Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling.
EMBO Mol Med
; 12(11): e11739, 2020 11 06.
Article
in En
| MEDLINE
| ID: mdl-33200460
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ellis-Van Creveld Syndrome
/
Hedgehog Proteins
/
G-Protein-Coupled Receptor Kinase 2
Limits:
Humans
Language:
En
Journal:
EMBO Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2020
Document type:
Article
Affiliation country:
Czech Republic