Jackson Laboratory Researchers Identify Neuromuscular Degeneration Gene

December 22, 1998

BAR HARBOR -- Scientists at The Jackson Laboratory have cloned the gene for the mouse mutation known as neuromuscular degeneration, or nmd, an advance that could boost research into such devastating neurological diseases in humans as amyotrophic lateral sclerosis and spinal muscular atrophy.

The results are published in a research paper, "Identification of the mouse neuromuscular degeneration gene and mapping of a second site suppressor allele," in the December 1998 issue of the scientific journal Neuron. The Jackson Laboratory team was led by Dr. Gregory A. Cox, Dr. Wayne N. Frankel, and Connie L. Mahaffey.

"There are no effective treatments for these diseases, and the underlying causes of neurodegeneration remain obscure," said Dr. Cox, a Research Scientist in Dr. Frankel's group. "Mouse models of human disease like nmd provide unique tools for both gene discovery and analysis of underlying disease mechanisms. Our findings provide an additional tool for understanding the complex process of motor neuron death."

The nmd mouse was originally discovered at The Jackson Laboratory and reported in Mammalian Genome (March 1995) by researchers Susan A. Cook and Drs. Kenneth R. Johnson, Roderick T. Bronson, and Muriel T. Davisson. The mutation causes severe muscle atrophy due to progressive degeneration of spinal motor neurons, which control the movement of voluntary muscles. The mice exhibit progressive paralysis that initially begins with the hindlimbs. Variable forelimb paralysis occurs in later stages of the disease, with life expectancy rarely exceeding four weeks.

Similar motor neuron degeneration is implicated in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). ALS, or "Lou Gehrig's Disease," is a fatal neurological disorder that attacks motor cells in the spinal cord and brain. The disease affects up to 30,000 people in the United States. About 5-10% of ALS cases are classified as familial and are suspected of having a genetic defect in a specific chromosome.

Spinal muscular atrophy, also characterized by degeneration of motor cells in the spinal cord and brain, is the second most common neuromuscular disorder of childhood, after Duchenne Muscular Dystrophy. SMA has three major childhood forms classified by age of onset. Most forms are genetic, and at least one gene involved in SMA has been identified to human chromosome 5q.

The Neuron paper reports that the defective gene in nmd mice, known as Smbp2, encodes a DNA-binding protein on chromosome 19. Although this protein has been studied previously by different laboratories as SMBP2 (immunoglobulin S-mu binding protein-2), GF1 (glial factor 1), RIP1 (rat insulin enhancer binding protein 1), or Catf1 (cardiac transcription factor 1), the new findings are the first indication of an essential role for the protein in motor neuron function and survival.

Proteins in the DNA helicase/ATPase family to which SMBP2 belongs are known to be involved in many cellular activities, including DNA replication, repair, and recombination. The gene encoding SMBP2 is widely expressed, with high levels in brain, heart, kidney, spleen, and testes, and lower levels in pancreas, liver, lung, and salivary gland. The human homolog of this gene is known to map to chromosome 11q, although it does not appear to be a major locus for familial ALS patients.

In another significant finding, the researchers report that severity of the nmd phenotype is suppressed by a modifier gene mapped to a locus (Mnm) on mouse Chromosome 13. The existence of such modifier genes has long been suspected in human ALS and SMA because of observed heterogeneity in age of onset and/or severity of symptoms.

The Mnm locus is in a mouse chromosomal region that shares homology with four different human regions containing many potential candidate genes, according to Dr. Cox. In addition, one potentially interesting mouse mutation that maps near Mnm is the progressive motor neuropathy (pmn) gene. The pmn phenotype is similar to that of nmd.

"The selective degeneration of motor neurons in this model and the dramatic effect that the single Mnm modifier gene has on the onset and progression of disease in the nmd mouse suggests that targets for intervention in motor neuron disease exist that can be manipulated to alter disease progression," Dr. Cox said.

The research at The Jackson Laboratory was supported in part by grants to Dr. Cox from the National Institutes of Health and the Amyotrophic Lateral Sclerosis Association, and to Dr. Frankel from the National Institutes of Health and the Klingenstein Fellowship in the Neurosciences.

Jackson Laboratory

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