Gene Discovery Opens Door to Further Research In Inherited Neurological Disorders|
Charcot-Marie-Tooth and Distal Spinal Muscular Atrophy Gene
May Shed Light on Carpel Tunnel Syndrome and Lou Gehrig's Disease
Bethesda, Maryland 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 carpel 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
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 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
"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
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.
Persons 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
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 carpel 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
"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.