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  • Review Article
  • Published:

Inherited disposition to cardiac myxoma development

Nature Reviews Cancer volume 6, pages 157–165 (2006)Cite this article

Key Points

  • Cardiac myxomas and various non-cardiac neoplasms occur in people who have the autosomal-dominant disorder Carney complex, which is also characterized by spotty pigmentation of the skin and endocrinopathy.

  • Although complete penetrance is the rule, Carney complex shows a highly variable phenotype.

  • Mutations in the chromosome 17q PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A (PKA), cause Carney complex in approximately two-thirds of affected individuals. No genotype–phenotype correlation has been established, and most mutations result in PRKAR1A haploinsufficiency through nonsense-mediated degradation of the transcribed, mutant mRNAs.

  • The contributions of loss of heterozygosity of PRKAR1A and increased PKA activity to Carney complex are unclear. Although both can occur in Carney complex tumours, analyses of human and murine tissues demonstrate that neither is required for tumorigenesis.

  • Changes in the ratio of type I to type II PKA isoenzymes are uniform features of human Carney complex tumours, as well as tumours that are found in genetically engineered mouse models of Carney complex. Such PKA isoform switching might mediate altered cell growth and tumorigenesis.

  • Mutation of the chromosome 17p MYH8 gene, which encodes perinatal myosin, results in a rare familial cardiac myxoma syndrome with features that are typical of Carney complex, except that affected individuals also suffer from the hereditary distal arthrogryposis syndrome, trismus–pseudocamptodactyly.

  • The mechanism by which PRKAR1A and MYH8 mutations foster the survival and proliferation of myxoma progenitor cells in the heart remains unknown.

Abstract

Carney complex is a genetic condition in which affected individuals develop benign tumours in various tissues, including the heart. Most individuals with Carney complex have a mutation in the PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A — a significant component of the cyclic-AMP signalling pathway. Genetically engineered mutant Prkar1a mouse models show an increased propensity to develop tumours, and have established a role for R1α in initiating tumour formation and, potentially, in maintaining cell proliferation. Ongoing investigations are exploring the intersection of R1α-dependent cell signalling with other gene products such as perinatal myosin, mutation of which can also cause cardiac myxomas.

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Figure 1: PRKAR1A mutations in CNC
Figure 2: Schematic diagram of PKA structure and activation.
Figure 3: Genetically engineered mouse models to study the function of each PKA subunit.

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References

  1. Kendall, D. & Symonds, B. Epileptiform attacks due to myxoma of the right auricle. Br. Heart J. 14, 139–143 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Frankenfeld, R. H., Waters, C. H. & Steiner, R. C. Bilateral myxomas of the heart. Ann. Intern. Med. 53, 827–838 (1960).

    CAS  PubMed  Google Scholar 

  3. Atherton, D. J., Pitcher, D. W., Wells, R. S. & MacDonald, D. M. A syndrome of various cutaneous pigmented lesions, myxoid neurofibromata and atrial myxoma: the NAME syndrome. Br. J. Dermatol. 103, 421–429 (1980).

    CAS  PubMed  Google Scholar 

  4. Rees, J. R., Ross, F. G. M. & Keen, G. Lentiginosis and left atrial myxoma. Brit. Heart J. 35, 874–876 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Koopman, R. J. & Happle, R. Autosomal dominant transmission of the NAME syndrome (nevi, atrial myxoma, mucinosis of the skin and endocrine overactivity). Hum. Genet. 86, 300–304 (1991).

    CAS  PubMed  Google Scholar 

  6. Carney, J. A., Gordon, H., Carpenter, P. C., Shenoy, B. V. & Go, V. L. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 64, 270–283 (1985). Elegant clinical description of the syndrome that bears the eponym Carney complex.

    CAS  PubMed  Google Scholar 

  7. Vidaillet, H. J. Jr, Seward, J. B., Fyke, F. E. 3rd, Su, W. P. & Tajik, A. J. 'Syndrome myxoma': a subset of patients with cardiac myxoma associated with pigmented skin lesions and peripheral and endocrine neoplasms. Br. Heart J. 57, 247–255 (1987).

