Background Information on MEN1

What is multiple endocrine neoplasia type 1 (MEN1)?

MEN1 is a gene that, when altered, is responsible for familial multiple endocrine neoplasia type 1--a rare inherited disorder leading to tumors in the glands that produce the body's hormones. Affected individuals develop varying combinations of tumors of parathyroids, pancreatic islets, duodenal endocrine cells, and the anterior pituitary. Researchers believe the MEN1 gene's normal function is to suppress tumor growth.

The gene's structure, and the protein it produces, are unlike any other gene or protein currently identified. Scientists hope the gene's structure will reveal a new way in which the body controls the proliferation of cells culminating in cancer.

Researchers also suspect MEN1 plays an important role in sporadic endocrine tumors that appear to be fairly common, such as parathyroid tumors, which are estimated to occur in one in every thousand postmenopausal women.

Researchers around the world have searched for the gene since its location was pinpointed on the long arm of chromosome 11 nearly a decade ago.

Scientists at the National Institutes of Health (NIH) led a collaborative effort that identified the gene. The results are being published in the April 18 issue of the journal Science.

How does MEN1 affect patients?

The hallmark of multiple endocrine neoplasia is tumors of endocrine glands. The endocrine glands secrete hormones into the bloodstream, carrying chemical messages throughout the body. These hormones control growth, timing of reproduction, and the composition of blood and other body fluids. There are two main types of multiple endocrine neoplasia, type 1 and type 2. Type 2 was traced to an oncogene on chromosome 10 and appears unrelated to type 1.

The location and seriousness of endocrine tumors in MEN1 is varied, although most are benign. Tumors are nearly always present in one or more of the parathyroid glands, which control levels of calcium in the blood. They are also often found in the anterior pituitary gland and the islet cells of the pancreas. The anterior pituitary produces growth hormone, prolactin, thyroid-stimulating hormone, and hormones that govern the ovaries, testes and adrenal gland. The pancreatic islets secrete insulin and glucagon, which control blood sugar and gastrin, which controls stomach acid secretion.

The disease called Zollinger-Ellison syndrome occurs in MEN1 patients when gastrin-secreting tumors form in the pancreas or duodenum. Before the recent development of effective acid-blocking drugs, gastrinomas caused severe, even fatal, bleeding ulcers. Tumors can also be present elsewhere, such as in the adrenal glands, as fatty tumors under the skin called lipomas, and as neuroendocrine tumors called lung carcinoids.

MEN1 is sometimes called Wermer's syndrome, after the physician who first described it in 1954 as a specific familial syndrome inherited as an autosomal dominant.

Though usually not life-threatening, MEN1 does require medication or specialized surgery to remove the tumors and continued medical monitoring. The incidence of familial MEN1 is unknown, but is estimated between 1 in 10,000 to 1 in 100,000. Sporadic parathyroid tumors are far more common, estimated at one in a thousand post-menopausal women.

How does the MEN1 gene cause tumors?

Individuals with the inherited form of the disorder receive an altered gene from one parent, which effectively destroys its function. For a while they develop no health problems because they still have a normal copy of the gene from the other parent. Then, apparently on a random basis, certain body cells acquire a second "hit" that knocks out the normal copy, which triggers overt neoplasia in those cells. The delayed appearance of MEN1 until the 20s or later may reflect the time it takes to acquire those mutations in the normal gene. Scientists speculate that in sporadic tumors both normal copies of the gene become mutated, leading to tumor formation.

How was the MEN1 gene discovered?

Identification of MEN1 is an example of positional cloning. Using positional cloning, scientists are able to identify a gene--even though they are unaware of its function--so long as they know its approximate location. To date, more than 75 disease genes have been identified using positional cloning.

The final phase of the search for MEN1 began in 1994 when Drs. Francis Collins and Settara C. Chandrasekharappa, experts in physical mapping and positional cloning, began collaborating with NIDDK's Drs. Stephen Marx and Allen Spiegel, who had been studying the disease for decades, in an attempt to find the responsible gene.

In 1988, researchers at the Karolinska Institute in Stockholm traced MEN1 to the long arm of chromosome 11, and Marx had confirmed the location the following year. Research groups around the world searched for the gene fruitlessly for several years thereafter. NIH researchers undertook a painstaking examination of DNA samples from several MEN1 families collected by NIDDK, and in 1994 began putting together a detailed physical map of the region that consisted of overlapping DNA fragments systematically assembled in their correct order. They carefully eliminated nearly a dozen candidate genes in the region, aided by scientists at the National Cancer Institute who helped narrow the candidate interval by elegant microdissection of tumors.

After targeted DNA sequencing by scientists at the University of Oklahoma, Dr. Marx and colleagues were able to locate one gene--the 12th they examined--that contained mutations only in affected family members. The Science paper reports that the researchers were able to identify 12 different mutations in 14 of the 15 families studied. The National Center for Biotechnology Information at the National Library of Medicine analyzed sequence data and found that the MEN1 protein product, menin, resembles no other protein in its databases.

How will identification of the gene help patients?

The ability to test directly for MEN1 will relieve the minds of those members of familial MEN type 1 families who haven't inherited an abnormal MEN1 gene and therefore run no special risk of developing endocrine tumors. For those who do possess an abnormal gene, focused screenings can be done in an effort to prevent some of the serious consequences of the disease. Having the gene and its protein in hand may lead to new drugs and other strategies for dealing with both MEN1 and sporadic endocrine tumors and, the researchers hope, perhaps tumors in other organs as well.

Researchers at the NIH have already launched the next phase of their research into this novel gene and its apparently unique protein; they are investigating whether altered MEN1 genes are found in sporadic endocrine tumors and other tumors as well. In addition, researchers hope to learn the gene's precise function by studying where it is located in cells and with what genes it interacts. They are also making knockout mice lacking MEN1 function, in an attempt to create a mouse model of the disease that will speed clinical studies.