| CDKL5 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | CDKL5, EIEE2, ISSX, STK9, CFAP247, cyclin dependent kinase like 5, DEE2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 300203 MGI: 1278336 HomoloGene: 55719 GeneCards: CDKL5 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[5] 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.[6]
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[edit]
Mutations in the CDKL5 gene cause CDKL5 deficiency disorder.[7] CDKL5 deficiency disorder had, earlier, been thought of as a variant of Rett syndrome, due to some similarities in the clinical presentation.[8] 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.[9] While CDKL5 is primarily found in girls, it has been seen in boys as well.[10] 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.[11]
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.[12] At one time, mutations in the CDKL5 gene were thought to cause a disorder called X-linked infantile spasm syndrome (ISSX),[13][14] or West syndrome.[15][16] Studies have established CDKL5 disorder as a distinct clinical entity.
Animal studies[edit]
GSK3β inhibitors in CDKL5 knockout (CDKL5 -/Y) mice permit normal hippocampal development and learning.[17]
IGF-1 treatment in CDKL5 knockout mice restores synaptic function.[further explanation needed][18]
Therapeutics[edit]
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.[19] 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[20][21]
A CDKL5 protein replacement therapy is in development.[22]
Location[edit]
The CDKL5 gene is located on the short (p) arm of the X chromosome at position 22.[23] More precisely, the CDKL5 gene is located from base pair 18,443,724 to base pair 18,671,748 on the X chromosome.[6]
ICD-10[edit]
G40.42
See also[edit]
References[edit]
- ^ a b c GRCh38: Ensembl release 89: ENSG00000008086 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031292 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, Landsberger N (2012). "What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy". (secondary). Neural Plasticity. 2012: 1–11. doi:10.1155/2012/728267. PMC 3385648. PMID 22779007.
- ^ a b CDKL5 on Genetics Home Reference
- ^ "CDKL5 deficiency disorder". Medlineplus. Retrieved 30 June 2021.
- ^ Weaving LS, Ellaway CJ, Gécz J, Christodoulou J (January 2005). "Rett syndrome: clinical review and genetic update". (secondary). Journal of Medical Genetics. 42 (1): 1–7. doi:10.1136/jmg.2004.027730. PMC 1735910. PMID 15635068.
- ^ 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 (March 2013). "The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy". (primary). European Journal of Human Genetics. 21 (3): 266–73. doi:10.1038/ejhg.2012.156. PMC 3573195. PMID 22872100.
- ^ Wong VC, Kwong AK (April 2015). "CDKL5 variant in a boy with infantile epileptic encephalopathy: case report". Brain & Development. 37 (4): 446–8. doi:10.1016/j.braindev.2014.07.003. PMID 25085838. S2CID 29966110.
- ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
- ^ Mangatt M, Wong K, Anderson B, Epstein A, Hodgetts S, Leonard H, Downs J (2016-01-01). "Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome". Orphanet Journal of Rare Diseases. 11: 39. doi:10.1186/s13023-016-0418-y. PMC 4832563. PMID 27080038.
- ^ "Infantile spasm syndrome, X-linked". Archived from the original on 2011-02-27. Retrieved 2010-06-05.
- ^ 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 (June 2003). "Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation". (primary). American Journal of Human Genetics. 72 (6): 1401–11. doi:10.1086/375538. PMC 1180301. PMID 12736870.
- ^ "West Syndrome". Archived from the original on 2010-06-10. Retrieved 2010-06-05.
- ^ Kato M (August 2006). "A new paradigm for West syndrome based on molecular and cell biology". (secondary). Epilepsy Research. 70 (Suppl 1): S87–95. doi:10.1016/j.eplepsyres.2006.02.008. PMID 16806828. S2CID 9806578.
- ^ Fuchs C, Rimondini R, Viggiano R, Trazzi S, De Franceschi M, Bartesaghi R, Ciani E (2015). "Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder". Neurobiology of Disease. 82: 298–310. doi:10.1016/j.nbd.2015.06.018. PMID 26143616. S2CID 207069267.
- ^ Della Sala G, Putignano E, Chelini G, Melani R, Calcagno E, Michele Ratto G, Amendola E, Gross CT, Giustetto M, Pizzorusso T (2015). "Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1" (PDF). Biological Psychiatry. 80 (4): 302–311. doi:10.1016/j.biopsych.2015.08.028. hdl:2158/1012551. PMID 26452614. S2CID 206105378.
