Mutation in myosin heavy chain 6 causes atrial septal defect



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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  1. 1.

    , & Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. Cardiovasc. Res. 38, 25–53 (1998).

  2. 2.

    , , , & Molecular cloning and characterization of human cardiac alpha- and beta-form myosin heavy chain complementary DNA clones. Regulation of expression during development and pressure overload in human atrium. J. Clin. Invest. 82, 524–531 (1988).

  3. 3.

    & Sequence motifs for calmodulin recognition. FASEB J. 11, 331–340 (1997).

  4. 4.

    et al. Structure of the regulatory domain of scallop myosin at 2.8 A resolution. Nature 368, 306–312 (1994).

  5. 5.

    , , , & Biospecific interaction analysis using surface plasmon resonance detection applied to kinetic, binding site and concentration analysis. J. Chromatogr. 597, 397–410 (1992).

  6. 6.

    et al. Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. Hum. Mol. Genet. 10, 1983–1994 (2001).

  7. 7.

    et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat. Genet. 15, 21–29 (1997).

  8. 8.

    et al. Mutations in human TBX5 cause limb and cardiac malformation in Holt-Oram syndrome. Nat. Genet. 15, 30–35 (1997).

  9. 9.

    et al. The complete sequence and expression patterns of the atrial myosin heavy chain in the developing chick. Biol. Cell 90, 605–613 (1998).

  10. 10.

    , , & Origin of mesenchymal tissue in the septum primum: a structural and ultrastructural study. J. Mol. Cell. Cardiol. 19, 641–651 (1987).

  11. 11.

    et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).

  12. 12.

    et al. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. Nat. Genet. 13, 63–69 (1996).

  13. 13.

    et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 105, 446–451 (2002).

  14. 14.

    & The genetic basis for cardiomyopathy: from mutation identification to mechanistic paradigms. Cell 104, 557–567 (2001).

  15. 15.

    , , & Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86, 386–390 (2000).

  16. 16.

    , , & Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am. J. Physiol. Heart Circ. Physiol. 280, H1814–H1820 (2001).

  17. 17.

    et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281, 108–111 (1998).

  18. 18.

    et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424, 443–447 (2003).

  19. 19.

    et al. The cardiac tissue-restricted homeobox protein Csx/Nkx2.5 physically associates with the zinc finger protein GATA4 and cooperatively activates atrial natriuretic factor gene expression. Mol. Cell. Biol. 18, 3120–3129 (1998).

  20. 20.

    et al. Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation. Nat. Genet. 28, 276–280 (2001).

  21. 21.

    et al. A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease. Cell 106, 709–721 (2001).

  22. 22.

    et al. GATA-4 and Nkx-2.5 coactivate Nkx-2 DNA binding targets: role for regulating early cardiac gene expression. Mol. Cell. Biol. 18, 3405–3415 (1998).

  23. 23.

    et al. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in genotyped children. Eur. Heart J. 19, 1377–1382 (1998).

  24. 24.

    et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413, 432–435 (2001).

  25. 25.

    , , & Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

  26. 26.

    et al. Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. Genome Res. 7, 996–1005 (1997).

  27. 27.

    & Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779–815 (1993).

  28. 28.

    et al. Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach. Dev. Genet. 24, 33–42 (1999).

  29. 29.

    & Connexin alpha1 and cell proliferation in the developing chick retina. Exp. Neurol. 156, 326–332 (1999).

  30. 30.

    et al. Isomyosin expression in developing chicken atria: a marker for the development of conductive tissue? Anat. Embryol. (Berl) 176, 515–523 (1987).

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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.