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Gene discovery aids understanding of common inherited neurological disorder

25.06.2007
Benefiting from Human Genome Project, University of Michigan scientists rapidly find mutation that causes one form of Charcot-Marie-Tooth disorder

Scientists have identified the gene responsible for one type of Charcot-Marie-Tooth disorder, a common inherited neurological disease, thanks to the chance appearance of a strain of impaired “pale tremor” mice in a University of Michigan research laboratory.

The discovery of the gene mutation means a genetic test will be possible for people with a less common subtype of the disorder -- one that until now was unidentified and had an unknown genetic basis, says Miriam Meisler, senior author of the study. This work now appears online ahead of print in the journal Nature.

Charcot-Marie-Tooth disorder, one of the most prevalent inherited neurological disorders, affects one in 2,500 people in the United States, usually beginning in youth or by mid-adulthood. It is actually a group of related disorders that affect the body’s peripheral nerves, with symptoms such as pain and.muscle weakness in the feet and legs that lead to foot deformities, tripping and difficulty walking.

The gene abnormalities responsible for 70 percent of cases are already known. Those patients and their families can choose to have genetic tests, which may be used to guide treatment or help family members find out if they are at risk.

But the remaining 30 percent of patients, who have different variants of the disease, have not had that option. Meisler, a professor of human genetics at the U-M Medical School, predicts the new discovery will quickly lead to a test that can diagnose which of those patients have the newly identified gene mutation. These probably represent about 5 percent of the unexplained 30 percent of cases, preliminary testing suggests. With genetic knowledge, “Family members can make decisions about reproduction,” Meisler says of the discovery’s implications. “It also opens up directions for developing therapies. Now pharmacologists and drug developers can target this gene.”

The genetic sleuthing that led to the discovery began when scientists in Meisler’s genetics lab noticed that some mice of a common laboratory type gave birth to offspring with a strange, wobbly gait and light coat color. The offspring quickly developed signs of severe central nervous system degeneration and peripheral neuropathy and died. The team named the strain “pale tremor” mice for their lack of normal pigment and the severe trembling they developed soon after birth.

What could explain the mice’s debilitating symptoms" And could that knowledge be relevant in people with neurological diseases" Clement Y. Chow, the study’s lead author and a U-M Ph.D. student in human genetics, pursued answers.

Chow was able to identify the gene involved, called FIG4, and find the mutation responsible for the symptoms in less than three years. That’s a third of the time it might have taken two decades ago, in part because of valuable data from the Human Genome Project, Meisler says.

Meisler’s research team, which included scientists at the U-M Life Sciences Institute, found that the mutation caused a signaling molecule, called PI(3,5)P2, to be under-produced in both yeast and mice cells. This little-studied signaling molecule was known to be present in yeast cells but has not been well studied in mammals.

The researchers also identified how the loss of normal FIG4 gene function results in disease in the pale tremor mice: Large fluid-filled chambers called vacuoles crowd the nerve cells and disrupt cell processes.

“In mice, the peripheral nervous system was most affected. So we decided to ask whether human patients with peripheral neuropathic disease had the same mutation,” says Meisler.

The researchers tested 95 patients with Charcot Marie Tooth disorder of unknown cause. In four patients, they found mutations of FIG4, the same gene implicated in the diseased mice. The finding has resulted in a newly identified form of the disease called CMT4J.

In the phase of the research involving human patients, the multidisciplinary team of U-M scientists collaborated with scientists at Wayne State University and Baylor College of Medicine in Houston.

The study also produced other intriguing findings:

The signaling function governed by the FIG4 gene, common to yeast, mice and humans, is what geneticists call a “conserved function,” persisting since very early in evolution.

The pale tremor mouse will be useful as a laboratory animal model in further research on Charcot-Marie-Tooth disorder as well as other conditions involving neuropathy. Meisler’s lab plans to use the mice in studies to find out why their neurons deteriorate so rapidly.

Anne Rueter | EurekAlert!
Further information:
http://www.charcot-marie-tooth.org

Further reports about: Discovery FIG4 Meisler Mutation U-M inherited neurological peripheral

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