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Gerodermia osteodysplastica (GO) is characterized by skin laxity and early-onset osteoporosis.  GORAB , the responsible disease gene, encodes a small Golgi protein of poorly characterized function. To circumvent neonatal lethality of the  Gorab   Null   full knockout,  Gorab  was conditionally inactivated in mesenchymal progenitor cells (Prx1-cre), pre-osteoblasts (Runx2-cre), and late osteoblasts/osteocytes (Dmp1-cre), respectively. While in all three lines a reduction in trabecular bone density was evident, only  Gorab  Prx1  and  Gorab  Runx2  mutants showed dramatically thinned, porous cortical bone and spontaneous fractures. Collagen fibrils in the skin of  Gorab   Null   mutants and in bone of  Gorab  Prx1  mutants were disorganized, which was also seen in a bone biopsy from a GO patient. Measurement of glycosaminoglycan contents revealed a reduction of dermatan sulfate levels in skin and cartilage from  Gorab   Null   mutants. In bone from  Gorab  Prx1  mutants total glycosaminoglycan levels and the relative percentage of dermatan sulfate were both strongly diminished. Accordingly, the proteoglycans biglycan and decorin showed reduced glycanation. Also in cultured  GORAB -deficient fibroblasts reduced decorin glycanation was evident. The Golgi compartment of these cells showed an accumulation of decorin, but reduced signals for dermatan sulfate. Moreover, we found elevated activation of TGF-β in  Gorab  Prx1  bone tissue leading to enhanced downstream signalling, which was reproduced in  GORAB -deficient fibroblasts. Our data suggest that the loss of  Gorab  primarily perturbs pre-osteoblasts. GO may be regarded as a congenital disorder of glycosylation affecting proteoglycan synthesis due to delayed transport and impaired posttranslational modification in the Golgi compartment.

plos genetics

Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica