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

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.

SAG therapy restores bone growth and reduces enchondroma incidence in a model of skeletal chondrodysplasias caused by Ihh deficiency

“… 16 , 17 , 36 SAG, a derivative of chlorobenzothiophene, is a Hh pathway agonist 37 that activates Smo to activate Hh 19 in the presence of an intact primary cilium. 38 , 39 , 40 , 41 , 42 , 43 , 44 Although Hynes et al. 45 demonstrated that SAG promotes ciliogenesis in renal epithelial cells with defective cilia formation, whether ablation of Ihh affects ciliogenesis is still unclear.…”

“…Using a standard microtome (RM2255, Leica), 6-μm sections were prepared and subsequently stained with Safranin O/fast green stain to visualize cartilage and assess proteoglycan content as described previously. 38 , 57 The slides were stained with Weigert’s iron hematoxylin and fast green and then stained with 0.1% Safranin O solution.…”

Differential Regulation of GPCRs—Are GRK Expression Levels the Key?

“…Besides adaptive dysregulation by pathophysiological conditions, gene mutations can also lead to altered expression levels. Mutations in GRK2 were detected in patients suffering from Jeune syndrome ( Bosakova et al, 2020 ). In one patient a mutation was identified to cause a functional loss of GRK2.…”

“…Interestingly, this did not lead to expected embryonic lethality as seen in mice ( Jaber et al, 1996 ), as the patient was born alive, but passed away 5 days after birth. GRK2 was identified as an essential regulator of skeletogenesis ( Bosakova et al, 2020 ). The patient had a very small chest and suffered from pulmonary insufficiency, but did not show gross abnormalities in the central nervous system.…”

The Primary Cilium on Cells of Developing Skeletal Rudiments; Distribution, Characteristics and Response to Mechanical Stimulation

“…We have previously characterized gene expression changes in the developing humerus under reduced mechanical stimulation ( Rolfe et al, 2014 ) and additionally showed that territories of Wnt and BMP signaling at the developing joint are disturbed under immobilization ( Rolfe et al, 2018 ; Singh et al, 2018 ). In this context it is intriguing that primary cilia potentially link mechanical and molecular signaling ( Elliott and Brugmann, 2019 ; Bosakova et al, 2020 ). Primary cilia loss has been shown to upregulate canonical Wnt signaling, in some contexts ( Corbit et al, 2008 ; Jiang et al, 2016 ; Patnaik et al, 2019 ).…”