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 Closing in on advanced prostate cancer
13.12.2017 | Institute for Research in Biomedicine (IRB Barcelona)

nachricht Visualizing single molecules in whole cells with a new spin
13.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

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

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

A whole-body approach to understanding chemosensory cells

13.12.2017 | Health and Medicine

Water without windows: Capturing water vapor inside an electron microscope

13.12.2017 | Physics and Astronomy

Cellular Self-Digestion Process Triggers Autoimmune Disease

13.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>