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.

[1]  J. Seidman,et al.  The Genetic Basis for Cardiomyopathy from Mutation Identification to Mechanistic Paradigms , 2001, Cell.

[2]  J. Seidman,et al.  A molecular basis for familial hypertrophic cardiomyopathy: A β cardiac myosin heavy chain gene missense mutation , 1990, Cell.

[3]  T. Vulliamy,et al.  The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita , 2001, Nature.

[4]  I. Schlichting,et al.  Structure of the regulatory domain of scallop myosin at 2.8 Ä resolution , 1994, Nature.

[5]  J. A. Los,et al.  Isomyosin expression in developing chicken atria: a marker for the development of conductive tissue? , 2004, Anatomy and Embryology.

[6]  Youngsook Lee,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 , 1998, Molecular and Cellular Biology.

[7]  K. Patel,et al.  Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach. , 1999, Developmental genetics.

[8]  A. Rhoads,et al.  Sequence motifs for calmodulin recognition , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  J. Schmitt,et al.  A Murine Model of Holt-Oram Syndrome Defines Roles of the T-Box Transcription Factor Tbx5 in Cardiogenesis and Disease , 2001, Cell.

[10]  P. Brommer,et al.  Study of the specific heat of a CeCoAl4 single crystal in high magnetic fields , 1998 .

[11]  David I. Wilson,et al.  Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family , 1997, Nature Genetics.

[12]  J. Seidman,et al.  Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome. , 1997, Nature genetics.

[13]  R. Schwartz,et al.  GATA-4 and Nkx-2.5 Coactivate Nkx-2 DNA Binding Targets: Role for Regulating Early Cardiac Gene Expression , 1998, Molecular and Cellular Biology.

[14]  P. Mobbs,et al.  Connexin alpha1 and cell proliferation in the developing chick retina. , 1999, Experimental neurology.

[15]  L. Leinwand,et al.  Myosin heavy chain isoform expression in the failing and nonfailing human heart. , 2000, Circulation research.

[16]  I. Rayment,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 , 1996, Nature Genetics.

[17]  A. Moorman,et al.  Patterns of expression in the developing myocardium: towards a morphologically integrated transcriptional model. , 1998, Cardiovascular research.

[18]  E. A. Packham,et al.  Characterization of the TBX5 binding site and analysis of mutations that cause Holt-Oram syndrome. , 2001, Human molecular genetics.

[19]  M. Strauss,et al.  Origin of mesenchymal tissue in the septum primum: a structural and ultrastructural study. , 1987, Journal of molecular and cellular cardiology.

[20]  J. Seidman,et al.  Sarcomere Protein Gene Mutations in Hypertrophic Cardiomyopathy of the Elderly , 2002, Circulation.

[21]  P. Mobbs,et al.  Connexin α1 and Cell Proliferation in the Developing Chick Retina , 1999, Experimental Neurology.

[22]  P. O'Reilly.  A structural and ultrastructural study of a fused tooth. , 1989, Journal of Endodontics.

[23]  R. Kucherlapati,et al.  Mutations in human cause limb and cardiac malformation in Holt-Oram syndrome , 1997, Nature Genetics.

[24]  M. Komajda,et al.  Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in genotyped children. , 1998, European heart journal.

[25]  Jonathan C. Cohen,et al.  GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 , 2003, Nature.

[26]  Ryozo Nagai,et al.  Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation , 2001, Nature Genetics.

[27]  R. Matsuoka,et al.  The complete sequence and expression patterns of the atrial myosin heavy chain in the developing chick. , 1998, Biology of the cell.

[28]  Y. Yazaki,et al.  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. , 1988, The Journal of clinical investigation.

[29]  R. W. Davis,et al.  Detection of numerous Y chromosome biallelic polymorphisms by denaturing high-performance liquid chromatography. , 1997, Genome research.

[30]  C. Moravec,et al.  Human cardiac myosin heavy chain isoforms in fetal and failing adult atria and ventricles. , 2001, American journal of physiology. Heart and circulatory physiology.

[31]  J. Ott,et al.  Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. , 1985, American journal of human genetics.

[32]  R. Karlsson,et al.  Biospecific interaction analysis using surface plasmon resonance detection applied to kinetic, binding site and concentration analysis. , 1992, Journal of chromatography.

[33]  J. Seidman,et al.  Congenital heart disease caused by mutations in the transcription factor NKX2-5. , 1998, Science.

[34]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.