Mutation in myosin heavy chain 6 causes atrial septal defect

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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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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.

Author information

Author notes

    • Andrew M Dearlove
    • , Gloria Ribas
    •  & Graham P Tyrrell

    Present addresses: MRC geneservice, Babraham Bioincubator, Babraham, Cambridge CB2 4AT, UK (A.M.D.); Centro Nacional de Investigaciones Oncologicas, E-28029 Madrid, Spain (G.R.); and PITO, London SE1 9QY, UK (G.P.T.).


  1. Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    • Yung-Hao Ching
    • , Tushar K Ghosh
    • , Steve J Cross
    • , Elizabeth A Packham
    • , Thelma E Robinson
    • , Andrew J Bonser
    •  & J David Brook
  2. Centre for Biochemistry and Cell Biology, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    • Louise Honeyman
    •  & Siobhan Loughna
  3. MRC UK HGMP Resource Centre, Hinxton, Cambridge CB10 1SB, UK.

    • Andrew M Dearlove
    •  & Gloria Ribas
  4. School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK.

    • Neil R Thomas
    •  & Andrew J Scotter
  5. Department of Biology, University of York, York YO10 5YW, UK.

    • Leo S D Caves
  6. Department of Chemistry, University of York, York YO10 5YW, UK.

    • Graham P Tyrrell
  7. Department of Clinical Genetics, Royal Hospital for Sick Children, Bristol BS2 8JJ, UK.

    • Ruth A Newbury-Ecob
  8. Departement de Pediatrie, INSERM U-393, Hopital des Enfants-Malades, 75743, Paris, France.

    • Arnold Munnich
  9. Service de Cardiologie Pediatrique, Hopital des Enfants-Malades, 75743, Paris, France.

    • Damien Bonnet


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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to J David Brook.