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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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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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  1. 1

    Franco, D., Lamers, W.H. & Moorman, A.F. Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. Cardiovasc. Res. 38, 25–53 (1998).

    CAS  Article  Google Scholar 

  2. 2

    Kurabayashi, M., Tsuchimochi, H., Komuro, I., Takaku, F. & Yazaki, Y. 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).

    CAS  Article  Google Scholar 

  3. 3

    Rhoads, A.R. & Friedberg, F. Sequence motifs for calmodulin recognition. FASEB J. 11, 331–340 (1997).

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Fagerstam, L.G., Frostell-Karlsson, A., Karlsson, R., Persson, B. & Ronnberg, I. Biospecific interaction analysis using surface plasmon resonance detection applied to kinetic, binding site and concentration analysis. J. Chromatogr. 597, 397–410 (1992).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Li, Q.Y. 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).

    Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  PubMed  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

    Poetter, K. 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).

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  Article  Google Scholar 

  14. 14

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

    CAS  Article  Google Scholar 

  15. 15

    Miyata, S., Minobe, W., Bristow, M.R. & Leinwand, L.A. Myosin heavy chain isoform expression in the failing and nonfailing human heart. Circ. Res. 86, 386–390 (2000).

    CAS  Article  Google Scholar 

  16. 16

    Reiser, P.J., Portman, M.A., Ning, X.H. & Schomisch Moravec, C. Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. Am. J. Physiol. Heart Circ. Physiol. 280, H1814–H1820 (2001).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

    Lee, Y. 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).

    CAS  Article  Google Scholar 

  20. 20

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

    CAS  Article  Google Scholar 

  21. 21

    Bruneau, B.G. 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).

    CAS  Article  Google Scholar 

  22. 22

    Sepulveda, J.L. 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).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am. J. Hum. Genet. 37, 482–498 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

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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.

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Correspondence to J David Brook.

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The authors declare no competing financial interests.

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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).

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