title: A loss-of-function mutation in the binding domain of HAND1 predicts hypoplasia of the human hearts.
abstract: 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 (LV) and mitral valve are underdeveloped. The molecular causes of HLHS are unclear, but the basic helix-loop-helix (bHLH) transcription factor heart and neural crest derivatives expressed 1 (Hand1), may be a candidate culprit for this condition. The absence of Hand1 in mice resulted in the failure of rightward looping of the heart tube, a severely hypoplastic LV 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 (wt) HAND1, was unable to modulate transcription of reporter constructs containing specific DNA-binding sites. Thus, in hypoplastic human hearts HAND1 function is impaired.
authors.affiliation: Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Strasse 1, D-30625 Hannover, Germany.
authors.forename: Stella Marie
authors.initials: SM
authors.lastname: Reamon-Buettner
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
authors.forename: Juergen
authors.initials: J
authors.lastname: Borlak
mesh_terms: D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D006321:Heart / Q000196:embryology* / Q000503:physiopathology; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000196:embryology / Q000235:genetics* / Q000503:physiopathology; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C097341:helix-loop-helix protein, eHAND