Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene mutation found that increases severity of multisystem syndrome

15.12.2005


Discovery mirrors expectations for genetic complexity of common diseases



Johns Hopkins scientists studying a rare inherited syndrome marked by eye and kidney problems, learning disabilities and obesity have discovered a genetic mutation that makes the syndrome more severe but that alone doesn’t cause it. Their report appears in the advance online edition of Nature (Dec. 4).

The new discovery about Bardet-Beidl syndrome (BBS) came from a panoply of studies -- starting with comparative genomics and experiments with yeast, and moving to experiments with zebrafish and genetic analysis of families with the syndrome -- and mirrors what experts expect for the genetically complex common diseases that kill most Americans, like diabetes, heart disease and cancer.


"Scientists are going to have to think very hard before they discount genetic variation that appears not to directly cause a disease," says the study’s leader, Nicholas Katsanis, Ph.D., associate professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. "The onus is on us to figure out how to dissect the effects of what appear to be silent genetic variants. I have a greatly renewed respect for the complexity of the genome, for the subtle ways that genes and gene products interact with each other."

Conventional wisdom says that a collection of subtle genetic variations contribute to a person’s risk of common diseases, but hunting for such subtle effects is daunting. As a result, most gene hunts have targeted relatively rare diseases that appear from their pattern in families to be fairly simple genetically.

Katsanis and his colleagues have recognized for years that BBS, although rare, is more similar to the genetic complexity of common diseases, in part because patients with this condition have extremely variable severity, even within families. The newly identified mutation, in a gene called MGC1203, is the first to affect only the severity of the syndrome. Mutations in eight other genes, all dubbed BBS genes, are known to cause the disease, often in combination with each other.

The identification of MGC1203’s role in BBS stems from the researchers’ earlier discovery that disease-causing mutations in the BBS genes disrupt the function of cilia, tiny structures that can act like antennae on cells (in the eye and brain, for instance), help cells move (e.g., in sperm), or help move fluid around cells (in the lung and brain, for example).

To build on this finding, Katsanis and his team combined results from two data-rich experiments. In one, Katsanis and members of his lab used yeast to identify proteins that interacted with the yeast’s BBS proteins. Sixty turned up in their first round of experiments. In the other, reported last year, a large research team compared the genomes of various species to identify genes involved in the function of cilia. More than 600 were found.

But by identifying which turned up in both sets of results, the researchers narrowed down the hunt to just one gene -- MGC1203.

Using standard tools of biology, the Johns Hopkins researchers determined that the MGC1203 protein is found in the same part of the cell as BBS proteins and that the MGC1203 and BBS proteins interact. Furthermore, by studying the genes of families with BBS, they also discovered that the most severely affected individuals have a single mutation in their MGC1203 gene. And zebrafish carrying mutations in both MGC1203 and BBS genes had more severe problems than zebrafish carrying only BBS gene mutations.

At first glance, the mutation appears not to affect the sequence of the MGC1203 protein, which stumped Katsanis. But because so much evidence pointed to a role for this mutation in the disease, Katsanis and postdoctoral fellow Jose Badano kept searching.

Their perseverance paid off. Like other genes, the MGC1203 gene is made of DNA, and its message is transcribed into DNA’s cousin, RNA. The RNA, in turn, can be cut apart and put back together in various ways and then "read" to build a protein, much like raw video footage can be edited to make different movies.

For MGC1203, two different RNA messages are normally produced, one that is used to make protein, and one that is destroyed by the cell, the researchers discovered with help from the Howard Hughes Medical Institute laboratory of Hopkins researcher Harry Dietz, M.D.

Badano and Katsanis then discovered that the genetic mutation in MGC1203 shifts the normal balance of the two RNA messages, increasing the amount of the destroyed message produced. That shift alone seems to be the problem, says Katsanis, who is now studying how it affects the biology of cells.

"Everyone’s cells make both messages, but people with the BBS-associated mutation make more of the version that the cell destroys right away," says Katsanis, whose laboratory also is studying the MGC1203 protein’s exact role in cells. "Somehow, this exacerbates the effects of mutations in the BBS genes."

Katsanis says that he suspects the human genome contains thousands of variants with similarly subtle effects that contribute to complex genetic diseases like obesity, diabetes and hypertension.

Joanna Downer | EurekAlert!
Further information:
http://www.jhmi.edu
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature04370.html
http://www.hopkinsmedicine.org/mediaII/RSSinstructions.html

More articles from Life Sciences:

nachricht More genes are active in high-performance maize
19.01.2018 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht How plants see light
19.01.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

Im Focus: Room-temperature multiferroic thin films and their properties

Scientists at Tokyo Institute of Technology (Tokyo Tech) and Tohoku University have developed high-quality GFO epitaxial films and systematically investigated their ferroelectric and ferromagnetic properties. They also demonstrated the room-temperature magnetocapacitance effects of these GFO thin films.

Multiferroic materials show magnetically driven ferroelectricity. They are attracting increasing attention because of their fascinating properties such as...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Let the good tubes roll

19.01.2018 | Materials Sciences

How cancer metastasis happens: Researchers reveal a key mechanism

19.01.2018 | Health and Medicine

Meteoritic stardust unlocks timing of supernova dust formation

19.01.2018 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>