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

M. Bosakova, SP. Abraham, A. Nita, E. Hruba, M. Buchtova, SP. Taylor, I. Duran, J. Martin, K. Svozilova, T. Barta, M. Varecha, L. Balek, J. Kohoutek, T. Radaszkiewicz, GV. Pusapati, V. Bryja, ET. Rush, I. Thiffault, DA. Nickerson, MJ. Bamshad,...

. 2020 ; 12 (11) : e11739. [pub] 20201014

Language English Country Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21026424

Grant support
Brno City Municipality
NV18-08-00567 Agency for Healthcare Research of the Czech Republic
T32 HG002536 NHGRI NIH HHS - United States
U24 HG008956 NHGRI NIH HHS - United States
CZ.02.1.01/0.0/0.0/15_003/0000460 Ministry of Education, Youth and Sports of the Czech Republic
Junior Researcher Award from the Faculty of Medicine, Masaryk University
Osteogenesis Imperfecta Foundation (OIF)
UM1 HG006493 NHGRI NIH HHS - United States
16-24043J Czech Science Foundation
GA17-09525S Czech Science Foundation
RO1 AR066124 HHS|National Institutes of Health (NIH)
KONTAKT II LH15231 Ministry of Education, Youth and Sports of the Czech Republic
GA19-20123S Czech Science Foundation
RO1 DE019567 HHS|National Institutes of Health (NIH)
GA17-16680S Czech Science Foundation
GA18-17658S Czech Science Foundation
GM118082 HHS|NIH|National Institute of General Medical Sciences (NIGMS)
LTAUSA19030 Ministry of Education, Youth and Sports of the Czech Republic
R01 AR062651 NIAMS NIH HHS - United States

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.

References provided by Crossref.org

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