CDKL5

CDKL5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4BGQ
Identifiers
Aliases	CDKL5 , EIEE2, ISSX, STK9, CFAP247, cyclin dependent kinase like 5, DEE2
External IDs	OMIM: 300203; MGI: 1278336; HomoloGene: 55719; GeneCards: CDKL5; OMA:CDKL5 - orthologs
Gene location (Human) Chr. X chromosome (human) [1] Band Xp22.13 Start 18,425,583 bp [1] End 18,653,629 bp [1]
Gene location (Mouse) Chr. X chromosome (mouse) [2] Band X F4|X 73.95 cM Start 159,554,919 bp [2] End 159,777,700 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in frontal pole Brodmann area 23 lateral nuclear group of thalamus middle temporal gyrus endothelial cell palpebral conjunctiva primary visual cortex superior frontal gyrus entorhinal cortex visceral pleura Top expressed in medial dorsal nucleus medial geniculate nucleus primary motor cortex lateral geniculate nucleus lateral septal nucleus cingulate gyrus piriform cortex Region I of hippocampus proper prefrontal cortex olfactory tubercle More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity protein kinase activity nucleotide binding kinase activity protein serine/threonine kinase activity ATP binding cyclin-dependent protein serine/threonine kinase activity Cellular component dendritic growth cone nucleoplasm ruffle membrane nucleus cytosol dendrite cytoplasm synapse perinuclear region of cytoplasm centrosome ciliary basal body ciliary tip cytoplasm microtubule organizing center cytoskeleton cell projection glutamatergic synapse postsynaptic density, intracellular component Biological process phosphorylation neuron migration protein phosphorylation positive regulation of GTPase activity positive regulation of dendrite morphogenesis protein autophosphorylation positive regulation of axon extension regulation of dendrite development positive regulation of dendritic spine development regulation of cilium assembly regulation of cell cycle regulation of postsynapse organization Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr X: 159.55 – 159.78 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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

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

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

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

• Cyclin-dependent kinase
• Rett syndrome
• West syndrome
• CDKL5 deficiency disorder

References

1. GRCh38: Ensembl release 89: ENSG00000008086 – Ensembl, May 2017
2. 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. 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. 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.
7. 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 . PMC   6747535 . PMID   31450582.
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. Bibcode:2017BBRC..482..239O. 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 . PMC   2662074 . PMID   18701457.
13. 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. 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.
15. 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. 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.
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.
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. 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. 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.
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.
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 . PMC   9723029 . PMID   36109452.

Further reading

• Grosso S, Brogna A, Bazzotti S, Renieri A, Morgese G, Balestri P (May 2007). "Seizures and electroencephalographic findings in CDKL5 mutations: case report and review". Brain & Development. 29 (4): 239–242. doi:10.1016/j.braindev.2006.09.001. PMID   17049193. S2CID   10356490.
• Rosas-Vargas H, Bahi-Buisson N, Philippe C, Nectoux J, Girard B, N'Guyen Morel MA, et al. (March 2008). "Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy". Journal of Medical Genetics. 45 (3): 172–178. doi:10.1136/jmg.2007.053504. PMID   17993579. S2CID   22176088.
• Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gérard M, et al. (June 2008). "The three stages of epilepsy in patients with CDKL5 mutations". Epilepsia. 49 (6): 1027–1037. doi:10.1111/j.1528-1167.2007.01520.x. PMID   18266744. S2CID   25784794.
• Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, et al. (October 2008). "Key clinical features to identify girls with CDKL5 mutations". Brain: A Journal of Neurology. 131 (Pt 10): 2647–2661. doi: 10.1093/brain/awn197 . PMID   18790821.
• Nabbout R, Depienne C, Chipaux M, Girard B, Souville I, Trouillard O, et al. (November 2009). "CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy". Epilepsy Research. 87 (1): 25–30. doi:10.1016/j.eplepsyres.2009.07.004. PMID   19734009. S2CID   8493096.
• Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, et al. (October 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. 76 (4): 357–371. doi:10.1111/j.1399-0004.2009.01194.x. PMID   19793311. S2CID   39651970.
• Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, et al. (September 2008). "CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology. 71 (13): 997–999. doi:10.1212/01.wnl.0000326592.37105.88. PMID   18809835. S2CID   24945396.
• Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, et al. (March 2008). "Toward a confocal subcellular atlas of the human proteome". Molecular & Cellular Proteomics. 7 (3): 499–508. doi: 10.1074/mcp.M700325-MCP200 . PMID   18029348.
• Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, et al. (July 2009). "Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes" (PDF). Neurogenetics. 10 (3): 241–250. doi:10.1007/s10048-009-0177-1. hdl: 2434/70585 . PMID   19241098. S2CID   21014209.
• Li MR, Pan H, Bao XH, Zhu XW, Cao GN, Zhang YZ, et al. (February 2009). "[Methyl-CpG-binding protein 2 gene and CDKL5 gene mutation in patients with Rett syndrome: analysis of 177 Chinese pediatric patients]". Zhonghua Yi Xue Za Zhi. 89 (4): 224–229. PMID   19552836.
• Li MR, Pan H, Bao XH, Zhang YZ, Wu XR (2007). "MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome". Journal of Human Genetics. 52 (1): 38–47. doi: 10.1007/s10038-006-0079-0 . PMID   17089071.
• Fichou Y, Bieth E, Bahi-Buisson N, Nectoux J, Girard B, Chelly J, et al. (July 2009). "Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology. 73 (1): 77–8, author reply 78. doi:10.1212/01.wnl.0000349658.05677.d7. PMID   19564592. S2CID   38029402.
• Pintaudi M, Baglietto MG, Gaggero R, Parodi E, Pessagno A, Marchi M, et al. (February 2008). "Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature". Epilepsy & Behavior. 12 (2): 326–331. doi:10.1016/j.yebeh.2007.10.010. PMID   18063413. S2CID   23638932.
• Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, et al. (October 2009). "Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder". Neurogenetics. 10 (4): 363–369. doi:10.1007/s10048-009-0195-z. PMID   19471977. S2CID   1431977.
• Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, et al. (March 2010). "A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder". European Journal of Paediatric Neurology. 14 (2): 188–191. doi:10.1016/j.ejpn.2009.03.006. PMID   19428276.
• Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, et al. (June 2007). "Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening". Proteomics. 7 (11): 1775–1785. doi:10.1002/pmic.200601006. PMID   17474147. S2CID   22474278.

External links

• Human CDKL5 genome location and CDKL5 gene details page in the UCSC Genome Browser .
• CDKL5+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Cure CDKL5 Disorder Archived 2016-07-13 at the Wayback Machine resources for Families and Professionals - based in the UK
• International Foundation for CDKL5 Research - based in the US
• CDKL5 Forum - a professional forum to share current research on CDKL5 and to stimulate peer-group discussion
• CDKL5 Foundation Netherlands - CDKL5 Foundation based in holland for research, information and collaboration