Scientists have uncovered the identity of the last of eight genes known to contribute to Bardet-Biedl syndrome

Aug 16 2004

By comparing three different species' genomes and adding some good old-fashioned genetic analysis, scientists have uncovered the identity of the last of eight genes known to contribute to Bardet-Biedl syndrome, a rare disorder characterized by a combination of some otherwise common problems, including obesity, learning difficulties, diabetes and asthma.

The identification of the BBS3 gene ends the search for primary BBS-causing genes in families studied for years by a team of scientists from the United States, Canada and the United Kingdom. However, the scientists are still hunting for other, less obvious genetic influences in these families.

Writing in the Aug. 15 advance online section of Nature Genetics, the international team reports that BBS3 is actually a gene formerly known as ARL6. Importantly, ARL6 is the first BBS culprit to belong to a family of genes and proteins with a known function, opening the door to figuring out what's really happening in people with the condition.

"We can use BBS3/ARL6 and its known function -- binding the molecule GTP -- as a great place to start to unravel the details of the other BBS proteins," says Nicholas Katsanis, Ph.D., assistant professor in Johns Hopkins' McKusick-Nathans Institute of Genetic Medicine. "And understanding BBS may provide important insight for understanding obesity, learning difficulties and other BBS-related problems that also appear in the general population."

Family studies had managed to link BBS3 to a region of chromosome 3, but getting to the gene had proven challenging. Now, by taking advantage of their recent discovery that faulty cellular structures called cilia are behind the problems seen in BBS patients, the researchers were able to zero in on the disease-causing gene.

Cilia are found on many different types of cells and can either act like antennae, sensing important signals, or help push fluid or mucous around, such as in the lungs. Some BBS-related mutations seem to disrupt the scaffolding upon which cilia are built, but others may cause ciliary dysfunction in other ways, perhaps preventing or misdirecting the shuttling of materials along the cilia.

By searching a database of cilia-related genes compiled by comparing three species' genomes -- a bacterium, a plant, and a human [see May 15, 2004, news release] -- the researchers found three possibilities in the right region of chromosome 3. Next, they determined the genetic sequences of those three genes in four families with BBS. One of the genes, ARL6, had a different, critical mutation in each of the families, the researchers found.

"ARL6 is the first member of its larger gene family to be tied to any disease," says Katsanis. "While not much is known about ARL6 specifically, we know quite a bit about its relatives, so we know which regions of ARL6 are crucial for the protein's correct function. The mutations in these families wouldn't let the protein work properly."

ARL6 is a member of a class of proteins that bind GTP, or guanosine triphosphate -- a class given the obvious title of GTP-binding proteins. GTP-binding is a critical step in a wide variety of signaling "cascades" that pass along messages and instructions inside cells -- such as to open or close the cell's entry points or to trigger relocation of "freight" within the cell.

"That this type of molecule could cause BBS is particularly intriguing," says Katsanis.

In additional experiments using the worm C. elegans, the researchers proved that ARL6 normally functions only in cilia, suggesting it might relay specific signals in that part of the cell. The next step is to figure out exactly what those signals might be.

"We don't know what its message is, but because we know that it binds GTP, we have some ideas of where to start looking," says Katsanis.

The Johns Hopkins researchers' contributions were funded by the National Institute of Child Health and Development, the National Institutes of Health and the March of Dimes.