Mutations in the R1α Regulatory Subunit of Protein Kinase A Cause Familial Cardiac Myxomas
Cardiac myxomas arise from primitive pluripotent mesenchymal cells within the subendocardium. In autosomal dominant Carney complex, intracardiac myxomas develop in the setting of lentiginosis and endocrinopathy. We previously localized the Carney complex gene defect to human chromosome 17q24. We now demonstrate that mutations in the chromosome 17 PRKAR1α gene encoding the R1α regulatory subunit of cAMP-dependent protein kinase A (PKA) cause inherited cardiac myxomas and Carney complex. We detect heterozygous deletions in the PRKAR1α gene in three unrelated kindreds (ΔFSterGly208 in Family YA, ΔFSterVal253 in Family YB, ΔFsterThr163 in Family YF). These mutations were confirmed by bidirectional sequence analysis and by denaturing acrylamide gel electrophoresis. Each mutant produces a frameshift and premature stop codon with consequent PRKAR1α haploinsufficiency. DNA and protein analysis of an atrial myxoma resected from an affected individual in Family YA reveals that the tumor cells retain both the wildtype and mutant PRKAR1α alleles, and that wildtype R1α but not mutant protein is stably expressed. However, western blot analysis demonstrates a reversal of the ratio of PKA regulatory subunits R1α to R1β in the myxoma that can alter PKA activity and contribute to tumor development. Our data, then, suggest that PRKAR1α acts as a tumor suppressor gene in the heart via regulation of PKA activity. These novel findings implicate the cAMP-dependent PKA signaling pathway as a critical modulator of cardiac cell growth and differentiation. Further research into the specific role of PKA in the heart may ultimately foster new therapeutic strategies for cardiac cell regeneration.
- Copyright © 2000 by American Heart Association