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.

Children's Mercy Kansas City Center for Pediatric Genomic Medicine Kansas City MO USA

Department of Biochemistry Stanford University Palo Alto CA USA

Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Genome Sciences University of Washington Seattle WA USA

Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic

Department of Human Genetics David Geffen School of Medicine at UCLA Los Angeles CA USA

Department of Medicine Stanford University Palo Alto CA USA

Department of Molecular Cell and Developmental Biology University of California at Los Angeles Los Angeles CA USA

Department of Obstetrics and Gynecology David Geffen School of Medicine at UCLA Los Angeles CA USA

Department of Orthopaedic Surgery David Geffen School of Medicine at UCLA Los Angeles CA USA

Department of Pediatrics University of Missouri Kansas City MO USA

Department of Pediatrics University of Washington Seattle WA USA

Division of Genetic Medicine Seattle Children's Hospital Seattle WA USA

Institute of Animal Physiology and Genetics of the CAS Brno Czech Republic

Institute of Experimental Biology Faculty of Science Masaryk University Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Veterinary Research Institute Brno Czech Republic

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