors must not be used just to fill rota gaps, says leading consultant". BMJ. 361: k2654. doi:10.1136/bmj.k2654. PMID 29907696.
  20. ^ Hieble JP, Pendleton RG (November 1979). "Effects of ring substitution on the pre- and postjunctional alpha-adrenergic activity of aryliminoimidazolidines". Naunyn-Schmiedeberg's Archives of Pharmacology. 309 (3): 217–224. doi:10.1007/BF00504753. PMID 43475.
  21. ^ a b Kadam SD, Sullivan BJ, Goyal A, Blue ME, Smith-Hicks C (October 2019). "Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic". International Journal of Molecular Sciences. 20 (20): 5098. doi:10.3390/ijms20205098. PMC 6834180. PMID 31618813.
  22. ^ "CDKL5 Deficiency Disorder - Symptoms, Causes, Treatment". NORD.
  23. ^ a b Voronin G, Narasimhan J, Gittens J, Sheedy J, Lipari P, Peters M, et al. (October 2024). "Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder". Molecular Therapy. 32 (10): 3331–3345. doi:10.1016/j.ymthe.2024.07.012. PMID 39033321.{{cite journal}}: CS1 maint: overridden setting (link)
  24. ^ Knight EM, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, et al. (May 2022). "Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial". The Lancet. Neurology. 21 (5): 417–427. doi:10.1016/S1474-4422(22)00077-1. PMID 35429480.{{cite journal}}: CS1 maint: overridden setting (link)
  25. ^ "Genetic Testing for CDKL5 Deficiency Disorder". Marinus Pharmaceuticals. 2 October 2024.
  26. ^ Medici G, Tassinari M, Galvani G, Bastianini S, Gennaccaro L, Loi M, et al. (October 2022). "Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder". Neurotherapeutics. 19 (6): 1886–1904. doi:10.1007/s13311-022-01295-8. hdl:11585/899314. PMID 36109452.{{cite journal}}: CS1 maint: overridden setting (link)

Further reading

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