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


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.
Carniel
Elisa
E
Familial Cardiomyopathy Registry Research Group, USA.
Taylor
Matthew R G
MR
Sinagra
Gianfranco
G
Di Lenarda
Andrea
A
Ku
Lisa
L
Fain
Pamela R
PR
Boucek
Mark M
MM
Cavanaugh
Jean
J
Miocic
Snjezana
S
Slavov
Dobromir
D
Graw
Sharon L
SL
Feiger
Jennie
J
Zhu
Xiao Zhong
XZ
Dao
Dmi
D
Ferguson
Debra A
DA
Bristow
Michael R
MR
Mestroni
Luisa
L
D002311:Cardiomyopathy, Dilated / Q000453:epidemiology / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D017720:Molecular Epidemiology; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics*
D024723:Ventricular Myosins; D018995:Myosin Heavy Chains