Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Nerve disorder in mice and men linked to mutated gene

13.10.2003


Discovery shows power of mouse genome to identify human genes for rare genetic diseases



In a small town on Grand Cayman Island in the Caribbean, people are living with a serious neurological disorder, called Cayman ataxia, found nowhere else in the world.

People born with this rare, inherited condition have poor muscle coordination, some degree of mental retardation, uncontrollable head and eye movements and difficulty speaking or walking.


Now, in a discovery that reinforces the importance of the mouse to human genetics, scientists at the University of Michigan Medical School have discovered two mutations in a gene called ATCAY, which appear to be responsible for Cayman ataxia in humans and for similar neurological disorders in mice.

Cayman ataxia is one of about 100 rare inherited neurological disorders with symptoms that include ataxia, according to Margit Burmeister, Ph.D., a senior associate research scientist at the U-M Mental Health Research Institute and an associate professor of psychiatry and of human genetics in the University of Michigan Medical School. While the severity of symptoms can vary, people with ataxia have limited or no control over posture or coordination of their arms and legs.

"Because these disorders are so rare, it is difficult to collect DNA samples from enough affected individuals in different families with the same disorder to pinpoint the mutations that cause them," Burmeiser says. "Unless we can identify the mutated gene, it’s hard to develop a diagnostic test or a therapy to help people with the disease."

A paper describing the research study will be published online October 12 by Nature Genetics, and will appear in the November issue of the journal. It is the result of a collaboration between scientists at the University of Michigan, the University of Miami, the University of Iowa and the National Human Genome Center at Howard University.

Before the U-M study, scientists knew that Cayman ataxia was caused by a recessive mutant gene originating in one of the early residents of Grand Cayman Island and passed on through the generations by his or her descendants. In 1994, scientists at the University of Iowa narrowed the search to one region on human chromosome 19, which included 50 to 100 genes, but couldn’t locate the specific gene responsible for the disorder.

Meanwhile, Burmeister was working with a strain of mutant mice, called "jittery", with similar neurological symptoms, but so severe that affected mice die a few weeks after birth. She wondered if the gene that caused the disorder in mice could be the same gene responsible for Cayman ataxia in humans. So she compared overlapping DNA sequences between the region on mouse chromosome 10 defined by the "jittery" mice and the region on human chromosome 19 implicated in Cayman ataxia.

"Comparing overlapping DNA sequences between human and mouse narrowed the interval down to a much smaller region that contained just seven genes," Burmeister says. "In one of these genes, we discovered two mutations – a recessive mutation that caused lethal ataxia in "jittery" mice and another mutation that caused milder symptoms in a different strain of mice called "hesitant".

Burmeister then analyzed anonymous DNA samples, provided by University of Iowa scientists, from Cayman Island residents with ataxia and from relatives who did not have the disorder. When they sequenced human DNA, U-M scientists found the same two mutations in the same gene, which they named ATCAY, for Ataxia, Cayman type. Both mutations were present in every patient with Cayman ataxia in the study. Neither mutation was found in 1,000 control chromosomes from people of European, Jamaican or African ancestry.

"One of the mutations in the ATCAY gene changes an amino acid and the other is a splice mutation expressing a non-functional, truncated form of caytaxin, the protein expressed by the gene," Burmeister explains.

When U-M scientists analyzed gene expression in tissue from mice in the study, they found caytaxin protein was present throughout the brain and in neurons, but nowhere else in the mouse’s body.

"We don’t know what this protein does, but it doesn’t appear to affect the physical development or structure of the brain or nervous system in mice, which appeared completely normal," Burmeister says. "Unlike other ataxias, there were no neurodegenerative changes."

According to Burmeister, the DNA sequence encoding caytaxin protein is somewhat similar to that of a Vitamin-E transporting protein, which is involved in another rare form of ataxia. People with this form of ataxia respond well to treatment with large doses of Vitamin E. But Vitamin E does not seem to bind to caytaxin, so the same treatment would not help people with Cayman ataxia.

Currently, Burmeister is working with structural biologists to determine what molecules will fit into the binding pocket of the caytaxin protein.

"If we can determine caytaxin’s function, that will tell us why these people have ataxia, which would be a major step toward finding ways to prevent or treat the disorder," Burmeister says.

She also plans additional research to see whether mutations in ATCAY could be responsible for other types of inherited ataxia.


###
The University of Michigan has filed two provisional patent applications on the ataxia-associated gene and its protein. The research was funded by the National Institutes of Health, the March of Dimes Birth Defect Foundation, and the government of the Cayman Islands.

Jamee Bomar, a U-M research assistant, was first author on the paper. Other co-authors from U-M included Roger Albin, M.D., U-M professor of neurology; Paresh Patel, M.D., Ph.D., U-M assistant professor of psychiatry; undergraduates Eric Slattery and Radhika Puttagunta; Larry Taylor, Ph.D, research associate; and Eunju Seong, a graudate student in neuroscience. Co-authors Arne Nystuen and Val C. Sheffield are from the University of Iowa Medical School. Co-authors Rick Kittles and Weidong Chen are from the National Human Genome Center at Howard University. Co-author Paul J. Benke, from the University of Miami Medical School, did the original clinical research on individuals with Cayman ataxia.

Kara Gavin | EurekAlert!
Further information:
http://www.med.umich.edu/1toolbar/whatsnew.htm

More articles from Life Sciences:

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

nachricht Asian dust providing key nutrients for California's giant sequoias
28.03.2017 | University of California - Riverside

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Researchers shoot for success with simulations of laser pulse-material interactions

29.03.2017 | Materials Sciences

Igniting a solar flare in the corona with lower-atmosphere kindling

29.03.2017 | Physics and Astronomy

As sea level rises, much of Honolulu and Waikiki vulnerable to groundwater inundation

29.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>