The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects


Ian M Bird, Susie H Kim, Devin K Schweppe, Joana Caetano-Lopes, Alexander G Robling, Julia F Charles, Steven P Gygi, Matthew L Warman, and Patrick J Smits. 2018. “The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects.” Development, 145, 1.


Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by ) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional knockout alleles and inactivated in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.