Abstract 122: A Novel Mutation in a X-linked Gene Causes Human Congenital Dilated Cardiomyopathy
Congenital dilated cardiomyopathy (cDCM) is a rare but often fatal disease. In most cases, there is no family history, and its etiology is unknown. A major hurdle to elucidating a mechanistic understanding of congenital cardiomyopathy, and primary cardiomyopathies in general, has been a lack of access to diseased human cardiac tissues. Recent advances in patient-derived induced pluripotent stem cells (iPSCs) now enable production of human cardiomyocytes (iPSC-CMs) and allows for a systematic study of normal and diseased cardiomyocytes. We hypothesize that cardiomyocytes generated from iPSCs derived from cDCM patients will exhibit cellular and molecular differences from those generated from healthy donor iPSCs and that a rare genetic mutation, or a collection of mutations, plays a critical role in cDCM pathogenesis. To test these hypotheses, we generated cardiomyocytes from iPSCs derived from a 7-month old male with cDCM using a robust cardiac induction protocol based on the “matrigel sandwich” method of Kamp and colleagues. With this remarkably robust induction method, iPSC-CMs from the cDCM patient and a healthy control donor exhibited proteomic profiles that were 99.7% superimposable. Despite the close similarity at the global proteome level, iPSC-CMs from the cDCM patient showed greatly reduced contractility and dramatic structural defects in the sarcomere and the mitochondria. Finally, bioinformatics analyses of the RNAseq data of the patient’s iPSC-CMs discovered a putative causal mutation in an evolutionarily conserved site in a X-linked gene with unknown function. In summary, our work demonstrates that iPSC-based approaches are particularly useful for the study of human congenital heart diseases. We plan to confirm the causality of this mutation using gene editing techniques such as CRISPR/Cas9 and explore the role of this novel gene in cardiomyocyte structure and function.
Author Disclosures: Y. Chun: None T.K. Feaster: None C.H. Williams: None C.C. Sheng: None A.Y. Frist: None Y. Su: None D.P. Bichell: None C.C. Hong: None.
- © 2014 by American Heart Association, Inc.