1. Mutation in myosin heavy chain 6 causes atrial septal defect
- Author
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Andrew M. Dearlove, Andrew J. Bonser, Andrew J. Scotter, Siobhan Loughna, Yung-Hao Ching, Graham P. Tyrrell, Neil R. Thomas, Damien Bonnet, Steve J. Cross, Tushar K. Ghosh, Leo S. D. Caves, Elizabeth A. Packham, Gloria Ribas, Louise Honeyman, Arnold Munnich, Ruth Newbury-Ecob, Thelma E. Robinson, and J. David Brook
- Subjects
Adult ,Male ,Morpholino ,Heart malformation ,Genetic Linkage ,Molecular Sequence Data ,Mutation, Missense ,Chick Embryo ,Biology ,Immunoglobulin light chain ,Heart Septal Defects, Atrial ,Myosin ,Genetics ,medicine ,Missense mutation ,Animals ,Humans ,cardiovascular diseases ,Child ,Transcription factor ,Heart septal defect ,Myosin Heavy Chains ,Infant, Newborn ,medicine.disease ,Cell biology ,Pedigree ,Amino Acid Substitution ,Child, Preschool ,cardiovascular system ,Female ,MYH6 ,T-Box Domain Proteins ,Cardiac Myosins - 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 alpha-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.
- Published
- 2004