Cyclin-dependent kinase-like 5 gene locus (CDKL5)

The Cyclin-dependent kinase-like 5 (CDKL5) gene locus, located on the X chromosome at p22.13, encodes a member of the CMGC family of serine/threonine kinases that is essential for normal brain development and function (Source: UniProt P60568). The regulatory DNA associated with this locus, including its promoter and intronic enhancers, governs the expression of CDKL5, which plays a pivotal role in neuronal migration, dendritic arborization, and synaptic plasticity (Source: PubMed PMID: 28604103). Pathogenic variants or deletions in this locus lead to CDKL5 Deficiency Disorder (CDD), a rare and severe neurodevelopmental condition characterized by early-onset, treatment-resistant epilepsy and significant motor and cognitive deficits (Source: NORD). As a therapeutic target, the CDKL5 gene locus is being addressed through novel genetic modalities, including gene replacement therapies like TSHA-104 and antisense oligonucleotides (ASOs) such as UX055, which seek to provide or boost functional CDKL5 protein (Source: Taysha Gene Therapies; Ultragenyx). Additionally, research into epigenetic modulation aims to reactivate the healthy but silenced CDKL5 allele on the inactive X chromosome in females (Source: PubMed PMID: 31515474). Therapeutic success depends on achieving physiological levels of the protein, as both deficiency and excessive CDKL5 activity can disrupt neuronal homeostasis (Source: PubMed PMID: 30245137).

Other names

STK9CDKL5 regulatory DNACyclin-dependent kinase-like 5 genomic regionEIEE2 locusSerine/threonine-protein kinase 9 gene

Restoration of functional CDKL5 protein expression through AAV-mediated gene replacement or antisense oligonucleotide-mediated modulation of gene regulatory elements.