Cyclin-dependent kinases and rare developmental disorders

Abstract

Extensive studies in the past 30 years have established that cyclin-dependent kinases (CDKs) exert many diverse, important functions in a number of molecular and cellular processes that are at play during development. Not surprisingly, mutations affecting CDKs or their activating cyclin subunits have been involved in a variety of rare human developmental disorders. These recent findings are reviewed herein, giving a particular attention to the discovered mutations and their demonstrated or hypothesized functional consequences, which can account for pathological human phenotypes. The review highlights novel, important CDK or cyclin functions that were unveiled by their association with human disorders, and it discusses the shortcomings of mouse models to reveal some of these functions. It explains how human genetics can be used in combination with proteome-scale interaction databases to loom regulatory networks around CDKs and cyclins. Finally, it advocates the use of these networks to profile pathogenic CDK or cyclin variants, in order to gain knowledge on protein function and on pathogenic mechanisms.

Keywords: CDKs; Cyclins; Developmental disorders; Interaction profiling; Regulatory networks.

Fig. 1

CDK5-centered regulatory network and its involvement in human neurodevelopmental disorders. PAFAH1B1 (aka LIS1) and YWHAE bind to CDK5/p35-phosphorylated NUDEL, thereby protecting it from degradation. Two other proteins involved in lissencephalic syndromes, DCX and NDE1 (aka LISX1 and LIS4, respectively), are also phosphorylated and regulated by CDK5, which thus plays a central role in the neuronal development mechanisms underlying lissencephaly

Fig. 2

CDK6/CycD2-centered regulatory network and its involvement in human neurodevelopmental disorders. Cyclin D2 stabilization causes MPPH and can be caused by mutations in the CCND2 gene or in the genes coding for AKT or for the PI3K subunits, which result in GSK3β phosphorylation and inhibition. A number of CDK6 putative phosphorylation substrates and putative interacting partners are involved in MCPH, other microcephalic syndromes, or other neurodevelopmental syndromes. Data sources: the Online Mendelian Inheritance in Man database (www.omim.org) and the Biological General Repository for Interaction Datasets (www.thebiogrid.org)

Fig. 3

CDK13/CycK-centered regulatory network and its involvement in human developmental and behavioral disorders. Except for the CDK13-CycK and CycK-SETD1A interactions, all other interactions have been detected by high-throughput studies and are thus putative. EZH2 and DVL3 are involved in the Weaver and Robinow syndromes, respectively. Data sources: same as Fig. 2

Fig. 4

Edgotyping disease-causing protein variants. a left: a wild-type protein (red) interacts with 5 different proteins; middle: all interactions are lost because the protein is no longer expressed (gene deletion, nonsense or frameshift mutations causing mRNA NMD), or its structure is severely compromised (all kinds of mutations); right: only one of the interactions is lost (truncation-inducing or missense mutation). b Edgotyping of the CDK6 A197T variant, which is suspected to retain its enzymatic activity but which no longer localizes in the centrosomes because of a hypothetic loss of interaction with a centrosomal protein that remains to be identified