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

CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays
Title:
CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays
Other Titles:
American Journal of Human Genetics (AJHG)
Keywords:
Publication Date:
07 September 2017
Citation:
ARTICLE| VOLUME 101, ISSUE 3, P391-403, SEPTEMBER 07, 2017
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.
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Funding Info:
We thank all families for partaking in this study. This work is the result of a fruitful collaboration between several research groups, and therefore it is difficult to give sufficient credit to each author. Nevertheless, the Kaldis, Reversade, and Al Kaissi laboratories contributed equally. The authors would also like to thank Isabelle Dalle Fusine and all past and current members of the Kaldis, Reversade, Windpassinger, and Al Kaissi labs for technical assistance and fruitful discussions. We acknowledge the technical expertise provided by the Advanced Molecular Pathology Laboratory at the Institute of Molecular and Cell Biology. We are grateful to Eileen Southon and Susan Reid for help in generating the Cdk10flox mice. This work was supported by the Intramural Research Program of the NIH , the National Cancer Institute , and the Center for Cancer Research (V.C. and L.T.); a Strategic Positioning Fund for the Genetic Orphan Diseases program (SPF2012/005) and an Industry Alignment Fund for the Singapore Childhood Undiagnosed Diseases program (IAF311019) from the A∗STAR (Agency for Science, Technology, and Research) Biomedical Research Council (B.R.); and the A∗STAR Biomedical Research Council (P.K.).
Description:
The full paper is available for download at the publisher's URL: https://doi.org/10.1016/j.ajhg.2017.08.003
ISSN:
0002-9297
1537-6605
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