Dhandapany PS et al. RAF1 mutations in childhood-onset dilated cardiomyopathy. Nat Genet. 2014 Apr 28. doi: 10.1038/ng.2963. [Epub ahead of print]
Acting on the hypothesis that some of the genes involved in RASopathy-associated hypertrophic cardiomyopathy may also be implicated in isolated dilated cardiomyopathy, Dhandapany et al resequenced nine genes of the RAS-MAPK pathway in 513 patients with non-syndromic dilated cardiomyopathy and 1500 controls. The group identified missense mutations in RAF1 in 9% of patients with childhood-onset dilated cardiomyopathy. The functional significance of the mutations was confirmed in vitro and, for two representative mutations, in a zebrafish model.
Interestingly, the RAF1 mutations implicated in dilated cardiomyopathy were distinct from those known to cause RASopathy-associated hypertrophic cardiomyopathy. They also had distinct functional consequences: unlike RASopathy-associated mutations, they caused hyperactivation of AKT. As a result, the cardiac phenotype in zebrafish could be rescued with rapamycin (an AKT-mTOR inhibitor); it remains to be seen whether this observation could have therapeutic implications in humans.
Posted by Alina Levtova, MD