Abstract
Congenital heart defects, dysmorphic facial features and intellectual developmental disorders (CHDFIDD) syndrome in humans was recently associated with mutation in CDK13 gene. In order to assess the loss of function of Cdk13 during mouse development, we employed gene trap knock-out (KO) allele in Cdk13 gene. Embryonic lethality of Cdk13-deficient animals was observed by the embryonic day (E) 16.5, while live embryos were observed on E15.5. At this stage, improper development of multiple organs has been documented, partly resembling defects observed in patients with mutated CDK13. In particular, overall developmental delay, incomplete secondary palate formation with variability in severity among Cdk13-deficient animals or complete midline deficiency, kidney failure accompanied by congenital heart defects were detected. Based on further analyses, the lethality at this stage is a result of heart failure most likely due to multiple heart defects followed by insufficient blood circulation resulting in multiple organs dysfunctions. Thus, Cdk13 KO mice might be a very useful model for further studies focused on delineating signaling circuits and molecular mechanisms underlying CHDFIDD caused by mutation in CDK13 gene.
Highlights
De novo missense variants in Cyclin-dependent kinase 13 (CDK13) gene have been identified as an emerging factor involved in the onset of congenial heart defects (CHD) in humans (Sifrim et al, 2016)
To examine the role of CDK13 during mouse development, the mice carrying Cdk13tm1a allele were generated at the Transgenic and Archiving Module CCP (Institute of Molecular Genetics of the CAS, Prague)
Our analysis revealed a new function of Cdk13 in the context of the mouse development and found that this protein is critical for proper development at later stages of embryogenesis
Summary
De novo missense variants in Cyclin-dependent kinase 13 (CDK13) gene have been identified as an emerging factor involved in the onset of congenial heart defects (CHD) in humans (Sifrim et al, 2016). Spectrum of clinical phenotypes of patients with CDK13 mutations varies from mild to severe with the ubiquitous intellectual disability and developmental delay (ID/DD) (van den Akker et al, 2018) Based on these observations, congenital heart defects, dysmorphic facial features and intellectual development disorder (CHDFIDD) have been recognized as novel syndrome caused by de novo variants of CDK13 gene (Sifrim et al, 2016; Bostwick et al, 2017; Carneiro et al, 2018; van den Akker et al, 2018). Our Cdk13-deficient mice may become an important model to study dysregulation of developmental processes occurring in human patients
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