CDKL5

The CDKL5 gene is located on the X chromosome at locus Xp22.{{cite journal | vauthors = Kittelberger R, Reichel MP, Joyce MA, Staak C | title = 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 | journal = Veterinary Microbiology | volume = 57 | issue = 4 | pages = 361–371 | date = October 1997 | pmid = 9444073 | doi = 10.1016/s0378-1135(97)00110-7 }}{{cite journal | vauthors = Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, Parrini E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R | display-authors = 6 | title = Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy | journal = Epilepsia | volume = 51 | issue = 4 | pages = 647–654 | date = April 2010 | pmid = 19780792 | doi = 10.1111/j.1528-1167.2009.02308.x }}{{cite journal | vauthors = Balestra D, Giorgio D, Bizzotto M, Fazzari M, Ben Zeev B, Pinotti M, Landsberger N, Frasca A | display-authors = 6 | title = Splicing Mutations Impairing CDKL5 Expression and Activity Can be Efficiently Rescued by U1snRNA-Based Therapy | journal = International Journal of Molecular Sciences | volume = 20 | issue = 17 | date = August 2019 | page = 4130 | pmid = 31450582 | doi = 10.3390/ijms20174130 | doi-access = free | hdl = 2434/738478 | hdl-access = free }} It undergoes alternative splicing to produce multiple transcript variants.{{cite journal | vauthors = Wu YT, Adnan A | title = Damage and Failure of Axonal Microtubule under Extreme High Strain Rate: An In-Silico Molecular Dynamics Study | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 12260 | date = August 2018 | pmid = 30115936 | doi = 10.1038/s41598-018-29804-w | bibcode = 2018NatSR...812260W | pmc = 6095851 }}{{cite journal | vauthors = Kessous R, Aricha-Tamir B, Sheizaf B, Shteiner N, Moran-Gilad J, Weintraub AY | title = Clinical and microbiological characteristics of Bartholin gland abscesses | journal = Obstetrics and Gynecology | volume = 122 | issue = 4 | pages = 794–799 | date = October 2013 | pmid = 24084536 | doi = 10.1097/AOG.0b013e3182a5f0de }} Pathogenic variants in CDKL5 can result in either loss of function or altered subcellular localization of the protein, which contributes to disease pathology.{{cite journal | vauthors = Skarsgard ED, Meuli M, VanderWall KJ, Bealer JF, Adzick NS, Harrison MR | title = Fetal endoscopic tracheal occlusion ('Fetendo-PLUG') for congenital diaphragmatic hernia | journal = Journal of Pediatric Surgery | volume = 31 | issue = 10 | pages = 1335–1338 | date = October 1996 | pmid = 8906656 | doi = 10.1016/s0022-3468(96)90823-4 }}{{cite journal | vauthors = Oi A, Katayama S, Hatano N, Sugiyama Y, Kameshita I, Sueyoshi N | title = Subcellular distribution of cyclin-dependent kinase-like 5 (CDKL5) is regulated through phosphorylation by dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) | journal = Biochemical and Biophysical Research Communications | volume = 482 | issue = 2 | pages = 239–245 | date = January 2017 | pmid = 27840050 | doi = 10.1016/j.bbrc.2016.11.048 }} The gene is expressed predominantly in the brain and is particularly active during early developmental stages.{{cite journal | vauthors = Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N | title = CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail | journal = The Journal of Biological Chemistry | volume = 283 | issue = 44 | pages = 30101–30111 | date = October 2008 | pmid = 18701457 | doi = 10.1074/jbc.M804613200 | doi-access = free | hdl = 2434/816769 | hdl-access = free }}{{cite journal | vauthors = Liao W, Lee KZ | title = CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome | journal = Human Molecular Genetics | volume = 32 | issue = 23 | pages = 3276–3298 | date = November 2023 | pmid = 37688574 | doi = 10.1093/hmg/ddad149 }}{{cite journal | vauthors = Tassinari M, Uguagliati B, Trazzi S, Cerchier CB, Cavina OV, Mottolese N, Loi M, Candini G, Medici G, Ciani E | display-authors = 6 | title = Early-onset brain alterations during postnatal development in a mouse model of CDKL5 deficiency disorder | journal = Neurobiology of Disease | volume = 182 | pages = 106146 | date = June 2023 | pmid = 37164289 | doi = 10.1016/j.nbd.2023.106146 | hdl = 11585/928833 | hdl-access = free }}

