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 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.
Ching
Yung-Hao
YH
Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
Ghosh
Tushar K
TK
Cross
Steve J
SJ
Packham
Elizabeth A
EA
Honeyman
Louise
L
Loughna
Siobhan
S
Robinson
Thelma E
TE
Dearlove
Andrew M
AM
Ribas
Gloria
G
Bonser
Andrew J
AJ
Thomas
Neil R
NR
Scotter
Andrew J
AJ
Caves
Leo S D
LS
Tyrrell
Graham P
GP
Newbury-Ecob
Ruth A
RA
Munnich
Arnold
A
Bonnet
Damien
D
Brook
J David
JD
D000328:Adult; D019943:Amino Acid Substitution; D000818:Animals; D024722:Cardiac Myosins / Q000235:genetics* / Q000378:metabolism; D002642:Chick Embryo; D002648:Child; D002675:Child, Preschool; D005260:Female; D008040:Genetic Linkage; D006344:Heart Septal Defects, Atrial / Q000196:embryology / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020825:T-Box Domain Proteins / Q000737:chemistry / Q000235:genetics*
C094239:MYH6 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains