CDKL5 explained
CDKL5 is a gene that provides instructions for making a protein called cyclin-dependent kinase-like 5 also known as serine/threonine kinase 9 (STK9) that is essential for normal brain development. Mutations in the gene can cause deficiencies in the protein. The gene regulates neuronal morphology through cytoplasmic signaling and controlling gene expression.[1] The CDKL5 protein acts as a kinase, which is an enzyme that changes the activity of other proteins by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. Researchers are currently working to determine which proteins are targeted by the CDKL5 protein.[2]
The CDKL5 protein acts as a kinase, which is an enzyme that modulates the activity of other proteins by adding a phosphate group to specific positions. The CDKL5 protein regulates neuronal morphology through cytoplasmic signaling and by controlling gene expression, playing a crucial role in the development and maintenance of the nervous system.
Studies have shown that the CDKL5 protein interacts with various signaling pathways and plays a role in controlling neurotransmitter release, synaptic plasticity, and cell survival. The CDKL5 protein has also been shown to regulate the activity of genes involved in neuronal development and the formation of synaptic connections.
Researchers are actively working to better understand the role of the CDKL5 protein in brain development and the underlying mechanisms of CDKL5 disorders. Further studies are needed to determine which proteins are targeted by the CDKL5 protein, as well as to develop effective treatments for individuals affected by CDKL5 disorders.
Mutations
Mutations in the CDKL5 gene cause CDKL5 deficiency disorder.[3] CDKL5 deficiency disorder had, earlier, been thought of as a variant of Rett syndrome, due to some similarities in the clinical presentation.[4] CDKL5 deficiency syndrome is now known to be an independent clinical entity caused by mutations in a distinct X-linked gene, and is considered separate from Rett Syndrome, rather than a variant of it.[5] While CDKL5 is primarily found in girls, it has been seen in boys as well.[6] This disorder includes many of the features of classic Rett syndrome, including developmental problems, loss of language skills, and repeated hand-wringing or "hand-washing" movements), but also causes recurrent seizures, beginning in infancy. Some CDKL5 mutations alter a single amino acid in a region of the CDKL5 protein that is critical for its kinase function. Other mutations lead to the production of an abnormally short, nonfunctioning version of the protein. At least 50 disease-causing mutations in this gene have been discovered.[7]
Further confirmation that CDKL5 is an independent disorder with its own characteristics is provided by a 2016 study which concluded that the clinical presentations of the two disorders were not identical.[8] At one time, mutations in the CDKL5 gene were thought to cause a disorder called X-linked infantile spasm syndrome (ISSX),[9] [10] or West syndrome.[11] [12] Studies have established CDKL5 disorder as a distinct clinical entity.
Animal studies
GSK3β inhibitors in CDKL5 knockout (CDKL5 -/Y) mice permit normal hippocampal development and learning.[13]
IGF-1 treatment in CDKL5 knockout mice restores synaptic function.[14]
Therapeutics
Anticonvulsants were the mainstay of treatment for most affected people. These have limited efficacy, pointing to a strong need to develop new treatment strategies for patients.[15] Some treatments might show efficacy in a relevant proportion of patients, such as valproic acid, vigabatrin, clobazam or sodium channel blockers, as well as a ketogenic diet[16] [17]
A CDKL5 protein replacement therapy is in development.[18]
Location
The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22.[19] More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.[2]
ICD-10
G40.42
See also
Further reading
- Ricciardi S, Kilstrup-Nielsen C, Bienvenu T, Jacquette A, Landsberger N, Broccoli V . CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery . Human Molecular Genetics . 18 . 23 . 4590–602 . December 2009 . 19740913 . 10.1093/hmg/ddp426 . free .
- Grosso S, Brogna A, Bazzotti S, Renieri A, Morgese G, Balestri P . Seizures and electroencephalographic findings in CDKL5 mutations: case report and review . Brain & Development . 29 . 4 . 239–42 . May 2007 . 17049193 . 10.1016/j.braindev.2006.09.001 . 10356490 .
- 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 . Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy . Journal of Medical Genetics . 45 . 3 . 172–8 . March 2008 . 17993579 . 10.1136/jmg.2007.053504 . 22176088 .