- ^ Müller A, Helbig I, Jansen C, Bast T, Guerrini R, Jähn J, et al. (January 2016). "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. doi:10.1016/j.ejpn.2015.09.001. hdl:10067/1315500151162165141. PMID 26387070.
- ^ 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. 13 (1): 40. doi:10.1186/s11689-021-09384-z. ISSN 1866-1947. PMC 8447578. PMID 34530725.
- ^ Aledo-Serrano, Ángel; Gómez-Iglesias, Patricia; Toledano, Rafael; Garcia-Peñas, Juan Jose; Garcia-Morales, Irene; Anciones, Carla; Soto-Insuga, Victor; Benke, Timothy A.; del Pino, Isabel; Gil-Nagel, Antonio (May 2021). "Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort". Epilepsy & Behavior. 118: 107946. doi:10.1016/j.yebeh.2021.107946. PMID 33848848. S2CID 233202425.
- ^ "Preclinical Program for Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency". Amicus Therapeutics Press Release (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 (August 1998). "Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region". (primary). Genomics. 51 (3): 427–33. doi:10.1006/geno.1998.5391. PMID 9721213.
Further reading[edit]
- 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" (PDF). Human Molecular Genetics. 18 (23): 4590–602. doi:10.1093/hmg/ddp426. PMID 19740913.
- 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): 239–42. 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, Gitiaux C, Lazaro L, Odent S, Jonveaux P, Chelly J, Bienvenu T (March 2008). "Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy". Journal of Medical Genetics. 45 (3): 172–8. doi:10.1136/jmg.2007.053504. PMID 17993579. S2CID 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 (June 2008). "The three stages of epilepsy in patients with CDKL5 mutations". Epilepsia. 49 (6): 1027–37. doi:10.1111/j.1528-1167.2007.01520.x. PMID 18266744. S2CID 25784794.
- Mei D, Marini C, Novara F, Bernardina BD, Granata T, Fontana E, Parrini E, Ferrari AR, Murgia A, Zuffardi O, Guerrini R (April 2010). "Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy". Epilepsia. 51 (4): 647–54. doi:10.1111/j.1528-1167.2009.02308.x. PMID 19780792.
- 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 (October 2008). "Key clinical features to identify girls with CDKL5 mutations". Brain. 131 (Pt 10): 2647–61. doi:10.1093/brain/awn197. PMID 18790821.
- 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 (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.
- Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, Landsberger N (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): 30101–11. doi:10.1074/jbc.M804613200. PMC 2662074. PMID 18701457.
- 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 (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): 357–71. 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, Carotenuto M, Musumeci SA, Lo Giudice M, Fichera M (September 2008). "CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology. 71 (13): 997–9. doi:10.1212/01.wnl.0000326592.37105.88. PMID 18809835. S2CID 24945396.
- Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H (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, Saletti V, Balestrini M, Ben-Zeev B, Larizza L (July 2009). "Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes" (PDF). Neurogenetics. 10 (3): 241–50. 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, Wu XR (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): 224–9. 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, Chaix Y, Bienvenu T (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, Russo S, Veneselli E (February 2008). "Clinical and electroencephalographic features in patients with CDKL5 mutations: two new Italian cases and review of the literature". Epilepsy & Behavior. 12 (2): 326–31. doi:10.1016/j.yebeh.2007.10.010. PMID 18063413. S2CID 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 (October 2009). "Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder". Neurogenetics. 10 (4): 363–9. doi:10.1007/s10048-009-0195-z. PMID 19471977. S2CID 1431977.
- Psoni S, Willems PJ, Kanavakis E, Mavrou A, Frissyra H, Traeger-Synodinos J, Sofokleous C, Makrythanassis P, Kitsiou-Tzeli S (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): 188–91. doi:10.1016/j.ejpn.2009.03.006. PMID 19428276.
- Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, Jia CY, Jurisica I, Li SS (June 2007). "Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening". Proteomics. 7 (11): 1775–85. doi:10.1002/pmic.200601006. PMID 17474147. S2CID 22474278.
External links[edit]
- 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
