Mutations in the protein kinase A R1 alpha regulatory subunit cause familial cardiac myxomas and Carney complex

Cardiac myxomas are benign mesenchymal tumors that can present as component s of the human autosomal dominant disorder Carney complex. Syndromic cardia c myxomas are associated with spotty pigmentation of the skin and endocrino pathy. Our linkage analysis mapped a Carney complex gene defect to chromoso me 17q24. We now demonstrate that the PRKAR1 alpha a gene encoding the R1 a lpha regulatory subunit of cAMP-dependent protein kinase A (PKA) maps to th is chromosome 17q24 locus. Furthermore, we show that PRKAR1 alpha frameshif t mutations in three unrelated families result in haploinsufficiency of R1 alpha and cause Carney complex. We did not detect any truncated R1 alpha pr otein encoded by mutant PRKAR1 alpha Although cardiac tumorigenesis may req uire a second somatic mutation, DNA and protein analyses of an atrial myxom a resected from a Carney complex patient with a PRKAR1 alpha deletion revea led that the myxoma cells retain both the wild-type and the mutant PRKAR1 a lpha alleles and that wildtype R1 alpha protein is stably expressed. Howeve r, in this atrial myxoma, we did observe a reversal of the ratio of R1 alph a to R2 beta regulatory subunit protein, which may contribute to tumorigene sis. Further investigation will elucidate the cell-specific effects of PRKA R1 alpha haploinsufficiency on PKA activity and the role of PKA in cardiac growth and differentiation.