Discovery sheds light on rare disease

October 20, 2005, vol. 34, no. 4
By Carol Thorbes



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Two Simon Fraser University molecular biologists have helped isolate the cause of a potentially fatal, rare disease with symptoms that are prevalent in the general population.

Working with scientists at the University of California, Davis in the United States, professor Michel Leroux and post-doctoral fellow Oliver Blacque have discovered what molecular defects in primary cilia likely cause Bardet-Biedl syndrome (BBS).

The team's groundbreaking findings, published in the July 28, 2005 issue of the journal, Nature, “makes the link between normal cilia function and health highly pertinent,” notes Leroux. “BBS patients suffer from an unusually large number of different ailments.” Obesity, blindness and kidney dysfunction are common illnesses that characterize BBS, a complex, hereditary disease that affects one in 160,000 people worldwide.

Primary cilia are solitary appendages, meaning there is one per cell. They enable cells to sense chemical and physical activities in their external environment.

Cilia are involved in seeing, smelling, hearing, touching, and moving fluid - for example, clearing mucous from the respiratory tract.

“Some proteins linked to cilia function are essential for life,” says Leroux. “On the other hand, partial loss of cilia function can cause blindness because specialized cilia are the primary light receptors in the eye.”

Having verified in previous research that BBS genes function in cilia, Leroux and his colleagues recently investigated what would happen if they disrupted or mutated BBS genes in C. elegans.

The tiny nematode has virtually the same genome as humans, but 30 times smaller. “Cilia act to sense the environment in C. elegans,” explains Leroux. “We used attractants to test and compare the ability of C. elegans with normal and mutated BBS genes to smell their environment. We found those lacking BBS gene function have a greatly reduced sense of smell.”

This new research indicates that mutated BBS genes cause cilia to partially malfunction because a key role of these genes is to coordinate the function of molecular motors known as kinesins. Like train engines, kinesins move cargo - such as different cilia components - up to the tips of cilia.

The researchers are now investigating how malfunctioning cilia with defective BBS genes can affect the function of different cells or tissues. “Why BBS patients have a tendency to become obese, sometimes morbidly obese, is not known. One can hypothesize that cilia in some regions of the brain are involved in satiety control, and that their dysfunction would lead to abnormal food intake,” offers Leroux.

Without significant funding commitments from the Canadian Institutes of Health Research, the Michael Smith Foundation, the Heart and Stroke Foundation and National Institutes of Health, BBS research would not be this far along.

“While directed to a specific group, this research has the potential to benefit many,” points out Rod McInnes, scientific director of CIHR's institute of genetics.

A federal, health-related research funding agency, CIHR has contributed approximately $750,000 to Leroux's research so far.

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