Genes behaving badly result in CMT neurological disorder

Date: September 21, 2006

Bar Harbor--When we hear about a genetic disease, we usually understand it to mean that a genetic mutation has resulted in an important protein losing its function. The disease is a direct consequence of the protein not working. But it's not always that simple, and recent work by scientists led by Robert Burgess, Ph.D., of The Jackson Laboratory indicates that a particular Charcot-Marie-Tooth (CMT) disorder probably results from a protein behaving badly rather than not at all.

CMT disorders are the most common genetic diseases of the peripheral nervous system, afflicting about 1 in 2,500 people. There are many types of CMT and many gene defects involved, but they all affect the nerves that carry messages back and forth between the spinal cord and muscles, leading to loss of muscle function, particularly in the hands/arms and feet/legs. Sensory nerves are often lost as well, leading to numbness.

Burgess and his colleagues have discovered a mouse mutation that provides an excellent model for a human CMT known as type 2D. CMT type 2D is caused by a mutation in a specific gene called GARS. The GARS gene produces a protein that helps build other proteins by matching the right amino acid (the building blocks that make up proteins) with the right genetic code. The mice that get the disease have a specific mutation in the gene and therefore make an abnormal GARS protein, but surprisingly the abnormal protein still does its job as expected and protein synthesis is not affected. Furthermore, in a different mouse model, if the GARS levels are reduced without actually making an abnormal GARS protein, there is no disease in the peripheral nervous system.

“Therefore, to get CMT type 2D disease in the mice, we hypothesize that the mutant protein is playing a detrimental role in the peripheral neurons,” said Burgess. “Understanding exactly what the mutant protein does to harm the cells is critical to understanding the root cause of the disease.”

Such understanding of the CMT type 2D model also offers the possibility of yielding insight into other conditions that affect the peripheral nervous system. Significantly, CMT type 2D is in some ways analogous to amyotropic lateral sclerosis (ALS), which also does not appear to result from a non-functioning gene, but instead requires the expression of specific mutant protein.

The research was published in the September 21, 2006, edition of the journal Neuron. Drs. Kevin L. Seburn and Gregory A. Cox of The Jackson Laboratory and Leslie A. Nangle and Paul Schimmel of The Scripps Institute of La Jolla, Calif., collaborated with Dr. Burgess.

The Jackson Laboratory, founded in 1929, is the world's largest mammalian genetics research institution, with facilities in Bar Harbor, Maine, and West Sacramento, Calif. Its research staff of more than 450 investigates the genetic basis of cancers, heart disease, osteoporosis, Alzheimer's disease, glaucoma, diabetes, and many other human diseases and disorders. The Laboratory is also the world's source for nearly 3,000 strains of genetically defined mice, home of the Mouse Genome Database and many other publicly available information resources, and an international hub for scientific courses, conferences, training and education.

Contact(s): Mark Wanner, 207-288-6051, mark.wanner@jax.org

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