An international team of researchers has discovered
how disruption of a single gene contributes to a complex
syndrome characterized in part by insatiable appetite,
they report April 25 in the Advance Online section of
Bardet-Biedl syndrome, characterized by obesity,
learning disabilities and eye and kidney problems, is
caused by genetic mutations in the BBS family of genes.
Now, researchers who've long studied the condition have
discovered that genetic mutations in one of those genes,
called BBS4, lead to cell death by disrupting the cells'
internal "highway" system.
In experiments with human and mouse cell lines in the
lab, the researchers found that the BBS4 protein normally
transports molecules that help guide the cell's internal
highway system, a network of so-called microtubules along
which tiny motors push and pull proteins, cellular packages
and even chromosomes. When the BBS4 gene doesn't work
correctly, the highway system falls apart, cell division
halts and the cell dies.
"But our experiments also revealed something really
interesting about pleiotropy — genetic diseases that
severely impact only a smattering of tissues," said
Nicholas Katsanis, head of the team's contingent from the
McKusick-Nathans Institute of Genetic
Medicine at Johns Hopkins. "Once we knew faulty BBS4
prevented correct microtubule construction and led to cell
death, the big question was, How do people survive when
every cell contains these mutations?"
The key is that the BBS4 protein acts through another
protein, called PCM1, or pericentriolar material 1 protein.
The two proteins are found together, or "co-localized,"
only in certain cell types in a specific subset of tissues,
so it is only in those cells that BBS4 mutations can lead
to cell death, the researchers report.
"There is very specific co-localization of the two
proteins in specific cells in the retina and in certain
brain cells, as well as small areas of other tissues,"
Katsanis said, describing the team's analysis of tissues
from mice and mouse embryos.
Based solely on where the two proteins are found in
mice, Katsanis can suggest a few reasons why obesity may be
common in people with the disorder, including improperly
controlled or targeted neurons, improper hormone release
and improper growth of fat cells, all of which may
short-circuit normal appetite controls. However,
experiments with genetically engineered mice will be
necessary to know for sure, he said.
Although the work is far from revealing an
anti-obesity "magic bullet," the researchers, also from
Simon Fraser University in Canada and the University
College London, said it does point to microtubule failure
as a primary mechanism for the problems seen in BBS,
particularly the disorder's obesity, diabetes and retinal
degeneration. Moreover, their discovery adds to evidence
that the cells' highway system could be a major factor in
other multisystem disorders.
"It's becoming very clear that microtubules are so
fundamental to cells that if you hit the system with a
genetic mutation, you will get a disease," Katsanis said.
"It's likely that some genes implicated in other
multisystem disorders may compromise microtubules'
functions, especially in diseases whose physical
characteristics overlap with those of BBS."
Microtubules act as the roads that chromosomes travel
in order to move to opposite sides of the cell during cell
division. They also transport molecules and packets of
molecules to the cell membrane for release from the cell
and are the primary skeleton in cellular structures called
cilia. BBS4 mutations are likely to affect different
microtubule functions in different cell types, including
the transport of proteins up and down cilia, Katsanis
"In our in vitro systems, if BBS4 didn't work, all the
cells died because of microtubule failure," Katsanis said.
"It's very likely that in engineered mice, we also may see
slower growth, less cell division, and other
mutation-induced changes that will explain the condition's
various effects. Cell death won't be the only problem."
The Johns Hopkins researchers were funded by the
National Institute of Child Health and Development and the
March of Dimes. Authors on the report from Johns Hopkins
are Katsanis, Jose Badano, Carmen Leitch and Stephen
Ansley, all of the McKusick-Nathans Institute of Genetic
— Joanna Downer