    PubMed  PubMed Central  Google Scholar 

  8. Veugelers, M. et al. Comparative PRKAR1A genotype–phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc. Natl Acad. Sci. USA 101, 14222–14227 (2004). Comprehensive survey of PRKAR1A mutations in CNC and description of the histological, biochemical and genetic features of a genetically engineered mouse model of CNC.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Veugelers, M. et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N. Engl. J. Med. 351, 460–469 (2004). Describes the identification of a gene that is responsible for trismus–pseudocamptodactyly syndrome and a variant form of CNC that includes trismus–pseudocamptodactyly.

    CAS  PubMed  Google Scholar 

  10. Burke, A. & Virmani, R. in Atlas of Tumor Pathology. Third Series. Fascicle 16. (Washington, DC: Armed Forces Institute of Pathology, 1996).

    Google Scholar 

  11. Burke, A. P. et al. in World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (eds Travis, W. D. et al.) 260–265 (IARC Press, Lyon, 2004).

    Google Scholar 

  12. Reynen, K. Cardiac myxomas. N. Engl. J. Med. 333, 1610–1617 (1995).

    CAS  PubMed  Google Scholar 

  13. Ferrans, V. J. & Roberts, W. C. Structural features of cardiac myxomas: histology, histchemistry and electron microscopy. Hum. Pathol. 4, 111–146 (1973).

    CAS  PubMed  Google Scholar 

  14. Lie, J. T. The identity and histogenesis of cardiac myxomas: a controversy put to rest. Arch. Pathol. Lab. 113, 724–726 (1989).

    CAS  Google Scholar 

  15. Basson, C. T. & Aretz, H. T. A 27-year-old woman with two intracardiac masses and a history of endocrinopathy. N. Engl. J. Med. 346, 1152–1158 (2002).

    PubMed  Google Scholar 

  16. McCarthy, P. M. et al. The significance of multiple, recurrent, and 'complex' cardiac myxomas. J. Thorac. Cardiovasc. Surg. 91, 389–396 (1986).

    CAS  PubMed  Google Scholar 

  17. Stratakis, C. A., Kirschner, L. S. & Carney, J. A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J. Clin. Endocrinol. Metab. 86, 4041–4046 (2001).

    CAS  PubMed  Google Scholar 

  18. Carney, J. A., Headington, J. T. & Su, W. P. Cutaneous myxomas. A major component of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Arch. Dermatol. 122, 790–798 (1986).

    CAS  PubMed  Google Scholar 

  19. Bennett, K. R. et al. The Carney complex: unusual skin findings and recurrent cardiac myxoma. Arch. Dermatol. 141, 916–918 (2005).

    PubMed  Google Scholar 

  20. Kennedy, R. H., Waller, R. R. & Carney, J. A. Ocular pigmented spots and eyelid myxomas. Am. J. Ophthal. 104, 533–538 (1987).

    CAS  PubMed  Google Scholar 

  21. Schweizer-Cagianut, M., Salomon, F. & Hedinger, C. E. Primary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas: a peculiar familial disease. Virchows. Arch. Path. Anat. 397, 183–192 (1982).

    CAS  Google Scholar 

  22. Kurtkaya-Yapicier, O. et al. Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study. Ultrastruct. Pathol. 26, 345–353 (2002).

    CAS  PubMed  Google Scholar 

  23. Stratakis, C. A. et al. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex) J. Clin. Endocrinol. Metab. 82, 2037–2043 (1997).

    CAS  PubMed  Google Scholar 

  24. Radin, R. & Kempf, R. A. Carney complex: report of three cases. Radiology 196, 383–386 (1995).

    CAS  PubMed  Google Scholar 

  25. Premkumar, A., Stratakis, C. A., Shawker, T. H., Papanicolaou, D. A. & Chrousos, G. P. Testicular ultrasound in Carney complex: report of three cases. J. Clin. Ultrasound. 25, 211–214 (1997).

