UConn Health

July 27, 2011 | Christopher DeFrancesco '95 (CLAS) - UConn Health

Greenstein Among Contributors to Genetic Discovery Published in New England Journal of Medicine

Researchers studying the rare disorder Proteus syndrome say they’ve answered an important question about the genetic mutation that causes it, potentially opening a path that could lead to a better understanding of cancer. The research, led by the National Human Genome Research Institute, had contributors throughout the world, including Dr. Robert Greenstein from the UConn […]

Dr. Robert Greenstein
Dr. Robert Greenstein is part of an international team of researchers who have identified a gene variant in Proteus syndrome that could have implications for cancer. (Janine Gelineau/UConn Health Center)

Researchers studying the rare disorder Proteus syndrome say they’ve answered an important question about the genetic mutation that causes it, potentially opening a path that could lead to a better understanding of cancer.

The research, led by the National Human Genome Research Institute, had contributors throughout the world, including Dr. Robert Greenstein from the UConn Health Center Departments of Genetics and Developmental Biology and Pediatrics and its Division of Human Genetics. It will be published in the New England Journal of Medicine and is now available online.

The scientists found that a point mutation—a single-letter misspelling in the DNA of the genetic code—in a particular gene activates the sporadic tissue growth characteristic of Proteus syndrome, which causes deformities by affecting how cells regulate their own growth. The irregular overgrowth gets worse with age and increases susceptibility to tumors.

“This genetic change is different than the type that causes breast or colon cancer,” Greenstein says. “In Proteus syndrome the mutation (changed gene) occurs after conception, leaving some fetal cells with defective cell growth and others as normal, a so-called mosaic pattern.”

Fewer than 500 people in the developed world are known to suffer from Proteus syndrome, and it took nearly five years to gather the data from patients.

“The question being raised was, in how many cells does the mutation have to be present before the disease shows up,” Greenstein says. “Through cooperative, inter-institutional research, we were able to prove, for the first time, that this indeed is a mosaic disorder, which means the gene variant occurs in only a subset of the body’s cells.”

The mutated gene, known as AKT1, is an oncogene, meaning that it can promote the kind of uncontrolled cell growth associated with cancer. The variant of AKT1 that causes Proteus syndrome is part of a cascade of mutations that also promotes metastasis, the process by which cancer cells spread to healthy parts of the body. AKT1 mutations have been detected in about 2 percent of cancer samples.

In the cancer field, there are a number of potential therapeutics being developed to inhibit the pathway involving this gene, some of them by inhibiting AKT1 itself.