Ching, Y. H. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nature Genet. 37, 423-428

Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Nature Genetics (Impact Factor: 29.35). 05/2005; 37(4):423-8. DOI: 10.1038/ng1526
Source: PubMed


Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.

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Available from: Yung-Hao Ching
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    • "Accumulating evidence suggests that genetic factors contribute to the persistence of PFO and other defects of atrial septation, including atrial septal defects (ASD) [9], [10], [11]. A number of studies have shown that ASD exhibits autosomal dominant inheritance, and a list of causative genes encoding cardiac transcription factors and their targets (NKX2-5 [12], TBX5 [13], GATA4 [10], MYH6 [14], ACTC [15], TBX20 [16]) have been identified. Variation in these genes or their expression may contribute to the development of PFO. "
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    ABSTRACT: Patent foramen ovale (PFO) is an atrial septal deformity present in around 25% of the general population. PFO is associated with major causes of morbidity, including stroke and migraine. PFO appears to be heritable but genes involved in the closure of foramen ovale have not been identified. The aim of this study is to determine molecular pathways and genes that are responsible to the postnatal closure of the foramen ovale. Using Sprague-Dawley rat hearts as a model we analysed the dynamic histological changes and gene expressions at the foramen ovale region between embryonic day 20 and postnatal day 7. We observed a gradual loss of the endothelial marker PECAM1, an upregulation of the mesenchymal marker vimentin and α-smooth muscle actin, the elevation of the transcription factor Snail, and an increase of fibroblast activation protein (FAP) in the foramen ovale region as well as the deposition of collagen-rich connective tissues at the closed foramen ovale, suggesting endothelial-to-mesenchymal transition (EndMT) occurring during foramen ovale closure which leads to fibrosis. In addition, Notch1 and Notch3 receptors, Notch ligand Jagged1 and Notch effector HRT1 were highly expressed in the endocardium of the foramen ovale region during EndMT. Activation of Notch3 alone in an endothelial cell culture model was able to drive EndMT and transform endothelial cells to mesenchymal phenotype. Our data demonstrate for the first time that FO closure is a process of EndMT-mediated fibrosis, and Notch signalling is an important player participating in this process. Elucidation of the molecular mechanisms of the closure of foramen ovale informs the pathogenesis of PFO and may provide potential options for screening and prevention of PFO related conditions.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Despite intensive screening, relatively few mutations have been found in the MYH6 gene that have been linked to cardiomyopathy [55–57], suggesting low penetrance of this phenotype compared to genes such as MYH7 (see below). With regards to a role in the developing heart, αMHC was the first structural protein that upon mutation of its gene was associated with a CHD, with members of a family carrying a MYH6 mutation afflicted with an ASD [2]. This mutation caused a hydrophobic isoleucine to change to a hydrophilic asparagine (I820N). "
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    ABSTRACT: Myosin is an essential component of cardiac muscle, from the onset of cardiogenesis through to the adult heart. Although traditionally known for its role in energy transduction and force development, recent studies suggest that both myosin heavy-chain and myosin light-chain proteins are required for a correctly formed heart. Myosins are structural proteins that are not only expressed from early stages of heart development, but when mutated in humans they may give rise to congenital heart defects. This review will discuss the roles of myosin, specifically with regards to the developing heart. The expression of each myosin protein will be described, and the effects that altering expression has on the heart in embryogenesis in different animal models will be discussed. The human molecular genetics of the myosins will also be reviewed.
    Full-text · Article · Sep 2012 · Cellular and Molecular Life Sciences CMLS
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    • "More than 200 different dominant mutations in MYH7 have been associated with hypertrophic and dilated cardiomyopathy. Mutations in slow/α-cardiac MyHC (MYH6) have been reported to cause hypertrophic and dilated cardiomyopathy and atrial septal defect [14, 16]. "
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    ABSTRACT: The myosin heavy chain (MyHC) is the molecular motor of muscle and forms the backbone of the sarcomere thick filaments. Different MyHC isoforms are of importance for the physiological properties of different muscle fiber types. Hereditary myosin myopathies have emerged as an important group of diseases with variable clinical and morphological expression depending on the mutated isoform and type and location of the mutation. Dominant mutations in developmental MyHC isoform genes (MYH3 and MYH8) are associated with distal arthrogryposis syndromes. Dominant or recessive mutations affecting the type IIa MyHC (MYH2) are associated with early-onset myopathies with variable muscle weakness and ophthalmoplegia as a consistent finding. Myopathies with scapuloperoneal, distal or limb-girdle muscle weakness including entities, such as myosin storage myopathy and Laing distal myopathy are the result of usually dominant mutations in the gene for slow/β cardiac MyHC (MYH7). Protein aggregation is part of the features in some of these myopathies. In myosin storage myopathy protein aggregates are formed by accumulation of myosin beneath the sarcolemma and between myofibrils. In vitro studies on the effects of different mutations associated with myosin storage myopathy and Laing distal myopathy indicate altered biochemical and biophysical properties of the light meromyosin, which is essential for thick filament assembly. Protein aggregates in the form of tubulofilamentous inclusions in association with vacuolated muscle fibers are present at late stage of dominant myosin IIa myopathy and sometimes in Laing distal myopathy. These protein aggregates exhibit features indicating defective degradation of misfolded proteins. In addition to protein aggregation and muscle fiber degeneration some of the myosin mutations cause functional impairment of the molecular motor adding to the pathogenesis of myosinopathies.
    Preview · Article · Aug 2012 · Acta Neuropathologica
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