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The newspaper of The Johns Hopkins University September 11, 2006 | Vol. 36 No. 2
JHU Team Develops Online Tool to Aid 'Orphaned' Diseases Research

Link is flaws in tiny, hairlike cilia; database gathers info on contributing genes

By Audrey Huang
Johns Hopkins Medicine

Many people are afflicted with rare illnesses of unknown cause, and finding a common link to such understudied or "orphaned" diseases as Bardet-Biedl, Alstrom and Meckel-Gruber syndromes can significantly advance the search for causes and treatment. Now, the Johns Hopkins research team that first identified as a common link flaws in the work of tiny, hairlike structures on the surface of cells called cilia has compiled — and made available on the World Wide Web — a database of all genes known to contribute to cilia operations in the body.

"It was hard labor but worth it to help accelerate research and drive the development of potential drug targets and cures for these diseases," said the project's leader, Nicholas Katsanis, an associate professor of molecular biology and genetics and ophthalmology at the McKusick-Nathans Institute of Genetic Medicine.

"But what's equally exciting is that the database should also advance the understanding of much more common diseases, because abnormal cilia are looking as if they have a role in these as well," he added.

The new Web-based resource, described online Aug. 29 in Nature Genetics, will be freely available to all researchers.

"In recent years it's become clear that there is a broad spectrum of human disorders, including polycystic kidney disease and left-right axis defects, for example, that share similar clinical problems and cilia malfunctions," Katsanis said.

Cilia are organelles whose main function was once thought to be confined to helping one-celled organisms propel themselves around. Although they had been observed in many tissues in humans and other mammals, some researchers considered them "vestigial," an evolutionary relic from our progenitors. But a small band of investigators, including Katsanis, have begun to assign function to cilia in numerous cell types in the human body and speculate that "anything so highly conserved by evolution is likely critical for survival."

Work by Katsanis' group and others in the field shows that more than 1,000 genes are known to play a role in cilia. Some genes contribute to their structure and others to function, and yet others only have been implicated in some sort of cilia-related role.

"There's a lot we still don't know about cilia, and much work needs to be done," Katsanis said. "But this new database consolidates a considerable volume of knowledge floating around out there, and we hope it will focus not only our research but [that of] others, as well as speed our way to better treating these patients."

Bardet-Biedl, Alstrom and Meckel-Gruber patients share similar symptoms, including kidney and vision problems and cognitive dysfunction.

Although all are marked by aberrant cilia, the different symptoms associated with each syndrome affect individual patients differently. Many first go to the doctor because they experience vision problems, for which they are treated, but the patients may be unaware that they are experiencing other problems, dubbed subclinical, such as slow kidney failure.

Studying the genes involved is expected to shed light on how cilia function. And a better understanding of normal cilia function, according to Katsanis, will lead to a better understanding of what goes wrong when cilia don't function. "Having a good handle on genes may lead to future genetic tests that can help doctors better diagnose and treat these syndromes," he said.

"Studying the genetics, heritability and molecular underpinnings of Bardet-Biedl syndrome uncovered the role of cilia in this and other syndromes," Katsanis said. "The clinic informing the science got us where we are today. Now we have the tool to enable the science to go back and inform the clinic."

The researchers were funded by the National Institute of Diabetes, Digestive and Kidney Disorders and by the National Institute of Child Health and Development branches of the National Institutes of Health.


Related Web sites

Cilia proteome database
Johns Hopkins Institute of Genetic Medicine
Nicholas Katsanis


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