2. Academic Validation
  3. 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

  • Am J Hum Genet. 2017 Sep 7;101(3):391-403. doi: 10.1016/j.ajhg.2017.08.003.
Christian Windpassinger 1,  Juliette Piard 2,  Carine Bonnard 3,  Majid Alfadhel 4,  Shuhui Lim 5,  Xavier Bisteau 5,  Stéphane Blouin 6,  Nur'Ain B Ali 3,  Alvin Yu Jin Ng 5,  Hao Lu 5,  Sumanty Tohari 5,  S Zakiah A Talib 5,  Noémi van Hul 5,  Matias J Caldez 7,  Lionel Van Maldergem 2,  Gökhan Yigit 8,  Hülya Kayserili 9,  Sameh A Youssef 10,  Vincenzo Coppola 11,  Alain de Bruin 10,  Lino Tessarollo 11,  Hyungwon Choi 12,  Verena Rupp 1,  Katharina Roetzer 13,  Paul Roschger 6,  Klaus Klaushofer 6,  Janine Altmüller 14,  Sudipto Roy 15,  Byrappa Venkatesh 16,  Rudolf Ganger 17,  Franz Grill 17,  Farid Ben Chehida 18,  Bernd Wollnik 8,  Umut Altunoglu 19,  Ali Al Kaissi 20,  Bruno Reversade 21,  Philipp Kaldis 22
Affiliations

Affiliations

  • 1 Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria.
  • 2 Centre de Génétique Humaine, Centre Hospitalier Universitaire Besançon, 25030 Besançon, France; Integrative and Cognitive Neuroscience Research Unit EA481, Université de Franche-Comté, 25030 Besançon, 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 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; National University of Singapore, Department of Biochemistry, Singapore 117597, Republic of Singapore.
  • 8 Institute of Human Genetics, University Medical Center Göttingen, 37099 Göttingen, Germany.
  • 9 Department of Medical Genetics, Koç 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 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Saw Swee Hock School of Public Health, National University Singapore, Singapore National University Health System, Singapore 117549, Republic of Singapore.
  • 13 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; Center for Medical Genetics, Hanusch Hospital, Heinrich-Collin-Strasse 30, 1140 Vienna, Austria; Sigmund Freud Private University, Medical School, Freudplatz 1, 1020 Vienna, Austria.
  • 14 Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931 Cologne, Germany.
  • 15 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Republic of Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117558, Republic of Singapore.
  • 16 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Republic of Singapore.
  • 17 Orthopedic Hospital of Speising, Speisinger Strasse 109, 1130 Vienna, Austria.
  • 18 Center of Radiology, Department of Imaging Studies-Ibn Zohr Institute, Tunis, City Khadra 1003, Tunisia.
  • 19 Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey.
  • 20 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; Orthopedic Hospital of Speising, Speisinger Strasse 109, 1130 Vienna, Austria.
  • 21 Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648, Republic of Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; Department of Medical Genetics, Koç University, School of Medicine, 34010 Topkapı, Istanbul, Turkey; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Republic of Singapore; Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address: [email protected].
  • 22 Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore; National University of Singapore, Department of Biochemistry, Singapore 117597, Republic of Singapore. Electronic address: [email protected].
PMID: 28886341 DOI: 10.1016/j.ajhg.2017.08.003
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

Al Kaissi syndrome knockout mice; CDK10; ETS2; cilia; congenital disorder; growth retardation; metabolism; spine malformation.

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