Scientists in Germany have found a gene mutation implicated in Mabry Symdrome, a rare genetic disease that causes mental retardation; they used a new process that analyzes all the genes in a human genome simultaeneously, thus vastly speeding up the search for rare mutations.
A paper on the discovery is expected to be published as an advanced online issue at the end of August in the journal Nature Genetics.
Mabry Syndrome is a rare recessive genetic disorder that causes mental retardation, seizures and characteristic raised blood levels of the enzyme alkaline phosphatase. And like all rare diseases, finding the genes responsible is the key to definitive diagnosis and developing new treatments.
To look for possible mutations that might cause Mabry Syndrome, resarchers from the Max Planck Institute for Molecular Genetics and the Institute of Medical Genetics at the Charité Universitätsmedizin in Berlin, scanned the genomes of three children in a family who have the rare disorder.
However, this is not as straightforward as it might sound, because looking for genes behind rare disorders is like looking for a “needle in a haystack”, as co-author Michal Ruth Schweiger from the Max Planck Institute for Molecular Genetics, said in a press statement.
To help them look for the proverbial “needle”, Schweiger and colleagues used a new process called high throughput sequencing technology to scan the whole genome simultaneously.
“We fished out solely the 22,000 genes from the entire genome, decoded their sequence and examined them for mutations,” said Schweiger.
“Using new bioinformatic analyses, we were able to limit the number of mutation candidates to two – one of which is ultimately responsible for Mabry Syndrome,” added Schweiger.
The researchers said their findings suggest that the technology would be suitable for scanning genomes in search of mutations of other rare genetic disorders. They also suggest the new method could help affected couples planning a family to identify genetic risk.
Schweiger and colleagues concluded that the gene implicated in Mabry Syndrome is the PIGV gene, and that the mutation they found in the children’s genomes stops certain proteins from being able to anchor effectively to the surface of cell membranes. One of these proteins is alkaline phosphatase.
They explained that the PIGV gene codes for an enzyme that is involved in the formation of the “GPI anchor”, a carbohydrate molecule that binds proteins to cell membranes, and suggest that the mutation present in people with Mabry Syndrome disrupts this anchoring process in some way.
Raised levels of alkaline phosphatase, which is also important in bone metabolism, can be measured in the blood. The scientists said that because the mutated PIGV gene prevents proteins like alkaline phosphatase from binding to cell membranes, they detach from the membrane and accumulate in the blood.
The researchers suggest PIGV may also be responsible for anchoring other proteins in the brain, and this is what leads to the mental retardation associated with Mabry Syndrome.
They now hope to continue with their work, and develop new options for treating the disease. They told the press that:
“The methods of genome analysis developed here enable the identification of mutations even in the case of extremely rare diseases and represent an important step forward in the direction of individualised molecular medicine.”
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Peter M. Krawitz, Michal R. Schweiger, Christian Rödelsperger, Carlo Marcelis, Uwe Kölsch, Christian Meisel, Friederike Stephani, Taroh Kinoshita, Yoshiko Murakami, Sebastian Bauer, Melanie Isau, Axel Fischer, Andreas Dahl, Martin Kerick, Jochen Hecht, Sebastian Köhler, Marten Jäger, Johannes Grünhagen, Birgit Jonske de Condor, Sandra Doelken, Han G. Brunner, Peter Meinecke, Eberhard Passarge, Miles D. Thompson, David E. Cole, Denise Horn, Tony Roscioli, Stefan Mundlos & Peter N. Robinson.
Source: Max-Planck-Gesellschaft.
Written by: Catharine Paddock, PhD