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

EMBO Molecular Medicine
Michaela BosakovaPavel Krejci

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.

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Citations

Mar 22, 2021·Pharmacology & Therapeutics·Dagmar Wachten, David U Mick
Jun 11, 2021·Frontiers in Cell and Developmental Biology·Edda S F MattheesJulia Drube
Sep 29, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sara P AbrahamMichaela Bosakova

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Methods Mentioned

BETA
cesarean section
proximity ligation assay
SMO
exome sequencing
Transfection
Assay
electrophoresis

Software Mentioned

Novoalign Analysis Toolkit
ZEN Black
ImageJ
Adobe Photoshop

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