- 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 . The three stages of epilepsy in patients with CDKL5 mutations . Epilepsia . 49 . 6 . 1027–37 . June 2008 . 18266744 . 10.1111/j.1528-1167.2007.01520.x . 25784794 .
- Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, Parrini E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R . Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy . Epilepsia . 51 . 4 . 647–54 . April 2010 . 19780792 . 10.1111/j.1528-1167.2009.02308.x . free .
- 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 . Key clinical features to identify girls with CDKL5 mutations . Brain . 131 . Pt 10 . 2647–61 . October 2008 . 18790821 . 10.1093/brain/awn197 . free .
- 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 . CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy . Epilepsy Research . 87 . 1 . 25–30 . November 2009 . 19734009 . 10.1016/j.eplepsyres.2009.07.004 . 8493096 .
- Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N . 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 . 30101–11 . October 2008 . 18701457 . 2662074 . 10.1074/jbc.M804613200 . free .
- 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 . 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 . 357–71 . October 2009 . 19793311 . 10.1111/j.1399-0004.2009.01194.x . 39651970 .
- Elia M, Falco M, Ferri R, Spalletta A, Bottitta M, Calabrese G, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M . CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy . Neurology . 71 . 13 . 997–9 . September 2008 . 18809835 . 10.1212/01.wnl.0000326592.37105.88 . 24945396 .
- Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H . Toward a confocal subcellular atlas of the human proteome . Molecular & Cellular Proteomics . 7 . 3 . 499–508 . March 2008 . 18029348 . 10.1074/mcp.M700325-MCP200 . free .
- Russo S, Marchi M, Cogliati F, Bonati MT, Pintaudi M, Veneselli E, Saletti V, Balestrini M, Ben-Zeev B, Larizza L . Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes . Neurogenetics . 10 . 3 . 241–50 . July 2009 . 19241098 . 10.1007/s10048-009-0177-1 . 2434/70585 . 21014209 . free .
- Li MR, Pan H, Bao XH, Zhu XW, Cao GN, Zhang YZ, Wu XR . [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 . 224–9 . February 2009 . 19552836 .
- Li MR, Pan H, Bao XH, Zhang YZ, Wu XR . MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome . Journal of Human Genetics . 52 . 1 . 38–47 . 2007 . 17089071 . 10.1007/s10038-006-0079-0 . free .
- Fichou Y, Bieth E, Bahi-Buisson N, Nectoux J, Girard B, Chelly J, Chaix Y, Bienvenu T . Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy . Neurology . 73 . 1 . 77–8; author reply 78 . July 2009 . 19564592 . 10.1212/01.wnl.0000349658.05677.d7 . 38029402 .
- Pintaudi M, Baglietto MG, Gaggero R, Parodi E, Pessagno A, Marchi M, Russo S, Veneselli E . Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature . Epilepsy & Behavior . 12 . 2 . 326–31 . February 2008 . 18063413 . 10.1016/j.yebeh.2007.10.010 . 23638932 .
- Erez A, Patel AJ, Wang X, Xia Z, Bhatt SS, Craigen W, Cheung SW, Lewis RA, Fang P, Davenport SL, Stankiewicz P, Lalani SR . Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder . Neurogenetics . 10 . 4 . 363–9 . October 2009 . 19471977 . 10.1007/s10048-009-0195-z . 1431977 .
- Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, Sofokleous C, Makrythanassis P, Kitsiou-Tzeli S . 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 . 188–91 . March 2010 . 19428276 . 10.1016/j.ejpn.2009.03.006 .
- Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, Jia CY, Jurisica I, Li SS . Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening . Proteomics . 7 . 11 . 1775–85 . June 2007 . 17474147 . 10.1002/pmic.200601006 . 22474278 .
External links
Notes and References
- Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, Landsberger N . What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy . Neural Plasticity . 2012 . 1–11 . 2012 . 22779007 . 3385648 . 10.1155/2012/728267 . (secondary) . free .
- http://ghr.nlm.nih.gov/gene/CDKL5 CDKL5 on Genetics Home Reference
- Web site: CDKL5 deficiency disorder . Medlineplus . 30 June 2021 .
- Weaving LS, Ellaway CJ, Gécz J, Christodoulou J . Rett syndrome: clinical review and genetic update . Journal of Medical Genetics . 42 . 1 . 1–7 . January 2005 . 15635068 . 1735910 . 10.1136/jmg.2004.027730 . (secondary) .
- Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, Vecchi M, Ho G, Polli R, Psoni S, Bao X, de Klerk N, Leonard H, Christodoulou J . The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy . European Journal of Human Genetics . 21 . 3 . 266–73 . March 2013 . 22872100 . 3573195 . 10.1038/ejhg.2012.156 . (primary) .
- Wong VC, Kwong AK . CDKL5 variant in a boy with infantile epileptic encephalopathy: case report . Brain & Development . 37 . 4 . 446–8 . April 2015 . 25085838 . 10.1016/j.braindev.2014.07.003 . 29966110 .
- Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4. 2019NatSR...918577S .
- Mangatt M, Wong K, Anderson B, Epstein A, Hodgetts S, Leonard H, Downs J . Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome . Orphanet Journal of Rare Diseases . 11 . 39 . 2016-01-01 . 27080038 . 4832563 . 10.1186/s13023-016-0418-y . free .
- Web site: Infantile spasm syndrome, X-linked . 2010-06-05 . https://web.archive.org/web/20110227112333/http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=944 . 2011-02-27 . dead .
- Kalscheuer VM, Tao J, Donnelly A, Hollway G, Schwinger E, Kübart S, Menzel C, Hoeltzenbein M, Tommerup N, Eyre H, Harbord M, Haan E, Sutherland GR, Ropers HH, Gécz J . Grant Robert Sutherland . Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation . American Journal of Human Genetics . 72 . 6 . 1401–11 . June 2003 . 12736870 . 1180301 . 10.1086/375538 . (primary) .
- Web site: West Syndrome . 2010-06-05 . 2010-06-10 . https://web.archive.org/web/20100610095529/http://www.westsyndrome.net/ . dead .
- Kato M . A new paradigm for West syndrome based on molecular and cell biology . Epilepsy Research . 70 . S87–95 . August 2006 . Suppl 1 . 16806828 . 10.1016/j.eplepsyres.2006.02.008 . 9806578 . (secondary) .
- Fuchs C, Rimondini R, Viggiano R, Trazzi S, De Franceschi M, Bartesaghi R, Ciani E . Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder . Neurobiology of Disease . 82 . 298–310 . 2015 . 26143616 . 10.1016/j.nbd.2015.06.018 . 207069267 .
- Della Sala G, Putignano E, Chelini G, Melani R, Calcagno E, Michele Ratto G, Amendola E, Gross CT, Giustetto M, Pizzorusso T . Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1 . Biological Psychiatry . 80. 4. 302–311. 2015 . 26452614 . 10.1016/j.biopsych.2015.08.028 . 2158/1012551 . 206105378 . free .
- Müller A, Helbig I, Jansen C, Bast T, Guerrini R, Jähn J, Muhle H, Auvin S, Korenke GC, Philip S, Keimer R, Striano P, Wolf NI, Püst B, ((Thiels Ch)), Fogarasi A, Waltz S, Kurlemann G, Kovacevic-Preradovic T, Ceulemans B, Schmitt B, Philippi H, Tarquinio D, Buerki S, von Stülpnagel C, Kluger G . 6 . Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy . European Journal of Paediatric Neurology . 20 . 1 . 147–51 . January 2016 . 26387070 . 10.1016/j.ejpn.2015.09.001 . 10067/1315500151162165141 . free .
- Olson. Heather E.. Daniels. Carolyn I.. Haviland. Isabel. Swanson. Lindsay C.. Greene. Caitlin A.. Denny. Anne Marie M.. Demarest. Scott T.. Pestana-Knight. Elia. Zhang. Xiaoming. Moosa. Ahsan N.. Fidell. Andrea. December 2021. Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder. Journal of Neurodevelopmental Disorders. en. 13. 1. 40. 10.1186/s11689-021-09384-z. 1866-1947. 8447578. 34530725 . free .
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- Preclinical Program for Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency . Amicus Therapeutics Press Release . 6 July 2016.
- Montini E, Andolfi G, Caruso A, Buchner G, Walpole SM, Mariani M, Consalez G, Trump D, Ballabio A, Franco B . Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region . Genomics . 51 . 3 . 427–33 . August 1998 . 9721213 . 10.1006/geno.1998.5391 . (primary) .