CDKL5 encodes a serine/threonine kinase with a highly conserved catalytic domain similar to cyclin-dependent kinases (CDKs), though it functions independently of cyclins.{{cite journal | vauthors = Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V | title = CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery | journal = Human Molecular Genetics | volume = 18 | issue = 23 | pages = 4590–4602 | date = December 2009 | pmid = 19740913 | doi = 10.1093/hmg/ddp426 | hdl = 2434/657521 | hdl-access = free }} The C-terminal region of the protein plays a critical role in its subcellular localization and regulation. During neuronal development, CDKL5 localizes to both the nucleus and cytoplasm, with nuclear localization being essential for its role in gene regulation and splicing.{{cite journal | vauthors = Baum RP, Hertel A, Lorenz M, Schwarz A, Encke A, Hör G | title = 99Tcm-labelled anti-CEA monoclonal antibody for tumour immunoscintigraphy: first clinical results | journal = Nuclear Medicine Communications | volume = 10 | issue = 5 | pages = 345–352 | date = May 1989 | pmid = 2662074 | doi = 10.1097/00006231-198905000-00005 }}

CDKL5 plays a central role in neuronal function by regulating signal transduction pathways that influence dendritic spine morphology, synaptogenesis, and neuronal survival.{{cite journal | vauthors = Massey S, Ang CS, Davidson NM, Quigley A, Rollo B, Harris AR, Kapsa RM, Christodoulou J, Van Bergen NJ | display-authors = 6 | title = Novel CDKL5 targets identified in human iPSC-derived neurons | journal = Cellular and Molecular Life Sciences | volume = 81 | issue = 1 | pages = 347 | date = August 2024 | pmid = 39136782 | doi = 10.1007/s00018-024-05389-8 | pmc = 11335273 }}{{cite journal | vauthors = Nguyen LB, Salen G, Shefer S, Bullock J, Chen T, Tint GS, Chowdhary IR, Lerner S | display-authors = 6 | title = Deficient ileal 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in sitosterolemia: sitosterol is not a feedback inhibitor of intestinal cholesterol biosynthesis | journal = Metabolism | volume = 43 | issue = 7 | pages = 855–859 | date = July 1994 | pmid = 8028508 | doi = 10.1016/0026-0495(94)90266-6 }} It is involved in the phosphorylation of target proteins that modulate neuronal activity and gene expression.{{cite journal | vauthors = Rimmer A | title = Overseas doctors must not be used just to fill rota gaps, says leading consultant | journal = BMJ | volume = 361 | pages = k2654 | date = June 2018 | pmid = 29907696 | doi = 10.1136/bmj.k2654 }}{{cite journal | vauthors = Hieble JP, Pendleton RG | title = Effects of ring substitution on the pre- and postjunctional alpha-adrenergic activity of aryliminoimidazolidines | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 309 | issue = 3 | pages = 217–224 | date = November 1979 | pmid = 43475 | doi = 10.1007/BF00504753 }} CDKL5 has also been shown to interact with nuclear speckles and influence RNA splicing machinery, which may underlie some of its neurodevelopmental functions.

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.{{cite journal | vauthors = Kadam SD, Sullivan BJ, Goyal A, Blue ME, Smith-Hicks C | title = Rett Syndrome and CDKL5 Deficiency Disorder: From Bench to Clinic | journal = International Journal of Molecular Sciences | volume = 20 | issue = 20 | date = October 2019 | page = 5098 | pmid = 31618813 | doi = 10.3390/ijms20205098 | doi-access = free | pmc = 6834180 }}{{cite web | url=https://rarediseases.org/rare-diseases/cdkl5/ | title=CDKL5 Deficiency Disorder - Symptoms, Causes, Treatment | publisher=NORD }} CDD is considered distinct from classic Rett syndrome, although overlapping features have been noted, especially in female patients. Clinical presentations of CDKL5 mutations can vary widely, and cases have been reported in both males and females.{{cite journal | vauthors = Voronin G, Narasimhan J, Gittens J, Sheedy J, Lipari P, Peters M, DeMarco S, Cao L, Varganov Y, Kim MJ, Pear L, Fotouh E, Sinha S, Ray B, Wu MC, Yalamanchili P, Southgate C, Pick J, Saadipour K, Jung S, Lee J, Mollin A, Welch EM, Wu Z, Weetall M | display-authors = 6 | title = Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder | journal = Molecular Therapy | volume = 32 | issue = 10 | pages = 3331–3345 | date = October 2024 | pmid = 39033321 | doi = 10.1016/j.ymthe.2024.07.012 }}{{cite journal | vauthors = Knight EM, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, Olson HE, Specchio N, Fleming TR, Aimetti AA, Gasior M, Devinsky O | display-authors = 6 | title = 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 | journal = The Lancet. Neurology | volume = 21 | issue = 5 | pages = 417–427 | date = May 2022 | pmid = 35429480 | doi = 10.1016/S1474-4422(22)00077-1 | url = https://discovery.ucl.ac.uk/id/eprint/10153307/ }} Genetic testing for CDKL5 is recommended in infants presenting with epileptic encephalopathy of unknown origin.{{cite web | url=https://marinuspharma.com/the-benefits-of-genetic-testing-for-patients-with-cdkl5-deficiency-disorder-and-other-rare-genetic-epilepsies/ | title=Genetic Testing for CDKL5 Deficiency Disorder | date=2 October 2024 | publisher=Marinus Pharmaceuticals }} Research is ongoing into potential therapies, including gene therapy{{cite journal | vauthors = Medici G, Tassinari M, Galvani G, Bastianini S, Gennaccaro L, Loi M, Mottolese N, Alvente S, Berteotti C, Sagona G, Lupori L, Candini G, Baggett HR, Zoccoli G, Giustetto M, Muotri A, Pizzorusso T, Nakai H, Trazzi S, Ciani E | display-authors = 6 | title = Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder | journal = Neurotherapeutics | volume = 19 | issue = 6 | pages = 1886–1904 | date = October 2022 | pmid = 36109452 | doi = 10.1007/s13311-022-01295-8 | hdl = 11585/899314 | hdl-access = free }} and molecular modulation of downstream targets.

