MCDS

Metaphyseal chondrodysplasia type Schmid (MCDS) is a dwarfism caused by mutations in a protein called type X (ten) collagen. MCDS is presents as child first starts to walk due to a waddling gait. X-rays show abnormalities with the ends of the bones and a hip dysplasia. Type X collagen is a protein made specifically by the hypertrophic (or large expanded) cells in the growth plate – the expansion of these cells are an important part of the bone growth process. 

Double labelled in situ hybridisation showing cells expressing type II (two) collagen in red (the proliferating cells) and cells expressing the type X (ten) collagen in green (the hypertrophic cells). Image courtesy of Dr Helen Rajpar, University of Manchester

We know that many of the mutations in type X collagen produce a stress in hypertrophic chondrocytes that reduces the expansion of these cells causing reduced growth and resulting in dwarfism. The mutant type X collagen cannot be secreted by the hypertrophic chondrocytes and remains in the cells. Deposits of mutant type X collagen can be found inside the cells in the organelle called the endoplasmic reticulum (ER). This results in a important cell stress reaction called ER stress.

Immunohistchemistry staining (brown) for type X collagen in the hypertrophic zone of the growth plate. Image courtesy of Dr Louise Kung (University of Manchester)

However, there is one type of mutation causing MCDS that has not been studied in detail (premature stop codons) and these mutations may cause the reduced growth by a slightly different route. The researchers at the University of Manchester are developing a drug treatment that they believe will relieve the stress caused by the majority of mutant forms of type X collagen and may therefore be an effective therapy. Part of the programme of research is to test this treatment strategy in their model systems. The second aspect of the programme is to establish the mechanism by which premature stop codons in type X collagen induce the MCDS dwarfism and to test whether the stress-relieving treatments being developed are also effective in these cases.