CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays
(2017) In American Journal of Human Genetics 101(3). p.391-403- 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... (More)
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.
(Less)
- 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
and Kaldis, Philipp
LU
(Less) - publishing date
- 2017-09-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Al Kaissi syndrome knockout mice, CDK10, cilia, congenital disorder, ETS2, growth retardation, metabolism, spine malformation
- in
- American Journal of Human Genetics
- volume
- 101
- issue
- 3
- pages
- 13 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:85029476157
- pmid:28886341
- ISSN
- 0002-9297
- DOI
- 10.1016/j.ajhg.2017.08.003
- language
- English
- LU publication?
- no
- id
- ccd30dd7-d7ab-4044-a1e4-9cbe6e9e5e6a
- date added to LUP
- 2019-09-18 10:11:18
- date last changed
- 2024-05-01 20:44:43
@article{ccd30dd7-d7ab-4044-a1e4-9cbe6e9e5e6a,
abstract = {{<p>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.</p>}},
author = {{Windpassinger, Christian and Piard, Juliette and Bonnard, Carine and Alfadhel, Majid and Lim, Shuhui and Bisteau, Xavier and Blouin, Stéphane and Ali, Nur'Ain B. and Ng, Alvin Yu Jin and Lu, Hao and Tohari, Sumanty and Talib, S. Zakiah A. and van Hul, Noémi and Caldez, Matias J. and Van Maldergem, Lionel and Yigit, Gökhan and Kayserili, Hülya and Youssef, Sameh A. and Coppola, Vincenzo and de Bruin, Alain and Tessarollo, Lino and Choi, Hyungwon and Rupp, Verena and Roetzer, Katharina and Roschger, Paul and Klaushofer, Klaus and Altmüller, Janine and Roy, Sudipto and Venkatesh, Byrappa and Ganger, Rudolf and Grill, Franz and Ben Chehida, Farid and Wollnik, Bernd and Altunoglu, Umut and Al Kaissi, Ali and Reversade, Bruno and Kaldis, Philipp}},
issn = {{0002-9297}},
keywords = {{Al Kaissi syndrome knockout mice; CDK10; cilia; congenital disorder; ETS2; growth retardation; metabolism; spine malformation}},
language = {{eng}},
month = {{09}},
number = {{3}},
pages = {{391--403}},
publisher = {{Cell Press}},
series = {{American Journal of Human Genetics}},
title = {{CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays}},
url = {{http://dx.doi.org/10.1016/j.ajhg.2017.08.003}},
doi = {{10.1016/j.ajhg.2017.08.003}},
volume = {{101}},
year = {{2017}},
}