Studying families with a relatively rare condition called Bardet-Biedl syndrome (BBS), characterized by obesity, learning disabilities and eye and kidney problems, the researchers discovered a new gene involved. Furthermore, the gene's protein, BBS8, is found only at the base of cilia, the scientists report in the Sept. 21 advance online section of Nature.
"BBS is a relatively rare genetic disorder, but it has traits common to many people," says Nicholas Katsanis, Ph.D., assistant professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "We don't know yet how the ciliary defect might lead to obesity or learning disabilities, but the finding provides a new avenue to studying these genetically murky traits.
"It is very difficult to translate genetic understanding into a cellular mechanism that explains what is seen in a disease. But such efforts are what genetic medicine is all about," adds Katsanis.
Some aspects of BBS have been linked to ciliary defects in other conditions. Cilia are known to play key roles in mammalian development, creating what's known as left-right asymmetry so organs like the heart, lungs and liver end up in the right place. In people with BBS, sometimes left-right asymmetry is reversed. Also, malfunctioning cilia in the back of the eye are known to cause retinal dystrophy and eventual blindness, and ciliary problems in the kidney lead to structural problems in the organ.
But even though these primary characteristics of BBS had been tied to ciliary defects, the condition itself and its other traits -- obesity, learning disabilities, extra fingers, and diabetes -- have never before been linked to cilia. These syndrome characteristics may be directly or indirectly caused by defects in cilia, but the research finding opens a never-before-pursued avenue to understanding these attributes in the general population.
Katsanis says the next step is to figure out exactly what is wrong with the cilia and how those problems affect different tissues. The problems could lie in cilia's movement or in their ability to sense cells' surroundings.
"Cilia are very overlooked," says Katsanis, whose laboratory has uncovered many of the genes known to be involved in the syndrome. "The majority of cilia in human cells act as a sort of communication device, which isn't the typical picture of waving, mobile cilia. Cilia can act as cells' private satellite dish."
The team's search for a new BBS gene began as an exploration, searching for genetic changes in families with the syndrome. BBS8 is similar in key ways to other genes implicated in BBS, and sure enough, affected members of three families had protein-altering mutations in the gene. Unaffected members of the families had normal BBS8.
In experiments with mammalian cells and tiny worms called C. elegans, Katsanis and colleagues at the Institute of Child Health in the United Kingdom and at Simon Fraser University in Canada used antibodies to pinpoint BBS8's location at the cilia's base, an organizational center where the structure connects to the cell.
"We can now identify the exact cells in organs likely to be at the root of the syndrome's characteristics," says Katsanis. "In many ways the work will no longer be exploratory but very focused."
Bardet-Biedl syndrome (pronounced BAR-day BEED-el) is an autosomal recessive disorder that appears worldwide. Incidence in the United States and Europe is roughly 1 in 150,000. In Kuwait incidence is estimated to be 1 in 13,500, and in Newfoundland, 1 in 17,500. To date, seven other genes have been linked to BBS, and six of them, including BBS8, have been studied in depth and cloned. However, none of the other genes has been clearly linked to a cellular problem that could result in the condition.
The Johns Hopkins researchers were funded by the National Institute of Child Health and Development and the March of Dimes. Authors on the paper are Katsanis, Stephen Ansley, Jose Badano, Bethan Hoskins, Carmen Leitch and Tanya Teslovich of Johns Hopkins; Oliver Blacque, Jun Chul Kim, Allan Mah, Robert Johnsen and Michel Leroux of Simon Fraser University, Burnaby, BC, Canada; Josephine Hill, Alison Ross, and Philip Beales of Institute of child Health, University College London; Erica Eichers and Richard Lewis of Baylor College of Medicine, Texas; and John Cavender of King Khaled Eye Hospital, Riyadh, Saudi Arabia.
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