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

Christian Windpassinger, Juliette Piard, Carine Bonnard, Majid Alfadhel, Shuhui Lim, Xavier Bisteau, Stéphane Blouin, Nur'Ain B. Ali, Alvin Yu Jin Ng, Hao Lu, Sumanty Tohari, S. Zakiah A. Talib, Noémi van Hul, Matias J. Caldez, Lionel Van Maldergem, Gökhan Yigit, Hülya Kayserili, Sameh A. Youssef, Vincenzo Coppola, Alain de Bruin & 17 others Lino Tessarollo, Hyungwon Choi, Verena Rupp, Katharina Roetzer, Paul Roschger, Klaus Klaushofer, Janine Altmüller, Sudipto Roy, Byrappa Venkatesh, Rudolf Ganger, Franz Grill, Farid Ben Chehida, Bernd Wollnik, Umut Altunoglu, Ali Al Kaissi, Bruno Reversade, Philipp Kaldis

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)391-403
Number of pages13
JournalAmerican journal of human genetics
Volume101
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

Cite this

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. / CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays. In: American journal of human genetics. 2017 ; Vol. 101, No. 3. pp. 391-403.
@article{86340594aa0d484b913ea218e22be8a7,
title = "CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays",
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, cilia, congenital disorder, ETS2, growth retardation, metabolism, spine malformation",
author = "Christian Windpassinger and Juliette Piard and Carine Bonnard and Majid Alfadhel and Shuhui Lim and Xavier Bisteau and St{\'e}phane Blouin and Ali, {Nur'Ain B.} and Ng, {Alvin Yu Jin} and Hao Lu and Sumanty Tohari and Talib, {S. Zakiah A.} and {van Hul}, No{\'e}mi and Caldez, {Matias J.} and {Van Maldergem}, Lionel and G{\"o}khan Yigit and H{\"u}lya Kayserili and Youssef, {Sameh A.} and Vincenzo Coppola and {de Bruin}, Alain and Lino Tessarollo and Hyungwon Choi and Verena Rupp and Katharina Roetzer and Paul Roschger and Klaus Klaushofer and Janine Altm{\"u}ller and Sudipto Roy and Byrappa Venkatesh and Rudolf Ganger and Franz Grill and {Ben Chehida}, Farid and Bernd Wollnik and Umut Altunoglu and {Al Kaissi}, Ali and Bruno Reversade and Philipp Kaldis",
year = "2017",
month = "9",
day = "7",
doi = "10.1016/j.ajhg.2017.08.003",
language = "English",
volume = "101",
pages = "391--403",
journal = "American journal of human genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

Windpassinger, C, Piard, J, Bonnard, C, Alfadhel, M, Lim, S, Bisteau, X, Blouin, S, Ali, NAB, Ng, AYJ, Lu, H, Tohari, S, Talib, SZA, van Hul, N, Caldez, MJ, Van Maldergem, L, Yigit, G, Kayserili, H, Youssef, SA, Coppola, V, de Bruin, A, Tessarollo, L, Choi, H, Rupp, V, Roetzer, K, Roschger, P, Klaushofer, K, Altmüller, J, Roy, S, Venkatesh, B, Ganger, R, Grill, F, Ben Chehida, F, Wollnik, B, Altunoglu, U, Al Kaissi, A, Reversade, B & Kaldis, P 2017, 'CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays' American journal of human genetics, vol. 101, no. 3, pp. 391-403. https://doi.org/10.1016/j.ajhg.2017.08.003

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

In: American journal of human genetics, Vol. 101, No. 3, 07.09.2017, p. 391-403.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

AU - Windpassinger, Christian

AU - Piard, Juliette

AU - Bonnard, Carine

AU - Alfadhel, Majid

AU - Lim, Shuhui

AU - Bisteau, Xavier

AU - Blouin, Stéphane

AU - Ali, Nur'Ain B.

AU - Ng, Alvin Yu Jin

AU - Lu, Hao

AU - Tohari, Sumanty

AU - Talib, S. Zakiah A.

AU - van Hul, Noémi

AU - Caldez, Matias J.

AU - Van Maldergem, Lionel

AU - Yigit, Gökhan

AU - Kayserili, Hülya

AU - Youssef, Sameh A.

AU - Coppola, Vincenzo

AU - de Bruin, Alain

AU - Tessarollo, Lino

AU - Choi, Hyungwon

AU - Rupp, Verena

AU - Roetzer, Katharina

AU - Roschger, Paul

AU - Klaushofer, Klaus

AU - Altmüller, Janine

AU - Roy, Sudipto

AU - Venkatesh, Byrappa

AU - Ganger, Rudolf

AU - Grill, Franz

AU - Ben Chehida, Farid

AU - Wollnik, Bernd

AU - Altunoglu, Umut

AU - Al Kaissi, Ali

AU - Reversade, Bruno

AU - Kaldis, Philipp

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - Al Kaissi syndrome knockout mice

KW - CDK10

KW - cilia

KW - congenital disorder

KW - ETS2

KW - growth retardation

KW - metabolism

KW - spine malformation

UR - http://www.scopus.com/inward/record.url?scp=85029476157&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2017.08.003

DO - 10.1016/j.ajhg.2017.08.003

M3 - Article

VL - 101

SP - 391

EP - 403

JO - American journal of human genetics

JF - American journal of human genetics

SN - 0002-9297

IS - 3

ER -