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.
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