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Mutation in myosin heavy chain 6 causes atrial septal defect

Abstract

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 α-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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Figure 1: Fine mapping of the critical region of chromosome 14q in pedigree F11 with ASD.
Figure 2: Mutation analysis of MYH6 exon 21.
Figure 3: A model of myosin.
Figure 4: Interaction studies on wild-type and mutant MYH6 and myosin RLC.
Figure 5: TBX5 activates transcription from the MYH6 promoter.
Figure 6: MHC is required for atrial septation in the chick.

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Acknowledgements

We thank A. Moorman for his gift of chick atrial myosin heavy chain antibody and C. Nolan for advice on immunolabeling. This work was supported by the British Heart Foundation, the Wellcome Trust and The Royal Society. The genome screen, mutation detection and sequencing were done at the Medical Research Council's UK Human Genome Mapping Project Resource Centre Linkage Hotel.

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Correspondence to J David Brook.

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Ching, YH., Ghosh, T., Cross, S. et al. Mutation in myosin heavy chain 6 causes atrial septal defect. Nat Genet 37, 423–428 (2005). https://doi.org/10.1038/ng1526

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