Wednesday, April 7, 2004

Duke Geneticists Find Basis For Nerve Disorder
By Mike Upchurch

Duke geneticists, along with international colleagues, continue to find the genetic roots for some of mankind’s most intractable diseases. Dr. Jeffery Vance of the Duke Center for Human Genetics and a team of fellow researchers have found a new genetic basis for one of the most common inherited neurological diseases.

The team, which published their results in the April 4 issue of Nature Genetics, found that a gene controlling mitochondria, the power supply of cells, is responsible for a form of Charcot-Marie-Tooth (CMT) disease. Their discovery could open new research avenues and possibly gene therapy for this debilitating illness.

Jeffery M. Vance, MD (courtesy DUMC)

CMT affects approximately 150,000 Americans and is characterized by gradual weakening of the extremities. Many CMT sufferers rely on leg and arm braces or may be dependent on a wheelchair. There is no known cure and treatment is often limited to physical therapy and limiting movement.

This latest study points to a genetic cause of CMT type 2A. Dr. Vance and his team found a mutation in the genetic sequence that controls how mitochondria fuse, an essential step in supplying the energy needed by nerves to communicate with muscles. This particularly mutation affects mitofusin 2, a gene critical to mitochondrial movement.

"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 lead author Dr. Stephan Züchner, who works at both Duke and the University Hospital of Aachen in Germany. "Mitofusin 2 is critical to that process."

There are 2 chief types of CMT. Type 1 erodes myelin, the protective sheath of tissue around the axon of a nerve cell, which is a cable-like structure stretching from the cell to the muscle it controls. Without this insulating myelin, nerve impulses slow.

Type 2 CMT weakens the axon itself and communication between nerves and muscle tissue is weakened. The result of both types of the disease is too little muscle stimulation and the muscles wither.

Previous research at Duke had narrowed the culprit for CMT type 2A to a part of chromosome 1. But at the time, the genetic map for this chromosome was not complete and further delineation wasn’t possible. The current study, capitalizing on advances in the mapping the human genome, sequenced that area in 7 families with known CMT type 2A.

In all 7 families, members with CMT type 2A showed mutations in mitofusin 2, while those without the disease did not. Healthy non-family members serving as control subjects also did not show this mutation. The research team then analyzed data from 36 families identified in other research as having CMT type 2A. Twenty percent of these patients had the same mutation.

"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," said Vance. "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 [nerve disorders] in general."

Other scientists have successfully “repaired” mice that were bred to have non-functioning mitofusin 2 genes by inserting a working copy. Dr. Vance and his team hope that this will lead to a gene therapy for human sufferers of CMT type 2A.

In addition to Drs. Vance and Züchner, researchers from Russia, Italy, Turkey, Belgium, and Japan participated in the study.