2003 Release: CMT Gene Discovery

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services


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Gene Discovery Opens Door to Further Research In Inherited Neurological Disorders

Charcot-Marie-Tooth and Distal Spinal Muscular Atrophy Gene
May Shed Light on Carpal Tunnel Syndrome and Lou Gehrig's Disease

BETHESDA, MD., April 28, 2003 - Scientists at the National Human Genome Research Institute (NHGRI) and at the National Institute of Neurological Disorders and Stroke (NINDS) have identified the gene responsible for two related, inherited neurological disorders, and have, for the first time, directly implicated this gene and its enzyme product in a human genetic disease.

The discovery supports further investigation of this gene family for additional neurological disease genes, research that may shed light on a range of disorders, including carpal tunnel syndrome, which affects the hands and the wrists, and the fatal degenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

NHGRI and NINDS scientists, working together at the National Institutes of Health (NIH), found the gene responsible for Charcot-Marie-Tooth (CMT) disease type 2D and distal spinal muscular atrophy (dSMA) type V. The gene, called GARS-the glycyl tRNA synthetase gene-is located on chromosome 7 and encodes, or provides the instructions to make, one of the aminoacyl tRNA synthetases, a family of enzymes vital to the cell's ability to build proteins.

"The identification of the defective gene on chromosome 7 responsible for a type of Charcot-Marie-Tooth disease provides another vivid example of how the recently completed human genome sequence is accelerating studies in human genetics," said Francis S. Collins, M.D., Ph.D., director of NHGRI. "With this discovery, we now know that the GARS gene-whose function is so fundamental to biological processes-can be mutated in a fashion that results in a highly discrete neurological disease."

The study, a collaboration between the laboratories of Eric Green, M.D., Ph.D., at NHGRI, Kenneth Fischbeck, M.D., at NINDS, and Lev Goldfarb, M.D., also at NINDS, will be available online [ncbi.nlm.nih.gov] in April and published in the May issue of the American Journal of Human Genetics. Lead author Anthony Antonellis, a graduate student in Dr. Green's laboratory, directed the project.

The scientists identified four disease-related mutations and speculate that a mutated copy of GARS leads to a reduction in the activity of the gene's enzyme product. More research into why this disruption produces the specific symptoms of CMT type 2D and dSMA type V will be necessary.

"Identifying this chromosome 7 disease gene at this particular time was especially gratifying in light of the recent completion of a finished sequence of this chromosome," said Dr. Green, who is the Scientific Director of NHGRI and chief of its Genome Technology Branch. Dr. Green also directs the NIH Intramural Sequencing Center. His laboratory has been involved in mapping and sequencing chromosome 7 as part of the Human Genome Project.

"This discovery is another piece of a jigsaw puzzle picture of how peripheral nerve diseases and motor neuron diseases happen," said Dr. Fischbeck, chief of the Neurogenetics Branch at NINDS. Dr. Fischbeck's laboratory studies hereditary motor neuron diseases and peripheral neuropathies. "It provides a more complete view of the mechanism of these diseases. This will hopefully lead to new treatment approaches. The more complete the picture, the more we know how to intervene."

Charcot-Marie-Tooth disease, named after the three physicians who first reported it in 1886, is a group of genetic diseases that causes muscle weakness and wasting, or atrophy, in the feet, legs, hands, and forearms, as well as diminished sensation in the limbs. CMT disease affects the peripheral nerves-the nerves that travel to the muscles of the limbs-and is therefore known as a peripheral neuropathy. Estimated to affect one in 2,500 individuals, it is the most common inherited neurological disorder.

Some forms of CMT disease are autosomal dominant, meaning that a person needs to inherit only one defective copy of the responsible gene to acquire the disease. Other forms are autosomal recessive, meaning both copies of the gene must be defective to result in illness. There is also a form of CMT that is X-linked, meaning that the responsible gene is located on the X chromosome, one of the two sex chromosomes.

In most cases, CMT disease begins with mild symptoms, typically foot and ankle weakness and fatigue. As atrophy progresses, the patient develops a distinct walk, a consequence of muscle weakness in the front of the leg: the feet slap with each step and the body may sway from side to side. Eventually the toes and the fingers curl due to weakness and atrophy in the small muscles of the feet and the hands. Writing and other functions of the hands become difficult. The sensory loss that accompanies the atrophy diminishes the patient's ability to distinguish between hot and cold and affects the patient's sense of touch.

People with CMT disease usually begin to experience symptoms in adolescence or early adulthood. There is no cure for the disease, but there are treatment options, including physical therapy and bracing. Life expectancy is usually normal.

CMT disease can be divided into two classes, depending on where the dysfunction occurs in the peripheral nerves. In CMT type 1, the peripheral nerves' axons-the part of the nerve cell that transmits electrical signals to the muscles-lose their protective outer coverings, their myelin sheaths. This disrupts the axons' function. In CMT type 2, the axons' responses are diminished due to a defect within the axons themselves.

CMT type 2, the less common of the two classes, can be further separated into at least six subtypes, caused by defects in different genes. The GARS gene is implicated in CMT type 2D, a form of CMT that primarily affects the hands and the forearms. CMT type 2D is inherited in an autosomal dominant fashion.

Spinal muscular atrophy (SMA) refers to a group of genetic diseases more diverse than those of CMT. SMA is characterized by weakness and wasting of the muscles of the limbs, but the types vary greatly in severity. Most common are autosomal recessive childhood-onset forms that may be fatal. Other types of SMA are inherited in an autosomal dominant fashion. All types of SMA are due to the degeneration of nerve cells within the spinal cord, as opposed to degeneration of the peripheral nerves.

Distal spinal muscular atrophy (dSMA) disease is a type of SMA that affects the hands and the feet. The GARS gene is implicated in dSMA type V. Its symptoms of muscle weakness and atrophy in the hands and the forearms mirror those of CMT type 2D, except that people with dSMA type V do not experience sensory loss. dSMA type V is also an autosomal dominant genetic disorder, like CMT type 2D.

Even though the GARS gene is implicated in only two specific types of CMT and SMA, this discovery will guide researchers in studying other forms of these diseases, as well as other neurological disorders. Because carpal tunnel syndrome affects the hands and the forearms, scientists may now investigate whether the GARS gene plays some role in this disorder. And two defective forms of the gene implicated in Lou Gehrig's disease are known to interact with a GARS family member.

Ultimately, the GARS gene and its family may provide a rich new resource for scientists investigating inherited and non-inherited neurological diseases.

"The next step is to explore what it is about motor nerve cells that make them particularly vulnerable to mutations in these genes," said Dr. Fischbeck.

NHGRI is one of the 27 institutes and centers at the National Institutes of Health, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site: www.genome.gov.

Contact:
Geoff Spencer
NHGRI
(301) 402-0911

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Last Updated: November 27, 2010