Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.
GRK2
Wnt
asphyxiating thoracic dystrophy
hedgehog
smoothened
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
06 11 2020
06 11 2020
Historique:
received:
10
11
2019
revised:
08
09
2020
accepted:
15
09
2020
entrez:
17
11
2020
pubmed:
18
11
2020
medline:
19
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33200460
doi: 10.15252/emmm.201911739
pmc: PMC7645380
doi:
Substances chimiques
Hedgehog Proteins
0
GRK2 protein, human
EC 2.7.11.15
G-Protein-Coupled Receptor Kinase 2
EC 2.7.11.16
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11739Subventions
Organisme : Brno City Municipality
Organisme : Agency for Healthcare Research of the Czech Republic
ID : NV18-08-00567
Organisme : NHGRI NIH HHS
ID : T32 HG002536
Pays : United States
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : Ministry of Education, Youth and Sports of the Czech Republic
ID : CZ.02.1.01/0.0/0.0/15_003/0000460
Organisme : Junior Researcher Award from the Faculty of Medicine, Masaryk University
Organisme : Osteogenesis Imperfecta Foundation (OIF)
Organisme : NHGRI NIH HHS
ID : UM1 HG006493
Pays : United States
Organisme : Czech Science Foundation
ID : 16-24043J
Organisme : Czech Science Foundation
ID : GA17-09525S
Organisme : HHS|National Institutes of Health (NIH)
ID : RO1 AR066124
Organisme : Ministry of Education, Youth and Sports of the Czech Republic
ID : KONTAKT II LH15231
Organisme : Czech Science Foundation
ID : GA19-20123S
Organisme : HHS|National Institutes of Health (NIH)
ID : RO1 DE019567
Organisme : Czech Science Foundation
ID : GA17-16680S
Organisme : Czech Science Foundation
ID : GA18-17658S
Organisme : HHS|NIH|National Institute of General Medical Sciences (NIGMS)
ID : GM118082
Organisme : Ministry of Education, Youth and Sports of the Czech Republic
ID : LTAUSA19030
Organisme : NIAMS NIH HHS
ID : R01 AR062651
Pays : United States
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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