UF Researchers Identify Gene Flaw Linked To Disfiguring Tumors

July 1, 1996

GAINESVILLE—By tackling one of the most difficult genes to analyze, researchers have pinpointed a genetic flaw involved in the development of skin tumors associated with a disfiguring disease of the nervous system.

UF geneticists described the discovery Sunday (June 30) at a meeting of the Federation of American Societies for Experimental Biology in Snowmass, Colo. They said the culprit abnormal gene is a potential target for future drug therapies against the disease, called neurofibromatosis type 1 (NF1).

About 100,000 Americans have this form of neurofibromatosis, often mistakenly called Elephant Man’s disease. Type 1 is the most common form of the disease, occurring in an estimated one in every 3,000 births. Besides tumors, or neurofibromas, which in some affected people are not noticeable, the disease also is characterized by brown skin splotches called cafe au lait spots.

“This is the first identification of the mechanism at work in the formation of benign (non-cancerous) tumors that often grow on the skin of people with neurofibromatosis,” said Margaret Wallace, a pediatric geneticist at the UF College of Medicine, who with post-doctoral fellow Steven Colman, detected the gene defect.

They earlier reported their finding in the September issue of the British scientific journal, Nature Genetics.

Although benign tumors are non-cancerous, they can kill if they develop in vital areas of the body. UF researchers say the newfound gene impairment may be one of the earliest in a cascade of events leading to the formation of benign and malignant NF1 tumors.

Scientists have known for several years that it took crippling mutations of both NF1 gene copies, found on the 17th chromosome, for malignant NF1 tumors to develop. (A chromosome is a collection of genes.) Until this study, it was unclear whether the same rule applied to benign tumors.

A person normally has 23 matching pairs of chromosomes — one copy from each parent — in the nucleus of every cell in the body. One of the inherited traits governed by chromosome 17 is the growth rate of certain cells that, when gone awry, causes NF1.

Scientists’ analysis of the NF1 gene has been difficult because of its large size, its variety of mutations, and the diversity of cell types found in NF1 tumors.

To study the supposedly normal gene copy in benign NF1 tumors, the Florida researchers isolated DNA from 22 skin tumors of five patients.

Using sophisticated genetic techniques, the researchers found that, in at least eight of the tumors, both NF1 gene copies appeared to harbor harmful mutations. The researchers identified the telltale mutation on the supposedly healthy gene copy — a piece of it was missing.

Wallace said it is likely that some or all of the other NF1 tumors they analyzed also had gene deletions or other mutations that escaped detection “because they were too small or subtle to be detected by the conservative technique we used.”

“The University of Florida study is the first report that implicates inactivation of both NF1 gene copies in benign tumor development,” said neurogeneticist Judy Small, health scientist administrator at the National Institute of Neurological Disorders and Stroke. “It shows that complete lack of the protein coded for this gene contributes to the development of neurofibromatosis tumors. Scientifically, this provides a target for developing potential therapies to replace the function of this protein and reverse or halt the course of tumor development.”