Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog
and canonical Wnt signaling

J 2020

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

BOSÁKOVÁ, Michaela, Sara POOVAKULATHU ABRAHAM, Alexandru NITĂ, Eva HRUBA, Marcela BUCHTOVA et. al.

Basic information

Original name

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

Authors

BOSÁKOVÁ, Michaela (203 Czech Republic, belonging to the institution), Sara POOVAKULATHU ABRAHAM (356 India, belonging to the institution), Alexandru NITĂ (642 Romania, belonging to the institution), Eva HRUBA (203 Czech Republic), Marcela BUCHTOVA (203 Czech Republic), S. Paige TAYLOR, Ivan DURAN, Jorge MARTIN, Kateřina SVOZILOVÁ (203 Czech Republic, belonging to the institution), Tomáš BÁRTA (203 Czech Republic, belonging to the institution), Miroslav VAŘECHA (203 Czech Republic, belonging to the institution), Lukáš BÁLEK (203 Czech Republic, belonging to the institution), Jiri KOHOUTEK (203 Czech Republic), Tomasz Witold RADASZKIEWICZ (616 Poland, belonging to the institution), Ganesh V. PUSAPATI, Vítězslav BRYJA (203 Czech Republic, belonging to the institution), Eric T. RUSH, Isabelle THIFFAULT, Deborah A. NICKERSON, Michael J. BAMSHAD, Rajat ROHATGI, Daniel H. COHN, Deborah KRAKOW and Pavel KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

EMBO MOLECULAR MEDICINE, HOBOKEN, WILEY-BLACKWELL, 2020, 1757-4676

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 12.137

RIV identification code

RIV/00216224:14110/20:00114425

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.15252/emmm.201911739

UT WoS

000577616000001

Keywords in English

asphyxiating thoracic dystrophy; GRK2; hedgehog; smoothened; Wnt

Abstract

V originále

Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.

Links

GA17-09525S, research and development project

Name: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Czech Science Foundation

GA17-16680S, research and development project

Name: Nové postupy pro určení aktivity dráhy planární buněčné polarity (PCP)

Investor: Czech Science Foundation

GA18-17658S, research and development project

Name: Odhalení tajemství signální dráhy WNT analýzou struktury proteinu Dishevelled

Investor: Czech Science Foundation

GA19-20123S, research and development project

Name: Regulace časného vývoje savčí končetiny pomocí nestabilních morfogenů z rodiny FGF (Acronym: Regulace časného vývoje savčí končetiny)

Investor: Czech Science Foundation

LH15231, research and development project

Name: Nové mechanismy vzniku fatálních kostních ciliopatií u člověka

Investor: Ministry of Education, Youth and Sports of the CR

MUNI/A/0951/2019, interní kód MU

Name: Buněčná a molekulární biologie pro Biomedicínské vědy

Investor: Masaryk University, Category A

ROZV/24/LF/2018, interní kód MU

Name: LF - Příspěvek na IP 2108

Investor: Ministry of Education, Youth and Sports of the CR, Internal development projects

Citovat

BOSÁKOVÁ, Michaela, Sara POOVAKULATHU ABRAHAM, Alexandru NITĂ, Eva HRUBA, Marcela BUCHTOVA, S. Paige TAYLOR, Ivan DURAN, Jorge MARTIN, Kateřina SVOZILOVÁ, Tomáš BÁRTA, Miroslav VAŘECHA, Lukáš BÁLEK, Jiri KOHOUTEK, Tomasz Witold RADASZKIEWICZ, Ganesh V. PUSAPATI, Vítězslav BRYJA, Eric T. RUSH, Isabelle THIFFAULT, Deborah A. NICKERSON, Michael J. BAMSHAD, Rajat ROHATGI, Daniel H. COHN, Deborah KRAKOW and Pavel KREJČÍ. Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling. EMBO MOLECULAR MEDICINE. HOBOKEN: WILEY-BLACKWELL, 2020, vol. 12, No 11, p. 1-20. ISSN 1757-4676. Available from: https://dx.doi.org/10.15252/emmm.201911739.

