Firulli, Beth A.Toolan, Kevin P.Harkin, JadeMillar, HannahPineda, SantiagoFirulli, Anthony B.2019-05-282019-05-282017-12-01Firulli, B. A., Toolan, K. P., Harkin, J., Millar, H., Pineda, S., & Firulli, A. B. (2017). The HAND1 frameshift A126FS mutation does not cause hypoplastic left heart syndrome in mice. Cardiovascular research, 113(14), 1732–1742. doi:10.1093/cvr/cvx166https://hdl.handle.net/1805/19490Aims: To test if a human Hand1 frame shift mutation identified in human samples is causative of hypoplastic left heart syndrome (HLHS). Methods and results: HLHS is a poorly understood single ventricle congenital heart defect that affects two to three infants in every 10 000 live births. The aetiologies of HLHS are largely unknown. The basic helix-loop-helix transcription factor HAND1 is required for normal heart development. Interrogation of HAND1 sequence from fixed HLHS tissues identified a somatic frame-shift mutation at Alanine 126 (NP_004812.1 p.Ala126Profs13X defined as Hand1A126fs). Hand1A126fs creates a truncated HAND1 protein that predictively functions as dominant negative. To determine if this mutation is causative of HLHS, we engineered a conditional Hand1A126fs mouse allele. Activation of this allele with Nkx2.5Cre results in E14.5 lethality accompanied by cardiac outflow tract and intraventricular septum abnormalities. Using αMHC-Cre or Mef2CAHF-Cre to activate Hand1A126fs results in reduced phenotype and limited viability. Left ventricles of Hand1A126FS mutant mice are not hypoplastic. Conclusions: Somatically acquired Hand1A126FS mutation is not causative of HLHS. Hand1A126FS mutation does exhibit embryonic lethal cardiac defects that reflect a dominant negative function supporting the critical role of Hand1 in cardiogenesis.en-USPublisher PolicyCardiac developmentHand1Hypoplastic left heart syndromeTranscriptionbHLHArticle