title: Axial distribution of myosin binding protein-C is unaffected by mutations in human cardiac and skeletal muscle.
abstract: Myosin binding protein-C (MyBP-C), a major thick filament associated sarcomeric protein, plays an important functional and structural role in regulating sarcomere assembly and crossbridge formation. Missing or aberrant MyBP-C proteins (both cardiac and skeletal) have been shown to cause both cardiac and skeletal myopathies, thereby emphasising its importance for the normal functioning of the sarcomere. Mutations in cardiac MyBP-C are a major cause of hypertrophic cardiomyopathy (HCM), while mutations in skeletal MyBP-C have been implicated in a disease of skeletal muscle-distal arthrogryposis type 1 (DA-1). Here we report the first detailed electron microscopy studies on human cardiac and skeletal tissues carrying MyBP-C gene mutations, using samples obtained from HCM and DA-1 patients. We have used established image averaging methods to identify and study the axial distribution of MyBP-C on the thick filament by averaging profile plots of the A-band of the sarcomere from electron micrographs of human cardiac and skeletal myopathy specimens. Due to the difficulty of obtaining normal human tissue, we compared the distribution to the A-band structure in normal frog skeletal, rat cardiac muscle and in cardiac muscle of MyBP-C-deficient mice. Very similar overall profile averages were obtained from the C-zones in cardiac HCM samples and skeletal DA-1 samples with MyBP-C gene mutations, suggesting that mutations in MyBP-C do not alter its mean axial distribution along the thick filament.
authors.affiliation: Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, UK. a.vydyanath@imperial.ac.uk
authors.forename: Anupama
authors.initials: A
authors.lastname: Vydyanath
authors.forename: Christina A
authors.initials: CA
authors.lastname: Gurnett
authors.forename: Steve
authors.initials: S
authors.lastname: Marston
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Luther
mesh_terms: D000818:Animals; D001176:Arthrogryposis / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D064211:Connectin; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D012518:Sarcomeres / Q000378:metabolism / Q000473:pathology; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D064211:Connectin; D009124:Muscle Proteins; D009218:Myosins; D020033:Protein Isoforms; D011494:Protein Kinases; D000099163:Myosin Binding Protein C; C577285:TTN protein, human