Cyclin-dependent kinase-like 5 (Cdkl5) is an X-linked gene encoding a serine/threonine kinase that is highly expressed in the brain. Genetic mutations that disrupt CDKL5 function have been found in humans with neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy 2 (EIEE2). These individuals, classified under CDKL5 Disorder for the common genetic defect, are characterized by early-onset seizures, intellectual disability, and autistic features.
Cdkl5R59X knock-in mice, carrying a nonsense mutation at arginine 59 of Cdkl5, were developed to mimic exactly the same mutation found in patients with CDKL5 disorder. R59X leads to an early truncation at the N-terminal kinase domain of CDKL5, resulting in a loss-of-function. Male carriers show hyperactivity, motor impairments, and deficits in social interaction, learning and memory, with the absence of spontaneous seizures. Homozygous females and hemizygous males are viable but are poor breeders. When maintaining a live colony, heterozygous females may be bred to wildtype males.
