Genetic mutations involved in heart failure 20/3/03. By Penny Bailey Researchers have discovered how a single genetic mutation triggers heart failure by disrupting the flow of calcium in heart muscle cells.

Christine and Jonathan Seidman and colleagues (Howard Hughes Medical Institute) found that a mutation in the gene encoding a protein called phospholamban could cause dilated cardiomyopathy in humans. Dilated cardiomyopathy causes the heart to become enlarged to the point where it can no longer pump blood efficiently and often leads to heart failure and death before the age of 40.

In healthy hearts, the contracting and relaxing of heart muscle is regulated by a mechanism in which calcium is released from a reservoir into the muscle cell and then pumped back into the reservoir.

Phospholamban is a key regulatory molecule in the calcium re-uptake pump. The Seidmans and colleagues discovered that a group of people with inherited dilated cardiomyopathy showed a single mutation in the DNA sequence of the gene for phospholamban.

To explore whether this mutation could cause the disease Joachim Schmitt, a fellow in the Seidman lab, created a transgenic mouse with the phospholamban genetic defect. He found that substituting only one amino acid in phospholamban had a profound impact on cardiac function, causing the mice to die prematurely of heart failure.

Further studies using cell cultures and tissue from affected people revealed in detail how the abnormal phospholamban disrupts the calcium pump in human heart muscle cells by blocking the action of a key enzyme. This disruption leads to a chronic malfunction of calcium regulation in their heart muscle, which ultimately leads to heart failure.

Previously known inherited defects underlying dilated cardiomyopathy affected muscle proteins, but these latest findings by the Seidmans and colleagues point to the recycling of calcium as a second major mechanism.

This molecular analysis of the genetic cause of heart failure might lead to more targeted treatments for heart patients. Certainly, restoring normal calcium recycling processes in patients with the phospholamban defect could help prevent heart failure.

Links

Schmitt JP et. al. Dilated Cardiomyopathy and Heart Failure Caused by a Mutation in Phospholamban. Science 2003 299, 5611: 1410-13. Abstract