Gene mutation found for a form of juvenile-onset motor neuron disease

Researchers have discovered a genetic mutation associated with an inherited form of motor neuron disease in which symptoms first appear in childhood or young adulthood. The finding is slated for publication in the American Journal of Human Genetics.

In studying families affected by the disease, researchers detected a mutation in the Senataxin gene. Although this gene’s exact function is unknown, scientists think the normal Senataxin gene may play a role in how cells rid themselves of faulty genetic messages during RNA processing, according to Dr. Craig Bennett, University of Washington (UW) research assistant professor of pediatrics, Division of Genetics and Developmental Medicine. The mutation may make it difficult for motor neuron cells to clear out mistakes made during encoding of DNA, and thereby contribute to the degeneration of these nerve cells.

The disease studied is a rare type of amyotrophic lateral sclerosis (ALS). Patients with this type of ALS have mild symptoms, a slow progression of muscle weakness, a normal life span, and relatives with the same disorder. In contrast, most ALS disorders appear in middle age or later life and cause paralysis and death within a few years. Only 10 percent of ALS disorders run in families; the rest appear sporadically. ALS claimed the life of baseball star Lou Gehrig, and is often called Lou Gehrig’s disease.

Locating the gene took scientists about seven years of difficult work. While the inherited juvenile type of ALS is rare, Dr. Phillip Chance, UW professor of neurology and pediatrics, said that finding the mutated gene opens up avenues of investigation for motor neuron diseases in general. Learning more about the biological repercussions of the mutation may lead to insights on how motor neurons are damaged in other forms of ALS.

“After scientists figure out what protein the normal gene produces and what this protein does in normal cells,” Chance said, “they may determine how the mutation disturbs cellular functions in ALS patients. We need to know more about the underlying basis of motor neuron degeneration to design rational treatments, to prevent the onset of ALS, or to slow down the rate of cell degeneration and subsequent disability.” Bennett noted that studies of the function of both the normal protein and the defective gene would likely be done in transgenic animal models and in yeast cells.

In addition to revealing the molecular basis of nerve damage, genetic studies may also help neurologists classify and diagnose motor neuron diseases.

“A number of patients with motor neuron problems lack a specific diagnosis,” Chance said. For example, one of the families he studied was mistakenly thought to carry a different kind of neuromuscular disorder.

“This study shows the power of large families to contribute to research critical for understanding the genetics of disease,” Chance added. Scientists from several countries worked together to locate and study families with this form of ALS.

“We scoured the planet to find families with the disorder,” Chance said.

The researchers, in addition to Bennett and Chance, were Ying-Zhang Chen, Huy Huynh, and Ian Blair, all from the UW; Imke Puls, Annette Abel, and Kenneth Fischbeck of the Neurogenetics Branch, National Institute of Neurological Disorders and Stroke; Joy Irobi, Ines Diereck, Peter De Jonghe, and Vincent Timmerman of the University of Antwerp in Belgium; Marina Kennerson and Garth Nicholson of the University of Sydney, Australia; Bruce Rabin, John W. Griffin and David Cornblath of Johns Hopkins University; and Klaus Wagner of Karl Franzens University in Graz, Austria.

Funding came from the National Institute of Neurological Diseases and Stroke, Muscular Dystrophy Association, Amyotrophic Lateral Sclerosis Association, Fund for Scientific Research, University of Antwerp, Medical Foundation Queen Elizabeth, Association Belge contre lest Maladies Neuro-Musculaires, Interuniversity Attraction Poles Program of the Belgian Federal Science Policy Office, and the Austria Science Fund.

National Institute of Neurological Diseases and Stroke

University of Washington: Leila Gray, 206-543-3620
Muscular Dystrophy Association: Margaret Wahl, 520-529-5343
National Institutes of Health: Natalie Frazin, 301-496-5924

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