Christian Windpassinger1,25, Juliette Piard2,22,25, Carine Bonnard3,25, Majid Alfadhel4,25,
Shuhui Lim5,23,25, Xavier Bisteau5, Ste´phane Blouin6, Nur'Ain B. Ali3, Alvin Yu Jin Ng5, Hao Lu5,
Sumanty Tohari5, S. Zakiah A. Talib5, Noe´mi van Hul5, Matias J. Caldez5,7, Lionel Van Maldergem2,22,
Go¨khan Yigit8, Hu¨lya Kayserili9, Sameh A. Youssef10, Vincenzo Coppola11,24, Alain de Bruin10,
Lino Tessarollo11, Hyungwon Choi5,12, Verena Rupp1, Katharina Roetzer6,13,14, Paul Roschge6,
Klaus Klaushofer6, Janine Altmu¨ller15, Sudipto Roy5,16,17, Byrappa Venkatesh5,16, Rudolf Ganger18,
Franz Grill18, Farid Ben Chehida19, Bernd Wollnik8, Umut Altunoglu20, Ali Al Kaissi6,18,26,*,
Bruno Reversade22.214.171.124,21,26,*, and Philipp Kaldis5,7,26,*.
1 Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria;
2 Centre de Ge´ne´tique Humaine, Centre Hospitalier Universitaire Besanc¸on, 25030 Besanc¸on, France;
3 Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648, Republic of Singapore;
4 King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh 11481, Saudi Arabia;
5 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore;
6 Ludwig Boltzmann Institute of Osteology at the Hanusch
Hospital of WGKK and AUVA Trauma Centre Meidling, 1st Medical Department, Hanusch Hospital, Heinrich-Collin-Strasse 30, 1140 Vienna, Austria;
7 National University of Singapore, Department of Biochemistry, Singapore 117597, Republic of Singapore;
8 Institute of Human Genetics, University Medical
Center Go¨ttingen, 37099 Go¨ttingen, Germany;
9 Department of Medical Genetics, Koc¸ University, School of Medicine, 34010 Topkapı, Istanbul, Turkey;
10 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, the Netherlands;
11 National Cancer Institute, Mouse
Cancer Genetics Program, NCI Frederick, Building 560, 1050 Boyles Street, Frederick, MD 21702-1201, USA;
12 Saw Swee Hock School of Public Health, National University Singapore, Singapore National University Health System, Singapore 117549, Republic of Singapore;
13 Center for Medical Genetics, Hanusch Hospital, Heinrich-Collin-Strasse 30, 1140 Vienna, Austria;
14 Sigmund Freud Private University, Medical School, Freudplatz 1, 1020 Vienna,
15 Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931 Cologne, Germany;
16 Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Republic of Singapore;
17 Department of Biological Sciences, National University of Singapore, Singapore 117558, Republic of Singapore;
18 Orthopedic Hospital of Speising, Speisinger Strasse 109, 1130 Vienna, Austria;
19 Center of Radiology, Department of Imaging Studies-Ibn Zohr Institute, Tunis, City Khadra 1003, Tunisia;
20 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey;
21 Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands;
22 Integrative and Cognitive Neuroscience Research Unit EA481, Universite´ de Franche-Comte´, 25030 Besanc¸on, France
23 Present address: Translational Medicine Research Center, Merck Research Laboratories, Singapore 138665, Republic of Singapore
24 Present address: The Ohio State University, Department of Molecular Virology, Immunology, and Medical Genetics, 988 Biomedical Research Tower,
460 West 12th Ave., Columbus, OH 43210, USA
25 These authors contributed equally to this work
26 These authors contributed equally to this work
*Correspondence: email@example.com (B.R.), firstname.lastname@example.org (P.K.)
Published in The American Journal of Human Genetics on September 7, 2017
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.
Figure legend: Lack of fusion of the posterior arches of S2–S5, right T4 hemivertebrae, and lack of fusion of the anterior arch of the atlas and partial
fusion of C2 and C3 vertebrae in proband F2-II:4.
For more information on Philipp KALDIS 's lab, please click here.
For more information on Byrappa VENKATESH 's lab, please click here.
For more information on Sudipto ROY 's lab, please click here.
For more information on Bruno REVERSADE 's lab, please click here.