Gene variation leads to earlier disease onset

8 December 2009 

A Canadian-led research group has discovered a genetic “spelling variation” that appears to bring forward the age at which a person first experiences symptoms of MND by almost a decade. The variation also increases the overall risk of developing the disease.

The researchers decided to investigate the genetic instructions for making a protein called chromogranin B (CHGB), which other studies had previously suggested might play a role in MND. The team, led by Prof Jean-Pierre Julien, analysed the CHGB genes from 289 French or French-Canadian people with MND and made careful comparisons with gene samples donated by 448 healthy individuals (controls) with the same ethnic background. This work revealed that a particular sequence of genetic “letters” appeared significantly more often in the CHGB genes of people with MND, suggesting that this particular spelling variation increases the risk of the disease.

Ethnic differences

To verify their results, the team repeated their analysis using gene samples donated by Swedish individuals. Again, the variation appeared to increase risk. However, this time there was a less pronounced difference in the frequency of the variation between the group with MND and the controls. This suggests that some subtle difference in overall genetic make-up between the French and Scandinavian populations might somehow alter the impact of the variation.


First variation to influence age of onset

Having established that the CHGB gene variation increases a person’s susceptibility to MND, Prof Julien’s group decided to investigate whether it also promoted earlier development of the disease. They found that those people with MND who carried the variation experienced their first symptoms an average of 7 years earlier than those who did not. This is the first time that scientists have established that a particular genetic variation can influence the age of onset of the disease.


What does this mean for me?

Not everybody who carries this variation in the CHGB gene will get MND – the Canadian researchers found the variation in lots of people who did not have the disease. This is because sporadic MND is triggered only when a number of genetic, lifestyle and environmental factors coincide. There is also no test available that can confirm whether or not somebody carries the variation. However, the discovery of the variation will provide scientists with clues to help them towards their ultimate aim of developing an effective treatment for MND.


Why does this variation increase susceptibility?

Prof Julien’s group do not yet understand exactly why this particular variation in the CHGB gene makes motor neurones more vulnerable to degeneration. Some of the substances produced by motor neurones must only be released from the neurone under certain circumstances, a little like valuable parcels that need to be put aside for courier collection rather than just dropped in the post box at any time. The chromogranin B protein normally labels substances for courier collection. It is possible that a slightly altered version of chromogranin B, produced by a CHGB gene with this particular spelling variation, cannot perform this labelling job properly. Further research to clarify whether this is indeed the case will provide scientists with another jigsaw piece to help complete the puzzle of why motor neurones become damaged in MND.