Biology:CDKL5
 Generic protein structure example |
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.[further explanation needed][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
- Cyclin-dependent kinase
- Rett syndrome
- West syndrome
- CDKL5 deficiency disorder
References
- ↑ "What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy". Neural Plasticity 2012: 1–11. 2012. doi:10.1155/2012/728267. PMID 22779007.
- ↑ 2.0 2.1 CDKL5 on Genetics Home Reference
- ↑ "CDKL5 deficiency disorder". https://medlineplus.gov/genetics/condition/cdkl5-deficiency-disorder/. Retrieved 30 June 2021.
- ↑ "Rett syndrome: clinical review and genetic update". Journal of Medical Genetics 42 (1): 1–7. January 2005. doi:10.1136/jmg.2004.027730. PMID 15635068.
- ↑ "The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy". European Journal of Human Genetics 21 (3): 266–73. March 2013. doi:10.1038/ejhg.2012.156. PMID 22872100.
- ↑ "CDKL5 variant in a boy with infantile epileptic encephalopathy: case report". Brain & Development 37 (4): 446–8. April 2015. doi:10.1016/j.braindev.2014.07.003. PMID 25085838.
- ↑ "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports 9 (1): 18577. December 2019. doi:10.1038/s41598-019-54976-4. PMID 31819097. Bibcode: 2019NatSR...918577S.
- ↑ "Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome". Orphanet Journal of Rare Diseases 11: 39. 2016-01-01. doi:10.1186/s13023-016-0418-y. PMID 27080038.
- ↑ "Infantile spasm syndrome, X-linked". http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=944.
- ↑ "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. doi:10.1086/375538. PMID 12736870.
- ↑ West Syndrome
- ↑ "A new paradigm for West syndrome based on molecular and cell biology". Epilepsy Research 70 (Suppl 1): S87–95. August 2006. doi:10.1016/j.eplepsyres.2006.02.008. PMID 16806828.
- ↑ "Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder". Neurobiology of Disease 82: 298–310. 2015. doi:10.1016/j.nbd.2015.06.018. PMID 26143616.
- ↑ "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. doi:10.1016/j.biopsych.2015.08.028. PMID 26452614. https://iris.unito.it/retrieve/handle/2318/1528158/63230/della%20sala%20postprint.pdf.
- ↑ "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. doi:10.1016/j.ejpn.2015.09.001. 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 et al. (December 2021). "Current neurologic treatment and emerging therapies in CDKL5 deficiency disorder" (in en). Journal of Neurodevelopmental Disorders 13 (1): 40. doi:10.1186/s11689-021-09384-z. ISSN 1866-1947. 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. et al. (May 2021). "Sodium channel blockers for the treatment of epilepsy in CDKL5 deficiency disorder: Findings from a multicenter cohort" (in en). Epilepsy & Behavior 118: 107946. doi:10.1016/j.yebeh.2021.107946. PMID 33848848. https://linkinghub.elsevier.com/retrieve/pii/S1525505021001803.
- ↑ "Preclinical Program for Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency". Amicus Therapeutics Press Release (Press release). 6 July 2016.
- ↑ "Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region". Genomics 51 (3): 427–33. August 1998. doi:10.1006/geno.1998.5391. PMID 9721213.
Further reading
- "CDKL5 influences RNA splicing activity by its association to the nuclear speckle molecular machinery". Human Molecular Genetics 18 (23): 4590–602. December 2009. doi:10.1093/hmg/ddp426. PMID 19740913. https://air.unimi.it/bitstream/2434/657521/2/CDKL5%20influences%20RNA%20splicing%20activity%20by%20its%20association%20to%20the%20nuclear%20speckle%20molecular%20machinery.pdf.
- "Seizures and electroencephalographic findings in CDKL5 mutations: case report and review". Brain & Development 29 (4): 239–42. May 2007. doi:10.1016/j.braindev.2006.09.001. PMID 17049193.
- "Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy". Journal of Medical Genetics 45 (3): 172–8. March 2008. doi:10.1136/jmg.2007.053504. PMID 17993579.
- "The three stages of epilepsy in patients with CDKL5 mutations". Epilepsia 49 (6): 1027–37. June 2008. doi:10.1111/j.1528-1167.2007.01520.x. PMID 18266744.
- "Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy". Epilepsia 51 (4): 647–54. April 2010. doi:10.1111/j.1528-1167.2009.02308.x. PMID 19780792.
- "Key clinical features to identify girls with CDKL5 mutations". Brain 131 (Pt 10): 2647–61. October 2008. doi:10.1093/brain/awn197. PMID 18790821.
- "CDKL5 and ARX mutations are not responsible for early onset severe myoclonic epilepsy in infancy". Epilepsy Research 87 (1): 25–30. November 2009. doi:10.1016/j.eplepsyres.2009.07.004. PMID 19734009.
- "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. doi:10.1074/jbc.M804613200. PMID 18701457.
- "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. doi:10.1111/j.1399-0004.2009.01194.x. PMID 19793311.
- "CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology 71 (13): 997–9. September 2008. doi:10.1212/01.wnl.0000326592.37105.88. PMID 18809835.
- "Toward a confocal subcellular atlas of the human proteome". Molecular & Cellular Proteomics 7 (3): 499–508. March 2008. doi:10.1074/mcp.M700325-MCP200. PMID 18029348.
- "Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes". Neurogenetics 10 (3): 241–50. July 2009. doi:10.1007/s10048-009-0177-1. PMID 19241098. https://air.unimi.it/bitstream/2434/70585/2/art_10.1007_s10048-009-0177-1.pdf.
- "[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. PMID 19552836.
- "MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome". Journal of Human Genetics 52 (1): 38–47. 2007. doi:10.1007/s10038-006-0079-0. PMID 17089071.
- "Re: CDKL5 mutations in boys with severe encephalopathy and early-onset intractable epilepsy". Neurology 73 (1): 77–8; author reply 78. July 2009. doi:10.1212/01.wnl.0000349658.05677.d7. PMID 19564592.
- "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. doi:10.1016/j.yebeh.2007.10.010. PMID 18063413.
- "Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder". Neurogenetics 10 (4): 363–9. October 2009. doi:10.1007/s10048-009-0195-z. PMID 19471977.
- "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. doi:10.1016/j.ejpn.2009.03.006. PMID 19428276.
- "Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening". Proteomics 7 (11): 1775–85. June 2007. doi:10.1002/pmic.200601006. PMID 17474147.
External links
- Human CDKL5 genome location and CDKL5 gene details page in the UCSC Genome Browser.
- CDKL5+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Cure CDKL5 Disorder 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
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