Scientists have discovered the gene behind Recessive Omodysplasia, a rare skeletal disease characterised by short-limbed dwarfism and craniofacial anomalies. The work, just published in the American Journal of Human Genetics, reports the identification on chromosome 13 of a gene - GPC6 – that is shown to be crucial for normal bone development.

The research will allow a better comprehension, as well as prevention, of the disease by permitting the screening of potential mutation carriers in pregnancy but most importantly will also help to understand better bone development and its molecular bases.

Dysplasia literally means “bad formation” in Greek, while “omos” means “humerus”; recessive omodysplasia is characterised by deficient bone growth, more marked at the long bones of the limbs – humerus and femur –resulting in short-limbed dwarfism, with adults measuring from 132 to 144 centimetres. Other abnormalities include forearms dislocation, facial dysmorphy, as well as occasional heart defects and cognitive delays.

Until now not much was known about its origin except for the fact that it had a genetic cause – as it was passed between generations of a family – and that was a recessive disease. Recessive diseases are those where both copies of the affected gene need to be abnormal for the disorder to manifest itself (humans, like most animals and plants, have two copies of every gene in their genome, one inherited from each parent) what in practice means that for a child to be sick both parents’ families have to be affected

With this information Ana Belinda Campos Xavier, a Portuguese scientist and Luisa Bonafé working at the Division of Molecular Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and colleagues decided to study nine patients and their families using a technique called genome-wide linkage scan to try to locate and then identify the mutated gene behind the disorder.

In fact, genome-wide linkage scan is an effective way to hunt unknown genes, basically consisting in following several genetic markers – which are pieces of DNA with a known localization in the chromosomes – checking their association with whatever visible sign of the gene exists, in this case disease, through the different generations of a family. The logic behind this resides in the fact that during embryo formation all pairs of chromosomes – one chromosome from each parent – can exchange small bits in a process called recombination. Linkage scans studies follow the different genetic markers after recombination and through generations, watching their connection to disease, and - by assuming that the closer the markers are from the gene, the more probable is that they are carried together in recombination – attempting to calculate the genes localization.

By using multiple markers throughout the entire genome Campos-Xavier and colleagues were able to pinpoint the responsible gene to chromosome 13 on a region containing about 15 genes, which then needed to be analysed individually. Two initial candidates genes were selected – Glypican 5 (GPC5) and Glypican 6 (GPC6) – since they both belonged to a family of proteins called Glypicans (GPC), which are known key players in the regulation of growth and differentiation during development.

So far only one human disease is known to be caused by a GPC mutation, in this case GPC3 mutations, causing Simpson-Golabi-Behmel syndrome, a disorder characterized by overgrowth (very tall individuals with large extremities) in opposition to the growth defect typical of recessive omodysplasia.

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. This is the first time that a glypican molecule has been associated to a specific bone dysplasia, 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.

Article: Ana Belinda Campos-Xavier, Danielle Martinet, John Bateman, Dan Belluoccio, Lynn Rowley, Tiong Yang Tan, Alica Baxová, Karl-Henrik Gustavson, Zvi U. Borochowitz, A. Micheil Innes, Sheila Unger, Jacques S. Beckmann, Lauréane Mittaz, Diana Ballhausen, Andrea Superti-Furga, Ravi Savarirayan and Luisa Bonafé, “Mutations in the Heparan-Sulfate Proteoglycan Glypican 6 (GPC6) Impair Endochondral Ossification and Cause Recessive Omodysplasia”,The American Journal of Human Genetics, Volume 84, Issue 6, 760-770, 28 May 2009 doi:10.1016/j.ajhg.2009.05.002