Dyggve–Melchior–Clausen syndrome: Chondrodysplasia resulting from defects in intracellular vesicle traffic

Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutations in dymeclin (Dym ), a gene with previously unknown function. Here we report thatDym -deficient mice display defects in endochondral bone formation similar to that of Dyggve–Melchior–Clausen syndrome and Smith-McCort dysplasia, demonstrating functional conservation between the two species.Dym -mutant cells display multiple defects in vesicle traffic, as evidenced by enhanced dispersal of Golgi markers in interphase cells, delayed Golgi reassembly after brefeldin A treatment, delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular basis for chondrodysplasia in mice and men.