By David N. Leff

This week's gene-of-the-month discovery comes with two unique features:

One, the gene just identified is responsible for a disease called multiple endocrine neoplasia. Its tumors, for a change, are not malignant, not metastatic, not as a rule fatal.

Two, this gene, and the protein it encodes, have nucleic acid and amino acid sequences, respectively, which appear to be matchless.

"If you troll through the entire data base," said endocrinologist Allen Spiegel, "at least up to the moment, there is no resemblance to any known gene, no clue to this gene's structure or function. There's clearly a mouse homologue, which we have in hand, that is very highly conserved at the amino-acid level."

Spiegel directs intermural research in the Metabolic Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, at the National Institutes of Health, in Bethesda, Md.

He is co-author of a paper in this week's issue of Science, dated April 18, 1997, titled "Positional cloning of the gene for multiple endocrine neoplasia-type 1."

This inherited hormonal disease, which is neither rare nor common, causes tumors in three of the body's main chemical signaling centers -- the Islets of Langerhans in the pancreas, and the parathyroid and pituitary glands.

"MEN1 is an autosomal, dominantly inherited disease," Spiegel told BioWorld Today, "in which one affected parent passes the disease to an average 50 percent of its offspring. Normally, these don't show clinical symptoms until in their 20s, at the earliest; typically in the third decade of life."

Disease Crosses All Population Groups

Estimates of MEN1 incidence in the U.S. range from one in 10,000 to one in 100,000. "The disease is worldwide," Spiegel said. "It affects individuals in every ethnic group -- Japanese, black, Caucasian -- and every geographical area."

Because the parathyroid glands, located in the neck, honcho the body's calcium balance. "The first overt sign of an MEN1 tumor there," Spiegel observed, "is a kidney stone."

In the anterior pituitary, at the base of the brain, the disease may show up in two ways: "Benign tumors," he observed, "can cause visual disturbances based on their mass -- impinging on the optic chiasm," where the optic nerves cross. And their over-production of growth hormone could lead to acromegaly -- gigantism.

When MEN1 strikes the pancreatic Islets, the resulting insulinomas churn out too much insulin, causing hypoglycemia.

But those Islet tumors, initially benign, Spiegel pointed out, "can become malignant, metastasize to the liver, and can cause lethality."

At the non-malignant extreme, MEN1 sometimes also produces lipomas -- fatty tumors under the skin.

"Right now," Spiegel pointed out, "the therapy for most of these manifestations is surgical. In Islet cell tumors, it can block insulinomas. But such surgery per se is rarely effective because of the diffuse nature of the tumors in the pancreas. In the parathyroid and pituitary glands," he continued, "treatment is principally surgical, but problematic."

Because most MEN1 tumors are not malignant, Spiegel observed, "they're not typically showing up as tumor-mass effects, but as hormonal effects. And these are a function of when there is sufficient hormonal secretion to cause clinical problems, as in peptic ulcers due to Islet involvement."

The Science article lists 23 co-authors in five research centers, involved in discovering the MEN1 gene. Historically, the project began two decades ago, when Spiegel and his co-worker, Stephen Marx, began treating and studying parathyroid patients who had failed surgery.

In recent years, they enlisted colleagues at the National Human Research Institute, the National Cancer Institute, the National Center for Biotechnology Information and the University of Oklahoma to join forces in isolating the MEN1 gene, already known to be hiding somewhere on the long arm of human chromosome 15.

From linkage analysis of MEN1-affected members in 15 families, followed by positional cloning, direct DNA sequencing, dideoxy fingerprinting and DNA extraction from tumors, they ultimately tracked down the gene in January of this year.

This feat recalls the familial breast cancer gene found in 1994, now testable in high-risk individuals. How will the now-known MEN1 gene affect patient practice?

"From a purely clinical point of view," Spiegel foresees, "unencumbered by all the ethical, legal and social implications in all the other gene-discovery situations, now one can determine at a very early stage the 50 percent of individuals who have not inherited the 'bad' MEN1 gene. This will relieve them and their families of the psychological burden."

He continued: "There is likely to be some value in terms of being able to pick up these tumors earlier on. On the other hand, there's no real prophylactic treatment that we know of that can be done."

R & D Opportunities For Industry

He added, "This of course is an opportunity for biotech companies. Obviously, patents have been applied for, and the issue here will be licensing and getting appropriate testing, if that turns out to be a commercially viable and necessary thing. We may be looking for CRADA [Cooperative Research and Development Agreement] partners or other interactions."

He and his co-authors propose that MEN1 is a tumor suppressor gene, which when mutated encodes a loss-of-function protein.

To explain why it takes the inherited disease decades to declare itself, Spiegel invokes, speculatively, "the classic second-hit hypothesis. That is," he explained, "the tumor suppressor gene has one copy mutated in the germ line, and lost function.

"Then the second, sporadic, hit will be somatic, acquired at some point in life, presumably from an environmental mutagen. The notion is that the time to acquire that second hit, and for that to lead to an overt tumor, is the time needed for clinical onset."

Spiegel concluded: "We feel it's likely that this gene will be involved in the pathogenesis of many, many more common tumors." *