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

{{Reflist|33em}}

{{refbegin|33em}}

• {{cite journal | vauthors = Grosso S, Brogna A, Bazzotti S, Renieri A, Morgese G, Balestri P | title = Seizures and electroencephalographic findings in CDKL5 mutations: case report and review | journal = Brain & Development | volume = 29 | issue = 4 | pages = 239–242 | date = May 2007 | pmid = 17049193 | doi = 10.1016/j.braindev.2006.09.001 | s2cid = 10356490 }}
• {{cite journal | vauthors = Rosas-Vargas H, Bahi-Buisson N, Philippe C, Nectoux J, Girard B, N'Guyen Morel MA, Gitiaux C, Lazaro L, Odent S, Jonveaux P, Chelly J, Bienvenu T | title = Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy | journal = Journal of Medical Genetics | volume = 45 | issue = 3 | pages = 172–178 | date = March 2008 | pmid = 17993579 | doi = 10.1136/jmg.2007.053504 | s2cid = 22176088 }}
• {{cite journal | vauthors = Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gérard M, Giuliano F, Motte J, Héron D, Morel MA, Plouin P, Richelme C, des Portes V, Dulac O, Philippe C, Chiron C, Nabbout R, Bienvenu T | title = The three stages of epilepsy in patients with CDKL5 mutations | journal = Epilepsia | volume = 49 | issue = 6 | pages = 1027–1037 | date = June 2008 | pmid = 18266744 | doi = 10.1111/j.1528-1167.2007.01520.x | s2cid = 25784794 }}
• {{cite journal | vauthors = Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, Cances C, Ville D, Afenjar A, Rio M, Héron D, N'guyen Morel MA, Arzimanoglou A, Philippe C, Jonveaux P, Chelly J, Bienvenu T | title = Key clinical features to identify girls with CDKL5 mutations | journal = Brain: A Journal of Neurology | volume = 131 | issue = Pt 10 | pages = 2647–2661 | date = October 2008 | pmid = 18790821 | doi = 10.1093/brain/awn197 | doi-access = free }}
• {{cite journal | vauthors = Nabbout R, Depienne C, Chipaux M, Girard B, Souville I, Trouillard O, Dulac O, Chelly J, Afenjar A, Héron D, Leguern E, Beldjord C, Bienvenu T, Bahi-Buisson N | title = CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy | journal = Epilepsy Research | volume = 87 | issue = 1 | pages = 25–30 | date = November 2009 | pmid = 19734009 | doi = 10.1016/j.eplepsyres.2009.07.004 | s2cid = 8493096 }}
• {{cite journal | vauthors = Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, Delobel B, Layet V, N'guyen MA, Saunier A, Verneau F, Jonveaux P, Philippe C | title = Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature | journal = Clinical Genetics | volume = 76 | issue = 4 | pages = 357–371 | date = October 2009 | pmid = 19793311 | doi = 10.1111/j.1399-0004.2009.01194.x | s2cid = 39651970 }}
• {{cite journal | vauthors = Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M | title = CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy | journal = Neurology | volume = 71 | issue = 13 | pages = 997–999 | date = September 2008 | pmid = 18809835 | doi = 10.1212/01.wnl.0000326592.37105.88 | s2cid = 24945396 }}
• {{cite journal | vauthors = Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H | title = Toward a confocal subcellular atlas of the human proteome | journal = Molecular & Cellular Proteomics | volume = 7 | issue = 3 | pages = 499–508 | date = March 2008 | pmid = 18029348 | doi = 10.1074/mcp.M700325-MCP200 | doi-access = free }}
• {{cite journal | vauthors = Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, Saletti V, Balestrini M, Ben-Zeev B, Larizza L | title = Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes | journal = Neurogenetics | volume = 10 | issue = 3 | pages = 241–250 | date = July 2009 | pmid = 19241098 | doi = 10.1007/s10048-009-0177-1 | url = https://air.unimi.it/bitstream/2434/70585/2/art_10.1007_s10048-009-0177-1.pdf | hdl = 2434/70585 | s2cid = 21014209 | hdl-access = free }}
• {{cite journal | vauthors = Li MR, Pan H, Bao XH, Zhu XW, Cao GN, Zhang YZ, Wu XR | title = [Methyl-CpG-binding protein 2 gene and CDKL5 gene mutation in patients with Rett syndrome: analysis of 177 Chinese pediatric patients] | journal = Zhonghua Yi Xue Za Zhi | volume = 89 | issue = 4 | pages = 224–229 | date = February 2009 | pmid = 19552836 }}
• {{cite journal | vauthors = Li MR, Pan H, Bao XH, Zhang YZ, Wu XR | title = MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome | journal = Journal of Human Genetics | volume = 52 | issue = 1 | pages = 38–47 | year = 2007 | pmid = 17089071 | doi = 10.1007/s10038-006-0079-0 | doi-access = free }}
• {{cite journal | vauthors = Fichou Y, Bieth E, Bahi-Buisson N, Nectoux J, Girard B, Chelly J, Chaix Y, Bienvenu T | title = Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy | journal = Neurology | volume = 73 | issue = 1 | pages = 77–8; author reply 78 | date = July 2009 | pmid = 19564592 | doi = 10.1212/01.wnl.0000349658.05677.d7 | s2cid = 38029402 }}
• {{cite journal | vauthors = Pintaudi M, Baglietto MG, Gaggero R, Parodi E, Pessagno A, Marchi M, Russo S, Veneselli E | title = Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature | journal = Epilepsy & Behavior | volume = 12 | issue = 2 | pages = 326–331 | date = February 2008 | pmid = 18063413 | doi = 10.1016/j.yebeh.2007.10.010 | s2cid = 23638932 }}
• {{cite journal | vauthors = Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, Cheung SW, Lewis RA, Fang P, Davenport SL, Stankiewicz P, Lalani SR | title = Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder | journal = Neurogenetics | volume = 10 | issue = 4 | pages = 363–369 | date = October 2009 | pmid = 19471977 | doi = 10.1007/s10048-009-0195-z | s2cid = 1431977 }}
• {{cite journal | vauthors = Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, Sofokleous C, Makrythanassis P, Kitsiou-Tzeli S | title = A novel p.Arg970X mutation in the last exon of the CDKL5 gene resulting in late-onset seizure disorder | journal = European Journal of Paediatric Neurology | volume = 14 | issue = 2 | pages = 188–191 | date = March 2010 | pmid = 19428276 | doi = 10.1016/j.ejpn.2009.03.006 }}
• {{cite journal | vauthors = Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, Jia CY, Jurisica I, Li SS | title = Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening | journal = Proteomics | volume = 7 | issue = 11 | pages = 1775–1785 | date = June 2007 | pmid = 17474147 | doi = 10.1002/pmic.200601006 | s2cid = 22474278 }}

{{refend}}

• {{UCSC gene info|CDKL5}}
• {{MeshName|CDKL5+protein,+human}}
• [https://www.curecdkl5.org/ Cure CDKL5 Disorder] {{Webarchive|url=https://web.archive.org/web/20160713205045/http://www.curecdkl5.org/ |date=2016-07-13 }} resources for Families and Professionals - based in the UK
• [http://www.cdkl5.com/ International Foundation for CDKL5 Research] - based in the US
• [http://www.cdkl5forum.org/ CDKL5 Forum] - a professional forum to share current research on CDKL5 and to stimulate peer-group discussion
• [http://www.cdkl-5.nl/ CDKL5 Foundation Netherlands] - CDKL5 Foundation based in holland for research, information and collaboration

{{Serine/threonine-specific protein kinases}}

{{Enzymes}}

{{Portal bar|Biology|border=no}}

Category:EC 2.7.11