Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy

Background—Mutations in the -myosin heavy-chain (MyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of MyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in MyHC could also lead to pleiotropic cardiac phenotypes, including HCM and DCM. Methods and Results—A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to 69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families, was screened for MyHC gene (MYH6) mutations. Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L, A1004S, and E1457K; 4.3% of probands). A Q1065H mutation was detected in 1 of 21 HCM probands and was absent in 2 unaffected offspring. All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of MyHC, and were absent in at least 300 control chromosomes from an ethnically similar population. The DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure. Conclusions—This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM.