Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex
Mairead Casey, … , Cynthia C. Morton, Craig T. Basson
Mairead Casey, … , Cynthia C. Morton, Craig T. Basson
Published September 1, 2000
Citation Information: J Clin Invest. 2000;106(5):R31-R38. https://doi.org/10.1172/JCI10841.
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Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex

Abstract

Cardiac myxomas are benign mesenchymal tumors that can present as components of the human autosomal dominant disorder Carney complex. Syndromic cardiac myxomas are associated with spotty pigmentation of the skin and endocrinopathy. Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24. We now demonstrate that the PRKAR1α gene encoding the R1α regulatory subunit of cAMP-dependent protein kinase A (PKA) maps to this chromosome 17q24 locus. Furthermore, we show that PRKAR1α frameshift mutations in three unrelated families result in haploinsufficiency of R1α and cause Carney complex. We did not detect any truncated R1α protein encoded by mutant PRKAR1α. Although cardiac tumorigenesis may require a second somatic mutation, DNA and protein analyses of an atrial myxoma resected from a Carney complex patient with a PRKAR1α deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1α alleles and that wild-type R1α protein is stably expressed. However, in this atrial myxoma, we did observe a reversal of the ratio of R1α to R2β regulatory subunit protein, which may contribute to tumorigenesis. Further investigation will elucidate the cell-specific effects of PRKAR1α haploinsufficiency on PKA activity and the role of PKA in cardiac growth and differentiation.

Authors

Mairead Casey, Carl J. Vaughan, Jie He, Cathy J. Hatcher, Jordan M. Winter, Stanislawa Weremowicz, Kate Montgomery, Raju Kucherlapati, Cynthia C. Morton, Craig T. Basson

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Figure 3

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Three frameshift mutations in PRKAR1α that cause Carney complex. A schem...
Three frameshift mutations in PRKAR1α that cause Carney complex. A schematic representation of PRKAR1α cDNA shows exons 1–11. Regions that encode functional domains (dimerization domain, antigenic sites, hinge/pseudophosphorylation site, cAMP-binding domains A and B) of R1α are denoted (13). Location of the PRKAR1α deletion mutations ΔFSterGly208 in family YA, ΔFSterVal253 in family YB, and ΔFSterThr163 in family YF are shown. Mutations are denoted by ΔFSter to indicate a deletion with resultant frameshift and premature stop codon, and by the first amino acid residue affected by the deletion.