CDKL5
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
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. 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.[17]
Therapeutics
 | This section needs to be updated. The reason given is: Ganaxolone is a recently-approved neurosteroid indicated for seizures associated with CDKL5 deficiency disorder.. (March 2022) |
A CDKL5 protein replacement therapy is in development.[22]
Location
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
G40.42
See also
- Cyclin-dependent kinase
- Rett syndrome
- West syndrome
- CDKL5 deficiency disorder
References
- ^ 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.
- PMID 22779007.
- ^ a b CDKL5 on Genetics Home Reference
- ^ "CDKL5 deficiency disorder". Medlineplus. Retrieved 30 June 2021.
- PMID 15635068.
- PMID 22872100.
- S2CID 29966110.
- PMID 31819097.
- PMID 27080038.
- ^ "Infantile spasm syndrome, X-linked". Archived from the original on 2011-02-27. Retrieved 2010-06-05.
- PMID 12736870.
- ^ "West Syndrome". Archived from the original on 2010-06-10. Retrieved 2010-06-05.
- S2CID 9806578.
- S2CID 207069267.
- S2CID 206105378.
- PMID 26387070.
- PMID 34530725.
- S2CID 233202425.
- ^ "Preclinical Program for Cyclin-Dependent Kinase-Like 5 (CDKL5) Deficiency". Amicus Therapeutics Press Release (Press release). 6 July 2016.
- PMID 9721213.
Further reading
- 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