@article{1688918,
   author = {Bosáková, Michaela and Poovakulathu Abraham, Sara and Nită, Alexandru and Hruba, Eva and Buchtova, Marcela and Taylor, S. Paige and Duran, Ivan and Martin, Jorge and Svozilová, Kateřina and Bárta, Tomáš and Vařecha, Miroslav and Bálek, Lukáš and Kohoutek, Jiri and Radaszkiewicz, Tomasz Witold and Pusapati, Ganesh V. and Bryja, Vítězslav and Rush, Eric T. and Thiffault, Isabelle and Nickerson, Deborah A. and Bamshad, Michael J. and Rohatgi, Rajat and Cohn, Daniel H. and Krakow, Deborah and Krejčí, Pavel},
   article_location = {HOBOKEN},
   article_number = {11},
   doi = {http://dx.doi.org/10.15252/emmm.201911739},
   keywords = {asphyxiating thoracic dystrophy; GRK2; hedgehog; smoothened; Wnt},
   language = {eng},
   issn = {1757-4676},
   journal = {EMBO MOLECULAR MEDICINE},
   title = {Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling},
   url = {https://www.embopress.org/doi/full/10.15252/emmm.201911739},
   volume = {12},
   year = {2020}
}

TY  - JOUR
ID  - 1688918
AU  - Bosáková, Michaela - Poovakulathu Abraham, Sara - Nită, Alexandru - Hruba, Eva - Buchtova, Marcela - Taylor, S. Paige - Duran, Ivan - Martin, Jorge - Svozilová, Kateřina - Bárta, Tomáš - Vařecha, Miroslav - Bálek, Lukáš - Kohoutek, Jiri - Radaszkiewicz, Tomasz Witold - Pusapati, Ganesh V. - Bryja, Vítězslav - Rush, Eric T. - Thiffault, Isabelle - Nickerson, Deborah A. - Bamshad, Michael J. - Rohatgi, Rajat - Cohn, Daniel H. - Krakow, Deborah - Krejčí, Pavel
PY  - 2020
TI  - Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling
JF  - EMBO MOLECULAR MEDICINE
VL  - 12
IS  - 11
SP  - 1-20
EP  - 1-20
PB  - WILEY-BLACKWELL
SN  - 17574676
KW  - asphyxiating thoracic dystrophy
KW  - GRK2
KW  - hedgehog
KW  - smoothened
KW  - Wnt
UR  - https://www.embopress.org/doi/full/10.15252/emmm.201911739
L2  - https://www.embopress.org/doi/full/10.15252/emmm.201911739
N2  - Mutations in genes affecting primary cilia cause ciliopathies, a diverse group of disorders often affecting skeletal development. This includes Jeune syndrome or asphyxiating thoracic dystrophy (ATD), an autosomal recessive skeletal disorder. Unraveling the responsible molecular pathology helps illuminate mechanisms responsible for functional primary cilia. We identified two families with ATD caused by loss-of-function mutations in the gene encoding adrenergic receptor kinase 1 (ADRBK1 or GRK2). GRK2 cells from an affected individual homozygous for the p.R158* mutation resulted in loss of GRK2, and disrupted chondrocyte growth and differentiation in the cartilage growth plate. GRK2 null cells displayed normal cilia morphology, yet loss of GRK2 compromised cilia-based signaling of Hedgehog (Hh) pathway. Canonical Wnt signaling was also impaired, manifested as a failure to respond to Wnt ligand due to impaired phosphorylation of the Wnt co-receptor LRP6. We have identified GRK2 as an essential regulator of skeletogenesis and demonstrate how both Hh and Wnt signaling mechanistically contribute to skeletal ciliopathies.
ER  -

BOSÁKOVÁ, Michaela, Sara POOVAKULATHU ABRAHAM, Alexandru NIT$\backslash$U A, Eva HRUBA, Marcela BUCHTOVA, S. Paige TAYLOR, Ivan DURAN, Jorge MARTIN, Kateřina SVOZILOVÁ, Tomáš BÁRTA, Miroslav VAŘECHA, Lukáš BÁLEK, Jiri KOHOUTEK, Tomasz Witold RADASZKIEWICZ, Ganesh V. PUSAPATI, Vítězslav BRYJA, Eric T. RUSH, Isabelle THIFFAULT, Deborah A. NICKERSON, Michael J. BAMSHAD, Rajat ROHATGI, Daniel H. COHN, Deborah KRAKOW and Pavel KREJČÍ. Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling. \textit{EMBO MOLECULAR MEDICINE}. HOBOKEN: WILEY-BLACKWELL, 2020, vol.~12, No~11, p.~1-20. ISSN~1757-4676. Available from: https://dx.doi.org/10.15252/emmm.201911739.

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