Figure 10. Proposed model: aberrant regulation of NSML mutants in developing hearts leads to adult-onset cardiac hypertrophy.

NSML mutations affect AKT signaling in the developing endocardium, decreasing the transcriptional regulation of FOXP1 and NOTCH, 2 integral signaling pathways involved in the endocardial-to-myocardial crosstalk necessary for proper cardiac development. This abnormal regulation results in enlarged and amorphic heart valves, decreased trabeculation and ventricular development, and cardiac developmental delay in the embryos. Ultimately, these abnormal signaling events that occur during development are responsible for adult-onset cardiac hypertrophy.