Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier ORCID: 0000-0002-8896-5098, Blouin, Stephane ORCID: 0000-0001-6575-8443, Ali, Nur'Ain B., Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S. Zakiah A., van Hul, Noemi, Caldez, Matias J., Van Maldergem, Lionel ORCID: 0000-0001-8880-5214, Yigit, Gokhan, Kayserili, Hulya, Youssef, Sameh A., Coppola, Vincenzo ORCID: 0000-0001-6163-1779, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon ORCID: 0000-0002-6687-3088, Rupp, Verena ORCID: 0000-0003-0234-3325, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmueller, Janine, Roy, Sudipto, Venkatesh, Byrappa ORCID: 0000-0003-3620-0277, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Wollnik, Bernd, Altunoglu, Umut ORCID: 0000-0002-3172-5368, Al Kaissi, Ali, Reversade, Bruno and Kaldis, Philipp ORCID: 0000-0002-7247-7591 (2017). CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. Am. J. Hum. Genet., 101 (3). S. 391 - 404. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Windpassinger, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piard, JulietteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonnard, CarineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alfadhel, MajidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lim, ShuhuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bisteau, XavierUNSPECIFIEDorcid.org/0000-0002-8896-5098UNSPECIFIED
Blouin, StephaneUNSPECIFIEDorcid.org/0000-0001-6575-8443UNSPECIFIED
Ali, Nur'Ain B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ng, Alvin Yu JinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lu, HaoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tohari, SumantyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Talib, S. Zakiah A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Hul, NoemiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Caldez, Matias J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van Maldergem, LionelUNSPECIFIEDorcid.org/0000-0001-8880-5214UNSPECIFIED
Yigit, GokhanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kayserili, HulyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Youssef, Sameh A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coppola, VincenzoUNSPECIFIEDorcid.org/0000-0001-6163-1779UNSPECIFIED
de Bruin, AlainUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tessarollo, LinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Choi, HyungwonUNSPECIFIEDorcid.org/0000-0002-6687-3088UNSPECIFIED
Rupp, VerenaUNSPECIFIEDorcid.org/0000-0003-0234-3325UNSPECIFIED
Roetzer, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roschger, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klaushofer, KlausUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roy, SudiptoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venkatesh, ByrappaUNSPECIFIEDorcid.org/0000-0003-3620-0277UNSPECIFIED
Ganger, RudolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grill, FranzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ben Chehida, FaridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wollnik, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altunoglu, UmutUNSPECIFIEDorcid.org/0000-0002-3172-5368UNSPECIFIED
Al Kaissi, AliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reversade, BrunoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaldis, PhilippUNSPECIFIEDorcid.org/0000-0002-7247-7591UNSPECIFIED
URN: urn:nbn:de:hbz:38-217944
DOI: 10.1016/j.ajhg.2017.08.003
Journal or Publication Title: Am. J. Hum. Genet.
Volume: 101
Number: 3
Page Range: S. 391 - 404
Date: 2017
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1537-6605
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME BROWSER; CDK10/CYCLIN M; STAR SYNDROME; KINASE; FAMILY; GENE; PISSLRE; MEMBER; ROLES; DNAMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21794

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