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Abstract:
Author summary Gerodermia osteodysplastica (GO) is segmental progeroid disorder affecting connective tissues and bone, leading to extreme bone fragility. The cause are loss-of-function mutations in the Golgi protein GORAB, whose function has been only partially unravelled. Using several mouse models and patient-derived primary cells we elucidate that loss of Gorab elicits a defect in proteoglycan glycanation, which is associated with collagen disorganization in dermis and bone. We also found evidence for TGF-β upregulation and enhanced downstream signalling. If these changes occur in mesenchymal stem cells or early osteoblasts they impair osteoblast differentiation resulting in cortical thinning and spontaneous fractures. We thus match GO mechanistically with also phenotypically overlapping progeroid connective tissue disorders with glycanation defects.