Title Pathogenic Studies of CDKL5 Disorder Abstract Mutations in the X-linked gene encoding cyclin-dependent kinase-like 5 cause CDKL5 disorder, an infantile epileptic encephalopathy sharing features with intellectual disability and autism. To understand the biological function of CDKL5 in vivo and the pathogenic mechanisms underlying CDKL5 disorder, we previously developed and characterized a knockout mouse model incorporating a CDKL5 patient-associated genetic defect. We found that mice with CDKL5 dysfunction develop behavioral phenotypes mimicking key symptoms of CDKL5 disorder. These mice also show deficits in neural circuit communication and alterations in multiple signal transduction pathways. Given that CDKL5 expression is highly enriched in the forebrain, we also employed a conditional knockout approach and ablated CDKL5 expression in different neuronal populations of the forebrain. We found that mice lacking CDKL5 from different neuronal cells show distinct behavioral phenotypes, mimicking intellectual disability-like and autism-like features of CDKL5 disorder. These findings raise a hypothesis that CDKL5 regulates cell type-specific signal transduction pathways and different neural circuit mechanisms underlying intellectual disability and autistic features of CDKL5 disorder. We therefore propose to develop an innovative mouse line to characterize cell type-specific functions of CDKL5, and take a combined biochemical, genetic, behavioral, and neurophysiological approach to investigate the molecular and cellular basis of CDKL5 disorder using knockout and conditional knockout mice in both male and females. Together, we expect to uncover new aspects of CDKL5 function, develop a framework for testing therapeutics, and ultimately reveal new opportunities for therapeutic development to alleviate symptoms associated with CDKL5 disorder, as well as other related disorders such as syndromic intellectual disability and autism.
CDKL5 disorder is a severe epileptic encephalopathy that results in intellectual disability, cognitive and motor impairment, and imposes a significant health burden. However, the pathogenic mechanisms underlying CDKL5 disorder are poorly understood, thus limiting the development of diagnosis and treatment options. The generation and characterization of mouse models of CDKL5 disorder will bring much insight into the field by defining biochemical properties of CDKL5 and cellular consequences of CDKL5 dysfunction, thus potentiating effective therapeutic development.
|Zhao, Ying-Tao; Kwon, Deborah Y; Johnson, Brian S et al. (2018) Long genes linked to autism spectrum disorders harbor broad enhancer-like chromatin domains. Genome Res 28:933-942|