CDKL5 Research Projects

Understanding the biological function of CDKL5

“Although rapidly growing evidence implies cdkl5 in these developmental disorders, the current understanding of the biological function of CDKL5 is limited. CDKL5 is heavily expressed in the brain during development and in adult. In cortical neurons CDKL5 shuttles between nucleus and cytoplasm and loss of CDKL5 function causes reduced dendrite arborization. The function of cdkl5 in synaptic development and dendritic spine morphogenesis has not been investigated. More importantly the molecular mechanisms by which CDKL5 exert its functions is unknown.”

SILA KONUR ULTANIR GROUP PROJECT:
Mechanistic understanding of CDKL5 function
http://www.nimr.mrc.ac.uk/research/sila-konur-ultanir/mechanistic-understanding-of-cdkl5-function

Understanding the molecular mechanism of CDKL5

“It has been recently shown that CDKL5 possesses a kinase activity and can shuttle between the nucleus and the cytoplasm suggesting that it may control the activity of several cellular targets (genes and proteins), whose function remain unknown. Based on these premises we will address the following specific aims: • To identify the physiological cellular targets of CDKL5 • To establish the effect of CDKL5 mutations on the expression and activity of CDKL5 cellular targets • To establish the role of CDKL5 and specific downstream targets of CDKL5 in the neuronal function, through appropriate in-vitro cell systems • To generate and characterize a CDKL5 loss-of-function mouse model with a special emphasis on those neuronal alterations that may derive from altered activity of CDKL5 cellular targets. The overall goal of this proposal consists in the identification of peculiar CDKL5 responsive genes and proteins that can be targets of treatments in order to eventually devise novel and efficient therapeutic interventions to slow down/cure the disease.”

MOLECULAR MECHANISMS UNDERLYING BRAIN ALTERATIONS IN THE CDKL5 VARIANT OF RETT’S SYNDROME
http://www.telethon.it/en/funding-research/funded-projects/details/molecular-mechanisms-underlying-brain-alterations-in-the-cdkl5-variant-of-retts-syndrome

Exploring Protein-based therapy

CDKL5 disorder, as most human diseases, is related to the malfunctioning of particular protein, CDKL5.
Protein therapy is a medical treatment showing promise that is still in mostly investigatory stages. The idea is to deliver specific amounts of protein to the patient’s target cells. This unique approach can replace the missing protein without the complexities of gene replacement or stem cell approaches.

Protein Therapy Founded by CDKL5 Italy www.cdkl5.org

http://www.dibinem.unibo.it/it/ricerca/progetti-di-ricerca/progetti-nazionali/fisiologia-umana-generale/terapia-proteica-sostitutiva-per-la-variante-cdkl5-della-sindrome-di-rett

http://www.cdkl5.com/Research/Updates.aspx

August 2012    (produced by the International Foundation for CDKL5 Research)   

For current research click on the International Foundation for CDKL5 Research link.
http://www.cdkl5.com/Research/Updates.aspx

Research Articles

CDKL5, a Protein Associated with Rett Syndrome, Regulates Neuronal Morphogenesis via Rac1 Signaling
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iPS cells to model CDKL5-related disorders
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CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells. Biochimica et Biophysica Acta 2012.
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Novel Mutations in Cyclin-Dependent Kinase-Like 5 (CDKL5) Gene in Indian Cases of Rett Syndrome. Neuromolecular Medicine 2013.
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Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-type phenotypes in mice. PNAS 2012.
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Treatment of Neurodevelopmental Disorders in Adulthood. The Journal of Neuroscience 2012.
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Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene. Developmental Medicine & Child Neurology 2012.
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Validation of high-resolution DNA melting analysis for mutation scanning of the CDKL5 gene: Identification of novel mutations. Gene 2012.
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The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. European Journal of Human Genetics 2012.
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Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships. American Journal of Medical Genetics 2012.
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Variant of Rett Syndrome and CDKL5 gene: Clinical and autonomic description of 10 cases. Neuropediatrics 2012.
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A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain. Human Genetics 2012.
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CDKL5 in different atypical Rett syndrome variants: Description of the first eight cases from Spain. Journal of Pediatric Epilepsy 2012.
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Historic, clinical and prognostic features of epileptic encephalopathies caused by CDKL5 mutations. Paediatric Neurology 2012.
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Adult Phenotypes in Angelman- and Rett- Like Syndromes. Molecular Syndromology. Published online: January 13 2012.
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Genes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotype. Paediatric Neurology 2012.
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CDKL5 Regulates Flagellar Length and Localises to the Base of the Flagella in Chlamydomonas. Molecular Biology of the Cell 2013.
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What We Know and Would Like to Know about CDKL5 and Its Involvement in Epileptic Encephalopathy
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Molecular mechanisms: Mouse models autism, Rett syndrome
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