Weill CU team finds gene that causes heart tumors and limb deformity

By Ernie Mundell

Like a clue in a medical detective novel, the discovery of a genetic mutation responsible for two rare disorders could have much wider implications for medicine as a whole, according to Dr. Craig Basson, the Weill Cornell Medical College researcher who led the study, the results of which are being reported today (July 29).

Basson

The mutation causes muscle protein dysfunction and is linked to both a crippling muscle condition and a type of rare heart tumor, Basson and his colleagues report in the latest issue of the New England Journal of Medicine. By fingering the one gene connecting these two diverse conditions, the researchers believe they have solved a longstanding medical mystery.

Even more intriguing, the mutation's connection to heart tumors hints at the existence of stem cells within the adult human heart -- cells doctors might someday use to repair failing cardiac muscle. Experts have hotly debated the very existence of these cells for decades.

"We've opened the door to a very exciting set of possibilities. Not only was the door closed before -- no one even knew the door was there," said Basson, who is director of cardiovascular research in the Greenberg Division of Cardiology, as well a professor of medicine and of cell and developmental biology at Weill Cornell.

The study focused on a rare form of a benign, but still quite dangerous, heart tumor called a myxoma, affecting about 1 in every 100,000 people. In what has been regarded as a medical puzzle, a subset of individuals with cardiac myxomas also are afflicted with a seemingly unrelated muscle disorder called trismus-pseudocamptodactyly syndrome, or TPC.

In TPC, which runs in families, infants are born with "a tightening of the muscles in the hands, feet and jaw," Basson explained. "None of these muscles move right. In the jaw they can't open the mouth fully; in the feet and in the hands, they can't bend fully."

Why do heart tumors and TPC appear so often in the same patients? To find out, Basson's team used high-tech gene analysis techniques to zero in on the genetic mutation responsible for both. "We found that there's a change in one particular amino acid in a gene for a muscle protein called perinatal myosin," Basson said.

The myosin proteins play key roles in the contraction-expansion dynamic that allows muscles to work the way they do. The genetic mutation responsible for TPC appears to undermine myosin's role in normal muscle growth in the developing fetus. Genetic mutations in other myosins cause abnormalities in skeletal muscles as well as a potentially lethal heart disorder, hypertrophic cardiomyopathy.

More puzzling, Basson said, was the question of how a mutation governing a muscle protein encourages heart tumors. "No one has ever suspected that changes in muscle myosin could be involved in tumor formation," he said. "It is possible that they promote survival of embryonic cells that are still able to divide within the adult heart."

It's this theory that has Basson and his colleagues most excited. "A debate has raged recently as to existence of stem cells in the heart," he explained. "If they are there, then in cardiac myxomas we may be seeing the survival of heart embryonic stem cells into adulthood, and these cells may carry this abnormal myosin into adult life."

This means that, besides identifying the genetic causes of two serious inherited conditions, the study could provide evidence of "cells competent to divide within the adult heart," Basson said.

"In heart myxomas, these cells are dividing to make a tumor, of course. But imagine if we could control that growth -- growing new heart cells. If there are already stem cells resident in the heart, and if you could manipulate those stem cells, you wouldn't have to give someone stem cells from elsewhere. And you wouldn't have to worry about transplanting stem cells into the patient's heart -- they're already there."

The study was funded by a grant from the National Institutes of Health. Study co-authors included Dr. Mark Veugelers, Michael Bressan and Deborah A. McDermott of Weill Cornell.