After analysing in patients the gene sequences of GPC5 and GPC6, the researchers found that, while GPC5 had no changes, GPC6 was mutated in all the cases of recessive omodysplasia. Further analyses, this time on the patients' families, confirmed GPC6 as the gene behind the disease. Interestingly in all the patients tested the mutations led to non-functional GPC6 proteins.

Next, Campos Xavier and colleagues looked at GPC6 in young and still growing mice to further understand the protein role in bone formation to find that GPC6 was present in much higher quantity - up to 50 fold more - in those areas of active bone growing.

In conclusion, Belinda Campos-Xavier and colleagues found that recessive omodysplasia is caused by a non-functional GPC6 protein probably by leading to the disruption of growth-factor signals - GPCs are known to promote the association of growth factors with their receptors -compromising long-bone formation.

Although recessive omodysplasia is a rare genetic disease, knowledge about its genetic cause is an important contribution for our understanding of bone growth biology. Furthermore, mutations that alter but still leave a functional GPC6 (contrary to recessive omodysplasia ) may lead to other types of bone dysplasias and possibly other diseases and can now be investigated. For the first time, a glypican molecule has been associated to a specific bone dysplasia, thus suggesting this family of molecules (6 different glypicans in humans) as candidate genes for other bone developmental disorders. Finally, in those families affected by omodysplasia, the identification of GPC6 as the diseased gene now allows pre-natal testing and genetic counselling for a better quality of life.

By Catarina Amorim

Full bibliographic information: American Journal of Human Genetics 84, 760-770, June 12, 2009 "Mutations in the Heparan-Sulfate Proteoglycan Glypican 6 (GPC6) Impair Endochondral Ossification and Cause Recessive Omodysplasia"

cell/AJHG/abstract/S0002-9297(09)00199-2