Single Amino Acid Substitution Enlarges Heart

Researchers have found that a mutation in the gene that codes for phospholamban, a transmembrane phosphoprotein, causes dilated cardiomyopathy, a disorder that results in the heart becoming enlarged to the point where it can no longer pump blood efficiently. This finding was published in the February 28, 2003, issue of Science.

Armed with the knowledge that a single amino acid substitution in phospholamban typified a group of patients with inherited dilated cardiomyopathy, researchers from Harvard Medical School (Boston, MA, USA) genetically engineered a line of mice that expressed the same mutation.

"Substituting only one amino acid in phospholamban produced profound changes in cardiac function, causing a premature death of the mice with evidence of heart failure that recapitulates what we saw in our human families,” said senior author Dr. Christine E. Seidman, a professor at Harvard Medical School.

The heart muscle is signaled to contract and relax by a mechanism in which calcium is released from the sarcoplasmic reticulum into the myocytes and then rapidly pumped back into the sarcoplasmic reticulum. Phospholamban is a key regulatory molecule in the calcium reuptake pump.

"We believe these findings point to defects in this recycling of calcium that do not allow the myocyte to fully relax. These can lead to profoundly devastating consequences,” explained Dr. Seidman. "Before our work, it was thought that calcium dysregulation might be involved in dilated cardiomyopathy, but it was uncertain whether this was contributing to myocyte dysfunction (i.e., an inciting event) or a secondary consequence, and that is a big difference.”