Reporting in the January 2002 issue of the American Journal of Human Genetics, investigators at Washington University School of Medicine in St. Louis describe a small, molecular variation in some tumor samples taken from neurofibromatosis patients.
Neurofibromatosis is a common, inherited genetic disease that affects about one in 3,500 people, says principal investigator Nicholas O. Davidson, M.D., professor of medicine and of molecular biology and pharmacology and director of the Division of Gastroenterology at Washington University School of Medicine. The gene responsible spans a large region of chromosome 17, but we have found that a very small change in the NF genes messenger RNA can inactivate the final product of this gene, a protein called neurofibromin.
Neurofibromin suppresses tumor development. When it is inactivated, its tumor-suppressing ability is lost, and patients with NF develop a wide variety of tumors. Approximately 25 percent of tumors studied had evidence of a single nucleotide RNA change called RNA editing that occurs when messenger RNA is edited before leaving the nucleus of the cell. Cells that did have the change, however, seemed to be more aggressive tumors, and a substantial percentage was malignant.
Since patients inherit two copies of the NF gene, most researchers believe in a two hit mechanism that launches neurofibromatosis. The first hit comes when a person is born with one copy of the gene already mutated to cause the disease, but that person would actually develop clinical manifestations of NF only after the second copy of the gene was hit. The faulty RNA editing seen by Davidson could provide that second hit.