UR Researcher Uncovers How Defective Gene May Lead to Lethal, Agonizing Child Disease
Results in May Issue of Nature Genetics
April 29, 1999
The way a genetic defect likely gives rise to a lethal disease that strikes young children has been found by a researcher at the Children’s Hospital at Strong of the University of Rochester. The finding, in today’s issue of Nature Genetics, is the first to successfully incorporate new genetic technology called "microarrays" with basic biochemistry to determine the cause of an inherited disease. The disease strikes apparently healthy four and five year-olds, blinds them by age seven, and degrades all their mental functions including speech until their death between ages 15-20. Researchers estimate that 7,000 children suffer from this disease, called Batten’s disease, in the U.S. alone.
An estimated 440,000 people are carriers of the gene that causes Batten’s disease. A carrier is a person who has inherited one copy of a defective gene from one parent, and a healthy copy of the same gene from the other. The gene from the healthy parent overrides the defective one, and the carrier does not come down with the disease. If, however, two carriers have a child, the child has a 25 percent chance of inheriting only the defective genes from both parents. Without an overriding healthy gene, the child is born with Batten’s disease.
David A. Pearce, Ph.D., lead researcher of the study, has found how the same defective gene that causes the disease in human cells, behaves in yeast cells. Many of the genes found in human DNA have similar counterparts in cells of other organisms like yeast. Pearce found that a yeast cell protein that exactly matches a certain human cell protein malfunctioned in yeast cells with the defective gene. Without this protein functioning properly, the yeast cell was unable to maintain proper levels of acidity in its lysosomes, tiny sacs that contain digestive enzymes to recycle the cell’s waste. The loss of the recycling lysosomes may allow for a potentially lethal build-up of waste material – the same condition found in children who have died of Batten’s disease.
This study is the first in which microarrays, tiny chips capable of analyzing thousands of genes at once, have been used by biochemists to help them chart how certain defective genes change a cell’s behavior and cause disease. Pearce used microarray technology at Stanford University to determine which genes in a yeast cell with Batten’s disease were expressed differently, and then looked to see how that cell functioned differently than a regular yeast cell.
"Parents usually have no idea that their child has this genetic defect," says Pearce. "It’s usually spotted when their child is having vision problems at age four and an optometrist can’t find anything specifically wrong. The child loses balance, the ability to walk, and even starts forgetting words. It’s not until a genetic test for Batten’s is performed that they really know what’s wrong with their child."
There is no cure or effective treatment for children with Batten’s disease. Though the gene that causes the disease has been known for years, doctors have not been able to create any kind of gene therapy because of the location and nature of the malfunctioning protein.
"Though gene therapy doesn’t seem like it will be the cure for Batten’s, now that we know the process by which the defective gene most likely causes the disease, we can concentrate on finding some way to interrupt that process," says Pearce.