MYPN mutations affect medication effectiveness for children with restrictive cardiomyopathy
Particularly in children, restrictive cardiomyopathy (RCM) has the poorest prognosis among heart muscle diseases. The condition can lead to heart failure, arrhythmias and sudden cardiac death, with a five-year mortality rate exceeding 70 percent.
To date, no medications have proven effective against RCM, which has left heart transplantation as the sole definitive treatment option. Now, fresh clues for finding new therapeutic targets are emerging thanks to a study led by Enkhsaikhan Purevjav, MD, PhD, a former researcher with the Heart Institute at Cincinnati Children’s who recently moved to the University of Tennessee Health Science Center.
Purevjav and former research fellow Anne-Cecile Huby, PhD, report that mutations in the myopalladin (MYPN) gene cause diverse cardiomyopathic phenotypes within a critical “final common pathway.” These mutations could explain why ACE inhibitors, beta-blockers and angiotensin receptor blockers are ineffective in patients with RCM. Their findings were published Dec. 30, 2014, in the Journal of the American College of Cardiology.
The study involved developing “knock-in” mice to carry mutations of the murine Mypn gene that would be homologous to the human MYPN-Q529X mutation. At six weeks, signs of restrictive physiology (RP) were detected in the mice carrying the mutation. At 12 weeks, the mice showed signs of impaired diastolic filling of the left ventricle, decreased T-wave duration, and other RCM symptoms.
“From these data, we hypothesize that the RCM phenotype results from persistence of dysfunctional truncated MypnQ526X protein and consequent multiple pathological ‘hits,’“ Purevjav says.
MYPN is one of several genes that appear to be involved in RCM. These findings suggest that further studies on time-dependent expression changes in CARP, MLP, DES, and ERK1/2 proteins in patients with RCM may provide useful information for discovering diagnostic and therapeutic targets.
