CDK10 mutations in humans and mice cause severe growth retardation, spine malformations, and developmental delays

Item Type:	Article
Title:	CDK10 mutations in humans and mice cause severe growth retardation, spine malformations, and developmental delays
Creators Name:	Windpassinger, C. and Piard, J. and Bonnard, C. and Alfadhel, M. and Lim, S. and Bisteau, X. and Blouin, S. and Ali, N.A.B. and Ng, A.Y.J. and Lu, H. and Tohari, S. and Talib, S.Z.A. and van Hul, N. and Caldez, M.J. and Van Maldergem, L. and Yigit, G. and Kayserili, H. and Youssef, S.A. and Coppola, V. and de Bruin, A. and Tessarollo, L. and Choi, H. and Rupp, V. and Roetzer, K. and Roschger, P. and Klaushofer, K. and Altmüller, J. and Roy, S. and Venkatesh, B. and Ganger, R. and Grill, F. and Ben Chehida, F. and Wollnik, B. and Altunoglu, U. and Al Kaissi, A. and Reversade, B. and Kaldis, P.
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.
Keywords:	CDK10, Growth Retardation, ETS2, Cilia, Metabolism, Spine Malformation, Al Kaissi Syndrome, Knockout Mice, Congenital Disorder, Animals, Mice
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	101
Number:	3
Page Range:	391-403
Date:	7 September 2017
Official Publication:	https://doi.org/10.1016/j.ajhg.2017.08.003
PubMed:	View item in PubMed

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