Public Release: 

Motion that powers sperm provides key to unravelling rare genetic disorder

University College London

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 appears 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).

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For further information please contact
Judith H Moore
Media Relations Manager
University College London
Tel: 44-0-20-7679-7678
Mobile: 44-0-77333-07596
Email: judith.moore@ucl.ac.uk

Notes to editors

Journal: Cell (14/05/04)

Title: "Comparative Genomics Identifies a Flagellar and Basal Body Proteome that Includes the BBS5 Human Disease Gene"

Authors: Jin Billy Li (1), Jantje M Gerdes (1), Courtney J Haycraft (3), Yanli Fan (4), Tanya m Teslovich (2), Helen May-Simera (5), Haitao Li (6) Oliver Blacque (4), Linya Li (1), Carmen C Leitch (2), Richard Allan Lewis (7), Jane S Green (8), Patrick S Parfrey (8), Michael R Leroux (4), William S Daidson (4), Philip L Beales (5), Lisa M Guay-Woodford (6), Bradley K Yoder (3), Gary D Stormo (1), Nicholas Katsanis (2), and Sunsan K Dutcher (1)

(1) Department of genetics, Washington University School of Medicine St. Louis, MO 63110, USA.

(2) McKusick-Nathans Institute of Genetic Medicine, Wilmer Eye Institute, John Hopkins University, Baltimore, MD 21205, USA.

(3) Department of Cell Biology, University of Alabama at Birmingham, Birmingham AL 35294, USA.

(4) Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada BC V5A 1S6.

(5) Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.

(6) Division of Genetic and Translational Medicine, Department of Medicine, Pediatrics and Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

(7) Department of Molecular and Human Genetics, Ophthalmology, Pediatrics and Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

(8) Department of Medical Genetics and Clinical Epidemiology, Memorial University, St John's Newfoundland, Canada.

About the Institute of Child Health

The Institute of Child Health merged with University College London (UCL) in 1996, and is part of UCL's Biomedical structure. The Institute has over 500 members of staff and is one of only four 5*A clinical Institution in the UK. It currently has an annual turnover of over £27m and is heavily dependent on non-Government money to finance its activities. Over £15.5m was raised in 2000/2001 through externally peer-reviewed research grants.

About University College London

UCL has been consistently rated amongst the top three multi-faculty universities in the UK. With an international reputation for excellence and innovation in teaching and learning, UCL has occupied a pioneering role in higher education since its inception. As well as being the first English university established after Oxford and Cambridge, UCL was the first university to offer undergraduate teaching in physics, chemistry and engineering. Visit the website at: http://www.ucl.ac.uk/.

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