Johns Hopkins researchers have discovered that many people with Bardet-Biedl syndrome (BBS), a rare, complex condition marked by an array of seemingly unconnected symptoms, including obesity, learning difficulties, eye problems and asthma, also have another, previously unreported problem: many of them can't detect odors.
Because people with the syndrome likely lose their sense of smell before or shortly after birth, it wouldn't occur to them to mention it, and so the problem, known as anosmia, had never been reported, the researchers say.
But spurred by new understanding that the problems seen in BBS are caused by faulty cellular structures called cilia, researchers led by Nicholas Katsanis, Ph.D., decided to look into patients' ability to detect odors. The olfactory system, which is responsible for the sense of smell, is perhaps the most cilia-rich system in the body, relying on a bed of the tentacle-like structures to detect odiferous molecules as they pass through the nose.
Sure enough, when colleagues at University College London administered a simple, standard smell test to BBS patients, 40 percent couldn't smell anything, and another 10 percent had a reduced odor-detecting ability. The Johns Hopkins researchers then turned to mice missing either of two BBS-causing genes to prove that faulty cilia, rather than any other problems, were to blame. The results are described in the Aug. 22 advance online section of Nature Genetics.
"This proves beyond a shadow of doubt that the mechanism we've proposed -- faulty cilia -- is behind the syndrome," says Katsanis, an assistant professor in Hopkins' McKusick-Nathans Institute of Genetic Medicine. "Without the mouse studies, the problem could have been at any step along the way: from detecting odors, to communicating with the brain, to pulling up the right word to describe the odor.
"But we've proven that loss of the BBS proteins causes ciliary problems in mice, and the ciliary problems cause the clinical symptom," he says. "I love it when science makes sense."
Last year, Katsanis and an international team of colleagues discovered that BBS-involved proteins were found in and near cilia, and they suggested that faulty cilia might explain the variable problems in BBS. But until now, there was no direct proof that the ciliary problems they'd observed in worms and cells were also present in mice or people with BBS-causing genetic mutations.
"We took a disease associated with cilia and looked at a system whose whole job, its raison d'etre, essentially is making cilia," says Randall Reed, Ph.D., a professor of molecular biology and genetics in Hopkins' Institute for Basic Biomedical Sciences and a Howard Hughes Medical investigator. "If the association was right, we'd expect an effect."
Reed's research assistant Heather Kulaga and Katsanis's research assistant Carmen Leitch studied mice missing either of two BBS-causing genes, BBS1 or BBS4, to figure out whether the animals' sense of smell was impaired. (All four of the patients who had mutations in BBS4 were unable to smell.)
The overall organization of the olfactory system in both sets of mice seemed normal, she discovered, but instead of the normal sea-grass-like patch of lengthy cilia where smelly molecules usually come to rest, the mice had only short, stumpy cilia wannabes. The stunted cilia couldn't detect odor-causing molecules, so virtually no electrical signals were sent to the brain, Kulaga discovered in experiments where she measured the electrical signals, or lack thereof.