Motion that powers sperm provides key to unravelling rare genetic disorder

Malfunction of the motor that powers sperm plays havoc with more than fertility: it may also be the root cause of the rare genetic disease Bardet-Biedl syndrome (BBS).

Reporting in the journal Cell tomorrow, researchers from the UK, US and Canada reveal they have discovered a novel gene for BBS that’s necessary for the generation of a cell’s cilia and flagella – hair like tentacles used to propel a cell or sweep substances over their exterior.

Cilia and flagella are commonly known as the cellular mechanism used to remove mucus from the lungs or power the wave like motion behind sperm, but they also function as part of a cell’s communication device.

Now the team have shown mutations in a gene called BBS5 appear to be responsible for the generation of cilia and flagella and are involved in the development of BBS – a recessive disease that affects one in around 100,000 births in the UK.

The first obvious symptom of BBS is children are born with extra fingers or toes but sufferers go on to dramatically gain weight, lose their eye sight and develop kidney problems. Half of individuals also exhibit some degree of learning difficulties.

To date, seven other genes have been linked to BBS, and six of them have been studied in depth and cloned. However, only one other gene has been linked to a cellular problem that could result in the condition.

The results of the study confirm that BBS is caused by defects in cilia, a theory first proposed by Dr Philip Beales of UCL’s Institute of Child Health, one of the study’s principle investigators.

“Cilia and flagella have long been thought to play a fundamental role in the development of many organisms including humans,” explains Dr Beales.

“Here we confirm the role they play in Bardet-Biedl syndrome, but it’s clear their malfunction is linked to a number of health problems such as obesity, kidney disease, blindness and mental retardation.”

“The way some cilia work is akin to trying to surf a crowd at a concert. If everyone works together, supports you and pushes you in the same direction you can sail across on top of the crowd. If they don’t you soon come down crashing to the ground. They must be synchronised so they work together in a wave like motion. A second type of cilium which is much more common but don’t beat together, serves to sense the environment surrounding the cell. If these key cellular function breakdown there can be a huge knock-on effect on normal running of the cell.

“The next step is to find out how mutations interfere with this process and either prevent them or develop an effective treatment.”

To establish which genes play a role in the development of cilia and flagella the researchers compared the genetic make up of algae and C. elegans, a worm commonly used in genetic research, with the family of vegetables that the give rise to broccoli, sprouts and cabbage – and known not to contain flagella and cilia.

Results identified 688 genes not present in the Arabidopsis family of vegetables. To narrow down which of these genes is responsible for flagella and cilia development the team removed the hair like extensions from a cell and observed which genes were activated to make them grow new copies. Amongst these genes required to make a new flagellum were all the previously identified BBS genes as well as several novel genes of unknown function.

By screening over 250 DNA samples from families with BBS, mutations were found in one of these new genes, now called BBS5.

Dr Beales added: “Not only does the discovery of BBS5 help us to more accurately diagnose BBS it will enable couples at risk of having further affected children to benefit from prenatal diagnosis.

“We are currently investigating the role of this and other BBS genes in causing the disease in the hope that one day we may be able to develop effective treatments to alleviate some of the problems encountered by sufferers. Understanding how rare diseases such as BBS arise, may also aid our understanding of the cause of more common diseases like obesity and diabetes.”

Dr Beales’ lab is funded by the Wellcome Trust and the Medical Research Council (MRC).