title: Mutation in myosin heavy chain 6 causes atrial septal defect.
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.
authors.affiliation: Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
authors.forename: Yung-Hao
authors.initials: YH
authors.lastname: Ching
authors.forename: Tushar K
authors.initials: TK
authors.lastname: Ghosh
authors.forename: Steve J
authors.initials: SJ
authors.lastname: Cross
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Packham
authors.forename: Louise
authors.initials: L
authors.lastname: Honeyman
authors.forename: Siobhan
authors.initials: S
authors.lastname: Loughna
authors.forename: Thelma E
authors.initials: TE
authors.lastname: Robinson
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Dearlove
authors.forename: Gloria
authors.initials: G
authors.lastname: Ribas
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Bonser
authors.forename: Neil R
authors.initials: NR
authors.lastname: Thomas
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Scotter
authors.forename: Leo S D
authors.initials: LS
authors.lastname: Caves
authors.forename: Graham P
authors.initials: GP
authors.lastname: Tyrrell
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Newbury-Ecob
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.forename: J David
authors.initials: JD
authors.lastname: Brook
mesh_terms: 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*
chemical_list: C094239:MYH6 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains