BACKGROUND: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC 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 alphaMyHC 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 alphaMyHC, 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.
BACKGROUND: Mutations in the beta-myosin heavy-chain (betaMyHC) gene cause hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy. In failing human hearts, downregulation of alphaMyHC mRNA or protein has been correlated with systolic dysfunction. We hypothesized that mutations in alphaMyHC 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 alphaMyHC 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 alphaMyHC, 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.
Authors: Mark Eijgelsheim; Christopher Newton-Cheh; Nona Sotoodehnia; Paul I W de Bakker; Martina Müller; Alanna C Morrison; Albert V Smith; Aaron Isaacs; Serena Sanna; Marcus Dörr; Pau Navarro; Christian Fuchsberger; Ilja M Nolte; Eco J C de Geus; Karol Estrada; Shih-Jen Hwang; Joshua C Bis; Ina-Maria Rückert; Alvaro Alonso; Lenore J Launer; Jouke Jan Hottenga; Fernando Rivadeneira; Peter A Noseworthy; Kenneth M Rice; Siegfried Perz; Dan E Arking; Tim D Spector; Jan A Kors; Yurii S Aulchenko; Kirill V Tarasov; Georg Homuth; Sarah H Wild; Fabio Marroni; Christian Gieger; Carmilla M Licht; Ronald J Prineas; Albert Hofman; Jerome I Rotter; Andrew A Hicks; Florian Ernst; Samer S Najjar; Alan F Wright; Annette Peters; Ervin R Fox; Ben A Oostra; Heyo K Kroemer; David Couper; Henry Völzke; Harry Campbell; Thomas Meitinger; Manuela Uda; Jacqueline C M Witteman; Bruce M Psaty; H-Erich Wichmann; Tamara B Harris; Stefan Kääb; David S Siscovick; Yalda Jamshidi; André G Uitterlinden; Aaron R Folsom; Martin G Larson; James F Wilson; Brenda W Penninx; Harold Snieder; Peter P Pramstaller; Cornelia M van Duijn; Edward G Lakatta; Stephan B Felix; Vilmundur Gudnason; Arne Pfeufer; Susan R Heckbert; Bruno H Ch Stricker; Eric Boerwinkle; Christopher J O'Donnell Journal: Hum Mol Genet Date: 2010-07-16 Impact factor: 6.150
Authors: Jason R Cowan; Lorien Salyer; Nathan T Wright; Daniel D Kinnamon; Pedro Amaya; Elizabeth Jordan; Michael J Bamshad; Deborah A Nickerson; Ray E Hershberger Journal: Circ Genom Precis Med Date: 2020-06-30
Authors: Neil E Bowles; Chuanchau J Jou; Cammon B Arrington; Brett J Kennedy; Aubree Earl; Norisada Matsunami; Lindsay L Meyers; Susan P Etheridge; Elizabeth V Saarel; Steven B Bleyl; H Joseph Yost; Mark Yandell; Mark F Leppert; Martin Tristani-Firouzi; Peter J Gruber Journal: Am J Med Genet A Date: 2015-08-18 Impact factor: 2.802