5 years ago

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

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.

Publisher URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30325-7

DOI: 10.1016/j.ajhg.2017.08.003

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