Gene Discovery Aids Understanding Of Common Inherited Neurological Disorder

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Gene Discovery Aids Understanding Of Common Inherited Neurological

Disorder

http://www.sciencedaily.com/releases/2007/06/070621102604.htm

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.

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.

Journal Citation: " Mutation of FIG4 causes neurodegeneration in the

pale tremor mouse and patients with CMT4J, " Nature on-line, June 17,

2007, doi:10.1038/nature05876

In addition to Meisler and Chow, U-M contributors to the study

include: Yanling Zhang, Natsuko Jin and Lois Weisman of the Life

Sciences Institute; Dowling of the Department of Neurology;

and Maja ka of the Department of Human Genetics The research

was funded by the National Institutes of Health.

Additional Information:

Patent protection has been applied for. The University of Michigan,

through its Office of Technology Transfer, is looking for licensing

partners to help bring the technology to market. At the time this

research was published the test for the CMT4J mutation was not

available for routine use in humans.