April 2, 2002
BETHESDA, MD (NIH) — Dental researchers have known for decades that some people are born with gums that grow abnormally over their teeth. What they have never known is why?
Now, in this month’s issue of the “American Journal of Human Genetics”, dental researchers have their first clue. An international team of scientists reports that it has identified the first gene that, when altered, triggers hereditary gingival fibromatosis, or HGF, the most common of these rare, inherited gum conditions.
Interestingly, the researchers note that the gene, called SOS1, encodes a protein that is known to activate the “ras” pathway, one of the key growth signals in our cells. The authors say this finding suggests that, when the SOS1 gene is “not” mutated, its protein and the “ras” pathway likely are involved in the normal growth of healthy gums, or gingiva, an idea that was previously unknown.
If confirmed, they say, learning how to turn on relevant portions of the pathway, like flipping a biological switch, might help dentists one day regenerate the gingiva naturally in people with receding gums or advanced periodontal disease. Conversely, by switching off the growth signal, dentists could prevent gingival overgrowth, meaning people with HGF might not need to have the excess tissue surgically cut away, now the standard treatment.
“This is yet another example of the importance of studying rare genetic diseases,” said Dr. Thomas Hart, lead author on the study and a scientist at the University of Pittsburgh School of Dental Medicine. “By identifying a gene involved in hereditary gingival fibromatosis, it was possible to uncover a key clue into normal gingival development, a clue that could have important implications for dentistry.”
Hart and his colleagues add that the discovery also could have important research implications for the gingival overgrowth that occurs in a number of human syndromes or as a side effect of certain frequently prescribed medications. These medications include: phenytoin for seizures, calcium channel blockers for hypertension, and cyclosporine for autoimmune diseases.
Researchers estimate that gingival overgrowth affects about 15 percent of people who use phenytoin, around 15 percent of those who take calcium channel blockers, and approximately 30 percent of people who use cyclosporine. For organ transplant patients who combine cyclosporine and nifedipine, about 40 percent have gingival overgrowth.
According to Hart, given the dearth of molecular information available on gingival overgrowth, HGF was a good place to start the search for clues. The condition was clearly genetic in origin, and, by the early 1990s, the tools were at hand to more efficiently track down inherited disease genes. What was lacking was a large family somewhere in the world with a long history of HGF, meaning many members of the family shared a gene mutation whose location in the human genome might be trackable.
In 1992, that family entered the picture when a woman walked into the University of Taubate dental clinic in Brazil to have her overgrown gingiva cut away from her teeth. Drs. Deborah Pallos and Jose Roberto Cortelli, after further consultation, correctly determined that the woman had HGF. Then, in close collaboration with Hart and his colleagues in the United States, the Brazilian scientists spent the next few years compiling an initial, 32-member family tree, recording each affected and unaffected member over three generations.
In 1998, after analyzing the DNA from many members of the family, the team reported that those affected shared an irregularity on the short arm of chromosome 2. But the researchers still didn’t know exactly where the irregularity was on the short arm. As Hart said, this was no trivial matter. The segment of the chromosome in question was found to contain 33 genes, any of which could be causing the gingival overgrowth, and they were spread out over nearly 5 million bases, or units, of DNA.
To hasten and narrow their search, the scientists contacted additional family members, collecting DNA samples and performing oral examinations on, in total, 83 family members spanning four generations. Meanwhile, Hart’s laboratory sequenced — or arranged in order — the five million bases in the region. By knowing the precise, highly repetitive order of the four possible bases, represented by the letters A, T, C, and G, the scientists hoped that, if needed, they would be able to detect even a single, one-letter typo in the sequence.
As reported in this month’s article, the group’s careful attention to detail paid off. Hart and colleagues found that the 38 family members with HGF shared a single one- letter change in the sequence of the previously mapped son of sevenless (SOS1) gene. Present in organisms on all rungs of the evolutionary ladder, the SOS1 protein complexes with other molecules in our cells to activate the “ras” signaling pathway, a much-studied topic in cancer research. This ancient biochemical signal, once activated and processed, can prompt our cells to grow, differentiate, or even commit suicide, tasks that are essential to life.
Hart said this single nucleotide change scrambled some of the genetic code required to produce a normal SOS1 protein. As a result, family members with HGF have shortened, abnormally shaped SOS1 proteins present in cells throughout their bodies, not just the gingiva. This raises the question of why this mutation would affect the gingiva only? Given the fundamental importance of the “ras” pathway to life, wouldn’t the change in the SOS1 protein lead to birth defects or an inherited susceptibility to tumors throughout the body?
However, according to Hart, family members with HGF do not seem to be susceptible to other developmental abnormalities or cancer. “This might speak to the developmental uniqueness of the gingiva, which clearly has a novel pattern of gene and protein expression. Or, it might speak to the redundancy of signaling systems in our cells as a whole. But we really don’t know, though biologically it is an extremely interesting lead that shows the power of genetic approaches in dental research.”
Hart’s study, which was supported by the NIH’s National Institute of Dental and Craniofacial Research, is being published in the April issue of the “American Journal of Human Genetics”. The paper is titled, “A mutation in the SOS1 gene causes hereditary gingival fibromatosis type I.” The authors are: Thomas C. Hart, Yingze Zhang, Michael C. Gorry, P. Suzanne Hart, Margaret Cooper, Mary L. Marazita, Jared M. Marks, Jose R Cortelli, and Deborah Pallos