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Adolescent idiopathic scoliosis (AIS) and pectus excavatum (PE) are common pediatric musculoskeletal disorders. Little is known about the tissue of origin for either condition, or about their genetic bases. Common variants near  GPR126/ADGRG6  (encoding the adhesion G protein-coupled receptor 126/adhesion G protein-coupled receptor G6, hereafter referred to as GPR126) were recently shown to be associated with AIS in humans. Here, we provide genetic evidence that loss of  Gpr126  in osteochondroprogenitor cells alters cartilage biology and spinal column development. Microtomographic and x-ray studies revealed several hallmarks of AIS, including postnatal onset of scoliosis without malformations of vertebral units. The mutants also displayed a dorsal-ward deflection of the sternum akin to human PE. At the cellular level, these defects were accompanied by failure of midline fusion within the developing annulus fibrosis of the intervertebral discs and increased apoptosis of chondrocytes in the ribs and vertebrae. Molecularly, we found that loss of  Gpr126  upregulated the expression of  Gal3st4 , a gene implicated in human PE, encoding Galactose-3-O-sulfotransferase 4. Together, these data uncover  Gpr126  as a genetic cause for the pathogenesis of AIS and PE in a mouse model.

Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice