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

Christian Windpassinger, Juliette Piard, Carine Bonnard, Majid Alfadhel, Shuhui Lim, Xavier Bisteau, Stéphane Blouin, Nur'Ain B. Ali, Alvin Yu Jin Ng, Hao Lu, Sumanty Tohari, S. Zakiah A. Talib, Noémi van Hul, Matias J. Caldez, Lionel Van Maldergem, Gökhan Yigit, Hülya Kayserili, Sameh A. Youssef, Vincenzo Coppola, Alain de BruinLino Tessarollo, Hyungwon Choi, Verena Rupp, Katharina Roetzer, Paul Roschger, Klaus Klaushofer, Janine Altmüller, Sudipto Roy, Byrappa Venkatesh, Rudolf Ganger, Franz Grill, Farid Ben Chehida, Bernd Wollnik, Umut Altunoglu, Ali Al Kaissi, Bruno Reversade*, Philipp Kaldis

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)391-403
Number of pages13
JournalAmerican journal of human genetics
Volume101
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

Cite this

Windpassinger, C., Piard, J., Bonnard, C., Alfadhel, M., Lim, S., Bisteau, X., Blouin, S., Ali, NA. B., Ng, A. Y. J., Lu, H., Tohari, S., Talib, S. Z. A., van Hul, N., Caldez, M. J., Van Maldergem, L., Yigit, G., Kayserili, H., Youssef, S. A., Coppola, V., ... Kaldis, P. (2017). CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. American journal of human genetics, 101(3), 391-403. https://doi.org/10.1016/j.ajhg.2017.08.003