Cellular Problems Found Behind Complex Obesity Syndrome

In experiments with human and mouse cell lines in the lab, the researchers found that the BBS4 protein normally transports molecules that help guide the cell's internal highway system -- a network of so-called microtubules along which tiny motors push and pull proteins, cellular packages and even chromosomes. When the BBS4 gene doesn't work correctly, the highway system falls apart, cell division halts and the cell dies.

"But our experiments also revealed something really interesting about pleiotropy -- genetic diseases that severely impact only a smattering of tissues," says Nicholas Katsanis, Ph.D., head of the team's contingent from the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "Once we knew faulty BBS4 prevented correct microtubule construction and led to cell death, the big question was how do people survive when every cell contains these mutations?"

The key is that the BBS4 protein acts through another protein, called PCM1, or pericentriolar material 1 protein. The two proteins are found together, or "co-localized," only in certain cell types in a specific subset of tissues, so it is only in those cells that BBS4 mutations can lead to cell death, the researchers report.

"There is very specific co-localization of the two proteins in specific cells in the retina and in certain brain cells, as well as small areas of other tissues," Katsanis says, describing the team's analysis of tissues from mice and mouse embryos.

Based solely on where the two proteins are found in mice, Katsanis can suggest a few reasons why obesity may be common in people with the disorder, including improperly controlled or targeted neurons, improper hormone release, and improper growth of fat cells, all of which may short-circuit normal appetite controls. However, experiments with genetically engineered mice will be necessary to know for sure, he says.

Although the work is far from revealing an anti-obesity "magic bullet," the researchers, also from Simon Fraser University in Canada and the University College London, say it does point to microtubule failure as a primary mechanism for the problems seen in BBS, particularly the disorder's obesity, diabetes and retinal degeneration. Moreover, their discovery adds to evidence that the cells' highway system could be a major factor in other multisystem disorders.

"It's becoming very clear that microtubules are so fundamental to cells that if you hit the system with a genetic mutation you will get a disease," says Katsanis. "It's likely that some genes implicated in other multisystem disorders may compromise microtubules' functions, especially in diseases whose physical characteristics overlap with those of BBS."

Microtubules act as the roads that chromosomes travel in order to move to opposite sides of the cell during cell division. They also transport molecules and packets of molecules to the cell membrane for release from the cell, and are the primary skeleton in cellular structures called cilia. BBS4 mutations are likely to affect different microtubule functions in different cell types, including the transport of proteins up and down cilia, Katsanis says.

"In our in vitro systems, if BBS4 didn't work, all the cells died because of microtubule failure," says Katsanis. "It's very likely that in engineered mice, we also may see slower growth, less cell division, and other mutation-induced changes that will explain the condition's various effects. Cell death won't be the only problem."

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The Johns Hopkins researchers were funded by the National Institute of Child Health and Development and the March of Dimes. Authors on the report are Katsanis, Jose Badano, Carmen Leitch and Stephen Ansley of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins; Jun Chul Kim, Muneer Esmail and Michel Leroux of Simon Fraser University, Canada; Sonja Sibold, Josephine Hill, Bethan Hoskins, Alison Ross and Philip Beales, University College London; and Kerrie Venner, Institute of Neurology, London.

On the Web: http://www.nature.com.ng

A related news release, BBS8 found in cilia, a microtubule-based cell structure: http://www.hopkinsmedicine.org/press/2003/SEPTEMBER/030921.HTM