The Carney complex gene PRKAR1A plays an essential role in cardiac development and myxomagenesis

Abstract

Cardiac myxomas are the most common primary tumors of the heart, although little is known about their etiology. Mutations of the protein kinase A regulatory subunit gene PRKAR1A cause inherited myxomas in the setting of the Carney complex tumor syndrome, providing a possible window for understanding their pathogenesis. We recently reported that cardiac-specific knockout of this gene causes myxomatous changes in the heart, although the mice die during gestation from cardiac failure. In this review, we discuss these findings and place them in the larger understanding of how protein kinase A dysregulation might affect cardiac function and cause myxomagenesis.

Figure 1. Model for the interactions of Prkar1a with other genes sharing a cardiac phenotype

Prkar1a KO (red text) causes reduction of cardiac-specific genes and a reduced number of cardiomyocytes with aberrant sarcomeres (Middle figure: white arrow: residual Z-disk; arrowhead: residual I-band)), eventually leading to a thin-walled, dilated heart (Right figure). At the end, these changes cause myxomagenesis (Left figure, arrows), and embryonic demise. These same pathways may be affected by knockout of other cardiac-specific transcription factors (blue text). A mechanism to account for myxomagenesis associated with mutation of MYH8 is also proposed in the same scheme. See text for details and references.