Researchers Find Gene Mutation That Causes Hyperparathyroidism-Jaw Tumor Syndrome

Mutations occur in a gene called HRPT2, which resides on the long arm of chromosome one, according to the researchers who published their findings in the Nov. 18 issue of Nature Genetics online.

"We are delighted that the more than 12-year search for this gene has borne fruit," said Maurine R. Hobbs, Ph.D., assistant research professor of internal medicine and human genetics at the University of Utah School of Medicine, researcher at the University's Huntsman Cancer Institute, and a senior author of the study. "We couldn't have done it without the help of many doctors and the selfless contributions of the patients and their families."

When it functions normally, HRPT2 encodes a protein, parafibromin, that suppresses tumor growth. But in HPT-JT, the gene's DNA sequence gets jumbled, causing the cell to put in the wrong amino acids or stop the manufacture of parafibromin prematurely. This prevents the protein from functioning properly in the cell.

Symptoms of the syndrome are nondescript, such as tiredness and depression. People usually learn they have the condition when a blood test shows their calcium level is too high. The excess calcium is a result of a parathyroid adenoma, a benign tumor in one of the four pea-size parathyroid glands lying near the thyroid gland. The adenoma puts out excess parathyroid hormone, a signal to the body that it needs to raise the calcium level. In response to this signal, the bones give up calcium that is released into the blood.

In HPT-JT families, children have a 50 percent chance of inheriting the syndrome from an affected parent. Of those who inherit the syndrome, 85 to 90 percent develop the benign tumors, and 10 to 12 percent of these may eventually develop parathyroid cancer, according to the researchers.

People with mutations within HPT-JT families can screen for developing thyroid tumors by getting their calcium and parathyroid hormone levels checked regularly.

"We hope that early detection and surgical removal of benign tumors will reduce the incidence of parathyroid cancer in these families," Hobbs said.

HPT-JT was identified in the late 1950s by Dr. Charles E. Jackson, and he and the Utah team began looking for the gene that causes it in 1993, under the direction of Dr. Hunter Heath III. In 1999, international research groups led by Drs. Raj Thakker, Catharina Larsson, Bin Teh, Hans Morreau, and Stephen Marx, joined with Hobbs and Drs. Jeff Trent and John Carpten at the National Institutes of Health (NIH), where Carpten, lead author, and his colleagues eventually identified mutations in the gene.

People and families with the mutation can find out if they have the syndrome by getting their calcium screened.

Ultimately, Hobbs and the other researchers hope the discovery of this new tumor gene will lead to a better understanding of the mechanisms that cause hyperparathyroidism and the initiation and progression of other tumors.

More than 40 researchers took part in the study.

Organizations involved include: the University of Utah; the NIH; Karolinska Hospital, Sweden; National Institute of Diabetes and Digestive and Kidney Diseases, Maryland; University of Oxford, England; Van Andel Research Institute, Michigan; Leiden University Medical Center; The Netherlands; Princess Alexandra Hospital, Australia; Eli Lily Company, Indiana; Royal North Shore Hospital, Australia; Henry Ford Hospital, Michigan; Instituto Portugues do Oncologica de Francisco Gentil, Portugal; Kings College School of Medicine and Dentistry, England; Mount Sinai, Canada; University Hospital, Sweden; Royal Devon and Exeter Hospital, England; St. Bartholomew's Hospital, England.