A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness

Abstract

The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non-motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11-year-old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin-dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non-sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated-tubulin, γ-tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association.

Cyclin-dependent kinases and rare developmental disorders

“…Here again, as could be expected, these skeletal defects are reminiscent of those of ETS2 transgenic mice [48]. Simultaneously, another study reported one patient with globally similar defects and additional features, attributed to a homozygous single nucleotide deletion in the 11th of the 13 exons of CDK10 [11]. In contrast to the above-described cases, the mRNA does not undergo NMD and it even appears to be slightly upregulated.…”

“…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.…”

Fetal midline anomalies: Diagnosis and counselling Part 1: Corpus callosum anomalies

“…WES allows examination of nucleotide sequence of expressed genes in the genome. Compound heterozygous variants in the CDK5RAP2 gene (also known as MCPH3, a causative gene for autosomal recessive primary microcephaly), ZBTB20, C12ofr57 and other gene mutations 30,32 have been described in patients with ACC [33][34][35][36] . These techniques, because ACC genetic heterogeneity, may play an important role in identifying cases affected by ACC at higher risk of intellectual disability.…”

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.…”