Scientists have found a gene that, when mutated, is linked to a hereditary neurological  disorder that causes mental dysfunction, immobility, seizure and a life expectancy of ten years. This discovery lays the foundation for the first genetic screening option for this form of neurodegenerative disease.

Neurodegenerative disease is the umbrella term for a group of incurable and debilitating conditions, including Huntington’s and Parkinson’s diseases, which lead to a progressive decline in the nervous system.

Researchers, led by Dr Reza Sharifi from St George’s, University of London’s Human Genetics Centre, have found that a mutation to the C6orf130 gene is responsible for one of the lesser-known forms of neurodegenerative disease. This is the first time that this gene has been linked to any disease.

The finding is published in the EMBO (European Molecular Biology Organisation) Journal this week.

Dr Reza Sharifi said: “Until now, the genetic cause of this particular neurodegenerative disorder has been unknown. This means, unlike better-understood neurodevelopment diseases, there is no genetic screening option available and people affected do not know they are affected until their symptoms start to show.”

The mutated gene was uncovered when the research team studied a number of families with a recessive form of neurodegeneration using state-of-the-art platform technology for genome screening and gene identification. This process identified the mutated gene in a large extended family with several members affected by the condition. All affected cases had two copies of the gene mutation, while those family members who had not inherited the condition either had one or no copies of the mutated gene.

While more work is needed to understand the exact biological mechanism by which the gene mutation causes the abnormality in the nervous system, the researchers say this could open up the first genetic screening option for this form of neurodegenerative disease.

Because this is the first time that this gene has been linked to any disease, the researchers suspect that the mutated version may be common in wider forms of neurodegenerative disorders. But they emphasise that further work is needed to investigate this possibility.

Dr Sharifi said: “Our discovery suggests a new pathologic mechanism that may operate in a wider range of neurodegenerative disorders, the genetics of which generally remain very poorly understood.

“A better understanding of the disease mechanisms underlying neurodegenerative disorders is urgently required if new treatments are to be developed.”

The same study also revealed that this gene produces a protein with enzymatic function, called C6orf130/TARG1, which is required for normal cell growth and repair. The researchers hope that the enzyme could become a target for new drugs aimed at inhibiting growth of cancer cells.

The team investigating this aspect of the gene function – comprising Dr Ivan Ahel (University of Manchester), Dr Scott Williams (National Institutes of Health, USA), Dr Gyula Timinszky and Dr Andreas Ladurner (both from Ludwig Maximilians University Munich) – have shown that the C6orf130/TARG1 protein can remove small chemical tags called ADP-ribose from modified proteins. ADP-ribose protein tags are known to be important in the control of a number of processes required for normal function of the cell such as repair of cellular DNA damage, control of gene expression, cell division and cell death. Pharmacological drugs called PARP inhibitors prevent the addition of ADP-ribose to proteins. Several of these drugs are undergoing clinical trials for the treatment of different types of cancers.

“For more than 30 years the cellular activity that completes the removal of ADP-ribose signals from proteins has been known to exist, but the exact protein responsible for this function in cells remained elusive” commented Dr Ivan Ahel, the team leader from the Paterson Institute for Cancer Research at the University of Manchester.

The full article can be found on The EMBO Journal website.