Genetic Basis of Hereditary Nerve Disorder Revealed
DURHAM, N.C. -- A major form of one of the most prevalent inherited neurological disorders in humans, Charcot-Marie-Tooth disease (CMT), stems from an abnormality in the cellular powerhouses, or mitochondria, that fuel the nerves required for muscle control, suggests new findings by neurogeneticists at the Duke Center for Human Genetics and their international colleagues. The unexpected discovery could open new research pathways to understanding an array of diseases of the peripheral nervous system, as well as treatments for CMT, the researchers said.
In seven families with a form of the degenerative nerve disorder CMT type 2A, the team discovered that defects in a gene critical to mitochondrial movement, known as mitofusin 2, underlies the disease symptoms. Restoring the lost gene function through gene therapy might ultimately serve as an effective treatment for the disorder, which currently has no cure, the researchers reported in the April 4, 2004, issue of Nature Genetics.
CMT affects people of all races, including 150,000 Americans. Hallmarks of CMT include weakening of the feet and hands that gradually extends to the legs and arms. The only treatments now available to patients with the disease include physical therapy and moderate activity to maintain muscle strength. Patients often rely on leg braces and, in some cases, become wheelchair-dependent.
While defects in multiple genes are known to underlie various forms of CMT, the current finding uncovers a whole new mechanism of action that can cause disease by damaging mitochondria, said lead author of the study Stephan Züchner, M.D., of the Duke Center for Human Genetics and the department of neuropathology at the University Hospital Aachen in Germany.
"Mitochondria must link into constantly shifting networks through fusion and fission in order to provide the energy required for neurons to fire and stimulate muscles to move," said Züchner. "Mitofusin 2 is critical to that process."
Two primary forms of CMT are recognized. CMT type 2 is characterized by a breakdown in the nerve axon -- the cable-like extension of the neuron from the cell body in the spinal cord to the juncture, or synapse, between the nerve and the muscle it controls. In contrast, the demyelinating form of the disease, CMT type 1, results from degradation of the insulation, called myelin, which covers the nerve axon. Without the protective myelin, the speed of the nerve impulse slows. In both types of CMT, muscles atrophy due to a lack of stimulation from the nerves.
"Our results indicate that mitofusin 2 is a major gene underlying CMT type 2A, and probably one of the major genes that cause all hereditary forms of the axonal neuropathy, CMT type 2," added senior author Jeffery Vance, M.D., associate director of the Center for Human Genetics and professor of medicine at Duke. "This marks the first time that mitochondrial fusion has been implicated in a human disease and opens up a whole new area of exploration for the basis of peripheral neuropathies in general."
Several years ago researchers at the Duke Center for Human Genetics led by Vance linked the gene responsible for CMT type 2A to chromosome 1. However, Vance said, the small region of the human genome containing this gene proved difficult to study because the sequencing of chromosome 1 was incomplete at that time.
In the current study, the researchers narrowed the chromosomal segment to a single gene by sequencing that genetic region in seven families with CMT type 2A having diverse ethnic backgrounds. In each family, individuals with CMT showed mutations in the gene sequence encoding the mitochondrial fusion gene, while unaffected family members and healthy non-relatives did not, reported the researchers. Further analysis of a pre-existing set of 36 small families with CMT type 2 found that 20 percent of those also carried mutations in mitofusin 2.
Other investigators have found that mouse cells lacking a working copy of the mitofusin 2 gene can be "rescued" by re-inserting a normal gene copy, the investigators noted. The finding suggests that CMT symptoms might be alleviated with gene therapy in patients with the type 2A form, they added.
Other collaborators include J. Michael Schröder, of the University Hospital Aachen, along with researchers from Russia, Italy, Belgium, Turkey and Japan.