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08
Apr

Motor Neuron Disease Linked to Gene-Environment Interactions

(Beyond Pesticides, April 8, 2008) A team of University of Michigan scientists discover interactions between genes and organophosphate exposure cause some forms of motor neuron disease (MND). The study, which appears in the March issue of the American Journal of Human Genetics, shows the mutations in one key gene (neuropathy target esterase, or NTE) that causes a previously unknown type of inherited MND. The scientists also find the mutations caused changes in a protein already known to be involved when people develop neurologic disorders as a result of exposure to toxic organophosphate chemicals commonly used in solvents and insecticides and also as “nerve gas” agents.

Motor neuron disease is a rare, devastating illness in which nerve cells that carry brain signals to muscles gradually deteriorate. One form of it is Lou Gehrig’s disease or ALS (amyotrophic lateral sclerosis). For most MND patients, the cause is unknown. Figuring out why these people develop the disease, which causes muscles to weaken, atrophy and cease to function, is an important step in developing therapies to treat or prevent motor neuron disease. Motor neuron disease affects five per 100,000 people.

“Our findings support the possibility that toxic organophosphates contribute to motor neuron disease in genetically vulnerable people,” says John K. Fink, M.D., professor of neurology at the U-M Medical School and senior author of the study. He believes the results suggest that altered activity of the gene found in patients in the study may also contribute to other motor neuron disorders, possibly including ALS. The findings are an exciting first step in uncovering a possible link between the environment and motor neuron disease, says Shirley Rainier, a research assistant professor at the U-M Department of Neurology and the first author of the study. “Why does one person in a family get it, and another doesn’t?”

Dr. Fink examined members of two families who had progressive weakness and tightness in their legs, as well as muscle atrophy in their hands, shins and feet. James Albers, M.D., Ph.D., a U-M professor of neurology and an expert in neuromuscular disorders, studied nerve and motor function. Dr. Rainier performed genetic studies and determined that the gene for the condition was on a region of chromosome 19. Mark Leppert, Ph.D., co-chair of human genetics at the University of Utah, and his team performed genetic analysis that confirmed this location and excluded other areas in the genome. Among the many genes in this region of chromosome 19, one gene stood out as particularly likely: the gene that encodes for NTE. Because of its known role in organophosphate-induced neurological disease, the NTE gene was considered an important candidate gene and was studied immediately.

Analysis showed that the affected people in each family had NTE gene mutations. These mutations altered a critical part of the NTE protein called the esterase domain. Dr. Fink has named the inherited condition “NTE motor neuron disease.” It begins in childhood and progresses slowly, with symptoms of weakness and spasticity in the legs and muscle atrophy in the hands and lower legs.

Next, Dr. Fink and his team want to learn if mutations in the NTE gene happen in other types of motor neuron disease such as ALS, and if the mutations make a person more vulnerable to neurological damage from organophosphate exposure. Dr. Fink’s lab is currently using fruit flies as a model to study the NTE mutations, with the goal of finding treatments for people with motor neuron disease.

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