Abstract
SUMMARYTo assess the effects during cardiac development of mutations that cause human cardiomyopathy, we modeled a sarcomeric gene mutation in the embryonic zebrafish. We designed morpholino antisense oligonucleotides targeting the exon 13 splice donor site in the zebrafish cardiac troponin T (tnnt2) gene, in order to precisely recapitulate a human TNNT2 mutation that causes hypertrophic cardiomyopathy (HCM). HCM is a disease characterized by myocardial hypertrophy, myocyte and myofibrillar disarray, as well as an increased risk of sudden death. Similar to humans with HCM, the morphant zebrafish embryos displayed sarcomere disarray and there was a robust induction of myocardial hypertrophic pathways. Microarray analysis uncovered a number of shared transcriptional responses between this zebrafish model and a well-characterized mouse model of HCM. However, in contrast to adult hearts, these embryonic hearts developed cardiomyocyte hyperplasia in response to this genetic perturbation. The re-creation of a human disease-causing TNNT2 splice variant demonstrates that sarcomeric mutations can alter cardiomyocyte biology at the earliest stages of heart development with distinct effects from those observed in adult hearts despite shared transcriptional responses.
Highlights
In the last two decades, genetic studies of inherited forms of human cardiomyopathy have offered important insights into the fundamental biology of myocardial hypertrophy and heart failure
The zebrafish Tnnt2 splice variant genocopies the human diseasecausing TNNT2 splice variant In order to precisely recapitulate an autosomal dominant hypertrophic cardiomyopathy mutation, we chose to model a mutation in the splice donor site of exon 15 in human TNNT2 (Thierfelder et al, 1994)
This morpholino allows the creation of a dominant mutation in Tnnt2 while retaining the full control of the native zebrafish tnnt2 promoter
Summary
In the last two decades, genetic studies of inherited forms of human cardiomyopathy have offered important insights into the fundamental biology of myocardial hypertrophy and heart failure. Many of the causal genes for inherited hypertrophic cardiomyopathy (HCM) encode for proteins involved in the proper function of the cardiac sarcomere. Substantial pleiotropy is seen for many cardiomyopathy genes. Even within families harboring the same mutation there is significant variation in the extent of hypertrophy, the risk of arrhythmias or the progression to heart failure (Alcalai et al, 2007; Arad et al, 2002). Different mutations in a single gene can lead to either HCM or dilated cardiomyopathy (DCM) (Seidman and Seidman, 2001). The major modifiers regulating this phenotypic diversity have not been defined
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