CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Abstract

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development.

Structural insights into the functional diversity of the CDK–cyclin family

“…It phosphorylates diverse substrates including the ETS2 oncoprotein and the protein kinase PKN2, and mutations in its cognate cyclin, cyclin M, result in STAR syndrome, a human developmental disorder [ 10 , 11 ]. CDK10 mutant and knockout mice also show growth and developmental delays [ 12 ]. CDK11–cyclin L complexes regulate RNA splicing, studied, for example, in the context of human immunodeficiency virus (HIV) transcript processing [ 13 ].…”

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

“…The identification of cyclin M as a CDK10 binding and activating partner enabled us to show that this kinase phosphorylates the ETS2 oncoprotein and controls its stability (Guen et al, 2013), and that it regulates actin network architecture and ciliogenesis (Guen et al, 2016), (reviewed in Guen et al, 2017). Yet, we still know little about CDK10/CycM, although it stands out as the only member of its family responsible for severe human developmental syndromes, when mutated either on the cyclin (Unger et al, 2008) or the CDK moiety (Windpassinger et al, 2017;Guen et al, 2018). CDK10 small-molecule inhibitors would complement the classical reverse genetics toolbox in exploring biological functions of this protein kinase.…”

Cyclin-dependent kinases and rare developmental disorders

“…In contrast to the above-described cases, the mRNA does not undergo NMD and it even appears to be slightly upregulated. Unexpectedly, patient fibroblasts present shorter, less abundant primary cilia [11], whereas RNAi-mediated CDK10 silencing in a human cell line or CDK10 knockout mouse embryonic fibroblasts exhibit longer, more abundant cilia [10,49]. This reported mutation results in a frameshift that might allow the translation of a shorter CDK10 protein (307 amino acids vs 360 for the longest wild-type isoform), containing 17 missense amino acids at its C-terminus.…”

“…Nine individuals from five families presenting growth retardation, spine malformation, facial dysmorphisms, developmental delay and intellectual disability were investigated and shown to harbor homozygous mutations in the CDK10 gene [10]. All mutations result in frameshifts or internal truncations that reduce CDK10 levels probably through NMD of the mRNAs.…”