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Human Molecular Genetics Advance Access published online on February 14, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn027
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts

Stella Marie Reamon-Buettner1, Yari Ciribilli2, Alberto Inga2 and Juergen Borlak1,*

1 Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, D-30625 Hannover, Germany 2 Unit of Molecular Mutagenesis, National Cancer Research Institute (IST), Largo R. Benzi, 10, 16132 Genoa, Italy

* Correspondence and reprint requests should be addressed to J.B. (e-mail: borlak{at}item.fraunhofer.de). Tel No. +49-511-5350-559, Fax No. +49-511-5350-573

Received November 23, 2007; Revised January 3, 2008; Accepted January 24, 2008

Hypoplasia of the human heart is the most severe form of congenital heart disease (CHD) and usually lethal during early infancy. It is a leading cause of neonatal loss, especially in infants diagnosed with hypoplastic left heart syndrome (HLHS), a condition where the left side of the heart including the aorta, aortic valve, left ventricle and mitral valve are underdeveloped. The molecular causes of HLHS are unclear, but the basic helix-loop-helix (bHLH) transcription factor Hand1, may be a candidate culprit for this condition. Absence of Hand1 in mice resulted in failure of rightward looping of the heart tube, a severely hypoplastic left ventricle and outflow tract abnormalities. Nonetheless, no HAND1 mutations associated with human CHD have been reported so far. We sequenced the human HAND1 gene in heart tissues derived from 31 unrelated patients diagnosed with hypoplastic hearts. We detected in 24 of 31 hypoplastic ventricles, a common frameshift mutation (A126fs) in the bHLH domain, which is necessary for DNA binding and combinatorial interactions. The resulting mutant protein, unlike wild type HAND1, was unable to modulate transcription of reporter constructs containing specific DNA binding sites. Thus, in hypoplastic human hearts HAND1 function is impaired.


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