Abstract 19570: A Multigenic Etiology 0f Hypoplastic Left Heart Syndrome: An Analysis Based on Three Novel Mutant Mouse Models of Hyoplastic Left Heart Syndrome
Hypoplastic left heart syndrome (HLHS) is a congenital heart defect characterized by severe hypoplasia of the left ventricle (LV) with aortic and/or mitral valve stenosis. Despite advances in HLHS surgical management, the etiology for HLHS remains unknown. Accumulating evidence supports a genetic etiology for HLHS, but mutant mouse models of HLHS have not been described. We recovered three HLHS mutant mouse models in a large scale recessive mouse mutagenesis screen (Figure). In mutant line 635 named Ohia, 2 mutants with HLHS were recovered (Figure). Exome sequencing analysis identified three mutations in each of three genes: prolidase (Pepd), NAD synthetase (Nadsyn1) and protocadherin b9 (Pcdhb9). All three mutations were homozygous and shared in common in the two HLHS mutants, suggesting a multigenic etiology for HLHS in Ohia. All 3 genes show parallels with defects seen in HLHS patients. Pepd, which regulates proline recycling and collagen metabolism, may have relevance for the marked collagen reduction seen in the LV of HLHS patients. Nadsyn1, which synthesizes NAD, a coenzyme essential for metabolic redox reactions, is of potential importance, given recent study of HLHS patient heart tissue showed many transcript expression changes associated with oxidative phosphorylation. Pcdhb9, which likely mediates cell-cell adhesion, also may have relevance, given the expression of adherens junction related genes is reported to be markedly changed in HLHS heart tissue. Collectively, these findings suggest mutations affecting energy metabolism/oxidative stress, and cell-cell/cell-matrix interactions may play critical roles in HLHS. Consistent with this, preliminary results from the analysis of the other HLHS mutant mouse lines revealed mutations in other genes with overlapping function, including a collagen gene mutation. These observations suggest HLHS has a multigenic etiology, which may account for its apparent complex genetics. Support by U01-HL098180
- © 2012 by American Heart Association, Inc.