Scientists have just 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, for example, the screening of potential mutation carriers for pregnancy advise but, and 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.