Researchers at the National Institute of Environmental Health Sciences have filled in a last bit of evidence showing how and why an inherited, degenerative disease generally gets worse with time.

The researchers reported in the Journal of Biological Chemistry that they have demonstrated in the laboratory for the first time that in the replication of a subset of genes (the mitochondrial genes) a damaged enzyme makes errors ten-fold to 100-fold more frequently than in healthy individuals.

The researchers compared what happens to a typewriter with a slightly damaged key: "This enzyme frequently makes mistakes while copying the mitochondrial genes, and the accumulation of the mistakes causes the muscle weakness to progress," according to one of the researchers.

This is the first time that such a damaged enzyme -- a DNA synthesis enzyme -- has been shown to play a role in a degenerative disease, in this case a condition called progressive external ophthalmoplegia.

The scientists said that their work applies specifically to this rare affliction in which the eye muscles deteriorate and the patient must move his head, rather than his eyes, to follow an object. However, they said, the principle of repeated, copying errors applies to other mitochondrial degenerative conditions as well, including aging itself.

The answer to the riddle of why degenerative diseases progress with time, the involved muscles getting progressively weaker, has been long in coming: Nearly 40 years ago, a patient with such a disease was found to have abnormal mitochondria, the main energy-producing component of the cells in the body. Mitochondria play an important role in the proper functioning of energy-hungry organs like the eyes, kidneys and heart and brain.

They act semi-independently from the rest of the cell, and they contain a set of 37 specialized genes on a tiny chromosome. Mutations in any of the mitochondrial genes can cause a cellular energy deficit, the first symptoms of which is often the muscular degeneration known as progressive external ophthalmoplegia. Recently, this disease was linked to a mutation (called Y955C) in one of the cell's genes that produces the enzyme (DNA polymerase gamma) that is responsible for replicating mitochondrial DNA.

In their report, the NIEHS researchers describe the first laboratory evidence that this faulty enzyme causes the ophthalmoplegia, or paralysis of the eye, by causing changes in the mitochondrial genes. The scientists said that this is also the first time that such a damaged enzyme has been shown to play a role in a degenerative disease.

Reporting the work are Mikhail V. Ponamarev, Ph. D., Matthew J. Longley, Ph.D., Dinh Nguyen, Thomas A. Kunkel, Ph.D., and William C. Copeland, Ph.D. Dr. Kunkel leads the DNA Replication Fidelity Section at NIEHS while Dr. Copeland leads the Mitochondrial Replication Section in the Laboratory of Molecular Genetics. Dr. Copeland's group was the first to clone the DNA that encodes polymerase gamma in 1996.