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

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

  2. Author Address

    Institute of Human Genetics, Medical University of Graz, 8010 Graz, Austria., Centre de G 233;n 233;tique Humaine, Centre Hospitalier Universitaire Besan 231;on, 25030 Besan 231;on, France; Integrative and Cognitive Neuroscience Research Unit EA481, Universit 233; de Franche-Comt 233;, 25030 Besan 231;on, France., Institute of Medical Biology, Agency for Science, Technology, and Research, Singapore 138648, Republic of Singapore., 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., Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research, 61 Biopolis Drive, Singapore 138673, Republic of Singapore., 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., 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., Institute of Human Genetics, University Medical Center G 246;ttingen, 37099 G 246;ttingen, Germany., Department of Medical Genetics, Ko 231; University, School of Medicine, 34010 Topkapi, Istanbul, Turkey., Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, the Netherlands., National Cancer Institute, Mouse Cancer Genetics Program, NCI Frederick, Building 560, 1050 Boyles Street, Frederick, MD 21702-1201, USA., 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., 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., Cologne Center for Genomics, University of Cologne, Weyertal 115b, 50931 Cologne, Germany., 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., 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., Orthopedic Hospital of Speising, Speisinger Strasse 109, 1130 Vienna, Austria., Center of Radiology, Department of Imaging Studies-Ibn Zohr Institute, Tunis, City Khadra 1003, Tunisia., Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey., 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., 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, Ko 231; University, School of Medicine, 34010 Topkapi, 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: bruno@reversade.com., 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: kaldis@imcb.a-star.edu.sg.,
    1. Year: 2017
    2. Date: Sep 07
  2. Journal: American journal of human genetics
    1. 101
    2. 3
    3. Pages: 391-403
  4. Type of Article: Article
  5. ISSN: 0002-9297
  1. 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. Copyright © 2017 American Society of Human Genetics. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.ajhg.2017.08.003
  3. PMID: 28886341
  4. View record in Web of Science®
  5. WOS: 000409530900006

Library Notes

  1. Fiscal Year: FY2016-2017
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