Genetic approaches for changing the heart and dissecting complex syndromes

The genetic, biochemical and molecular bases of human cardiac disease have been the focus of extensive research efforts for many years. Early animal models of cardiovascular disease used pharmacologic or surgical interventions, or took advantage of naturally occurring genetic abnormalities and the data obtained were largely correlative. The inability to directly alter an organismʹs genetic makeup and cellular protein content and accurately measure the results of that manipulation precluded rigorous examination of true cause–effect and structure–function relationships. Directed genetic manipulation in the mouse gave researchers the ability to modify and control the mammalian heartʹs protein content, resulting in the rational design of models that could provide critical links between the mutated or absent protein and disease. Two techniques that have proven particularly useful are transgenesis, which involves the random insertion of ectopic genetic material of interest into a “host” genome, and gene targeting, which utilizes homologous recombination at a pre-selected locus. Initially, transgenesis and gene targeting were used to examine systemic loss-of-function and gain-of-function, respectively, but further refinements in both techniques have allowed for investigations of organ-specific, cell type-specific, developmental stage-sensitive and dose-dependent effects. Genetically engineered animal models of pediatric and adult cardiac disease have proven that, when used appropriately, these tools have the power to extend mere observation to the establishment of true causative proof. We illustrate the power of the general approach by showing how genetically engineered mouse models can define the precise signaling pathways that are affected by the gain-of-function mutation that underlies Noonan syndrome. Increasingly precise and modifiable animal models of human cardiac disease will allow researchers to determine not only pathogenesis, but also guide treatment and the development of novel therapies.