Two studies published in the April issue of Nature Genetic identify new genetic mutations underlying congenital heart malformations. Together, these studies provide a link between transcription factors (which regulate gene expression), structural proteins of the heart muscle, and normal heart function.
David Brook and colleagues identify a genetic region associated with cardiac defects through examination of a large family with dominantly inherited atrial septal defect (ASD). Although individuals with ASD are usually asymptomatic through infancy and childhood, defects of the atrial septum account for 30-40% of congenital heart disease seen in adults. Symptoms include fatigue, shortness of breath and arrhythmia. The mutation identified by the team occurs in a structural protein of heart muscle (alpha-myosin heavy chain) found at high levels in developing atria. The abundance of this protein was found to be regulated by the transcription factor TBX5. Mutations in TBX5 were previously associated with cardiac defects in the related Holt-Oram syndrome -- a genetic disorder that can cause ASD and upper limb abnormalities.
Christine Seidman and colleagues identify a gene deletion that causes dilated cardiomyopathy and heart failure in humans. The importance of this gene for normal heart function was confirmed with experiments in zebrafish embryos. While previous mutations associated with this disease have been found in structural proteins, the current mutation deletes a large region of a transcriptional activator called EYA4.
J. David Brook (University of Nottingham, UK)
Tel: +44 115 8493217
Brook paper available online.
Christine E. Seidman (Harvard Medical School, Boston, USA)
Tel: +1 617 432 7871
Seidman paper available online.
(C) Nature Genetic press release.
Message posted by: Trevor M. D'Souza