A novel beta-myosin heavy chain gene mutation, p.Met531Arg, identified in isolated left ventricular non-compaction in humans, results in left ventricular hypertrophy that progresses to dilation in a mouse model.
Mutations in the betaMHC (beta-myosin heavy chain), a sarcomeric protein are responsible for hypertrophic and dilated cardiomyopathy. However, the mechanisms whereby distinct mutations in the betaMHC gene cause two kinds of cardiomyopathy are still unclear. In the present study we report a novel betaMHC mutation found in a patient with isolated LVNC [LV (left ventricular) non-compaction] and the phenotype of a mouse mutant model carrying the same mutation. To find the mutation responsible, we searched for genomic mutations in 99 unrelated probands with dilated cardiomyopathy and five probands with isolated LVNC, and identified a p.Met531Arg mutation in betaMHC in a 13-year-old girl with isolated LVNC. Next, we generated six lines of transgenic mice carrying a p.Met532Arg mutant alphaMHC gene, which was identical with the p.Met531Arg mutation in the human betaMHC. Among these, two lines with strong expression of the mutant alphaMHC gene were chosen for further studies. Although they did not exhibit the features characteristic of LVNC, approx. 50% and 70% of transgenic mice in each line displayed LVH (LV hypertrophy) by 2-3 months of age. Furthermore, LVD (LV dilation) developed in approx. 25% of transgenic mice by 18 months of age, demonstrating biphasic changes in LV wall thickness. The present study supports the idea that common mechanisms may be involved in LVH and LVD. The novel mouse model generated can provide important information for the understanding of the pathological processes and aetiology of cardiac dilation in humans.
Kaneda
Tomoya
T
Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa, Japan. tomoya1311@yahoo.co.jp
Naruse
Chie
C
Kawashima
Atsuhiro
A
Fujino
Noboru
N
Oshima
Toru
T
Namura
Masanobu
M
Nunoda
Shinichi
S
Mori
Sumio
S
Konno
Tetsuo
T
Ino
Hidekazu
H
Yamagishi
Masakazu
M
Asano
Masahide
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006352:Heart Ventricles / Q000648:ultrastructure; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000235:genetics*; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D024723:Ventricular Myosins / Q000235:genetics*
D024723:Ventricular Myosins; D018995:Myosin Heavy Chains