    CAS  PubMed  Google Scholar 

  26. Utiger, C. A. & Headington, J. T. Psammomatous melanotic schwannoma: a new cutaneous marker for Carney's complex. Arch. Dermatol. 129, 202–204 (1993).

    CAS  PubMed  Google Scholar 

  27. Claessens, N. et al. Cutaneous psammomatous melanotic schwannoma: non-recurrence with surgical excision. Am. J. Clin. Dermatol. 4, 799–802 (2003).

    PubMed  Google Scholar 

  28. Carney, J. A. & Toorkey, B. C. Myxoid fibroadenoma and allied conditions (myxomatosis) of the breast. A heritable disorder with special associations including cardiac and cutaneous myxomas. Am. J. Surg. Pathol. 15, 713–721 (1991).

    CAS  PubMed  Google Scholar 

  29. Carney, J. A. & Toorkey, B. C. Ductal adenoma of the breast with tubular features. A probable component of the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Am. J. Surg. Pathol. 15, 722–731 (1991).

    CAS  PubMed  Google Scholar 

  30. Stratakis, C. A. et al. Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. J. Clin. Endocrinol. Metab. 85, 4359–4366 (2000).

    CAS  PubMed  Google Scholar 

  31. Barlow, J. F. et al. Myxoid tumor of the uterus and right atrial myxomas. S. D. J. Med. 36, 9–13 (1983).

    CAS  PubMed  Google Scholar 

  32. Stratakis, C. A. et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J. Clin. Invest. 97, 699–705 (1996). Survey of clinical features of CNC and a potential CNC locus on chromosome 2, although several families that were subsequently described were shown to be associated with PRKAR1A defects on chromosome 17 (see references 33–35).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Casey, M. et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 98, 2560–2566 (1998). Demonstration that the most important gene defect that causes CNC is associated with chromosome 17.

    CAS  PubMed  Google Scholar 

  34. Casey, M. et al. Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex. J. Clin. Invest. 106, R31–R38 (2000). Initial published report that mutations in the PRKAR1A gene cause CNC.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Kirschner, L. S. et al. Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex. Nature Genet. 26, 89–92 (2000). Identification of mutations in the PRKAR1A gene that cause CNC.

    CAS  PubMed  Google Scholar 

  36. Boshart, M., Weih, F., Nichols, M. & Schutz, G. The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase. Cell 66, 849–859 (1991).

    CAS  PubMed  Google Scholar 

  37. Jones, K. W., Shapero, M. H., Chevrette, M. & Fournier, R. E. Subtractive hybridization cloning of a tissue-specific extinguisher: TSE1 encodes a regulatory subunit of protein kinase A. Cell 66, 861–872 (1991).

    CAS  PubMed  Google Scholar 

  38. McKnight, G. S. et al. Analysis of the cAMP-dependent protein kinase system using molecular genetic approaches. Recent Prog. Horm. Res. 44, 307–335 (1988).

    CAS  PubMed  Google Scholar 

  39. Beebe, S. J. & Corbin, J. D. Rat adipose tissue cAMP-dependent protein kinase: a unique form of type II. Mol. Cell. Endocrinol. 36, 67–78 (1984).

    CAS  PubMed  Google Scholar 

  40. Scott, J. D. Cyclic nucleotide-dependent protein kinases. Pharmacol. Ther. 50, 123–145 (1991).

    CAS  PubMed  Google Scholar 

  41. Taylor, S. S., Buechler, J. A. & Yonemoto, W. cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Ann. Rev. Biochem. 59, 971–1005 (1990). Review of PKA structure and function.

    CAS  PubMed  Google Scholar 

  42. Kirschner, L. S. et al. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum. Mol. Genet. 9, 3037–3046 (2000). Survey of PRKAR1A mutations in CNC and illustration of NMD of mutant alleles.

    CAS  PubMed  Google Scholar 

  43. Gibson, R. M., Ji-Buechler, Y. & Taylor, S. S. Interaction of the regulatory and catalytic subunits of the cAMP-dependent protein kinase. Electrostatic sites on the type Iα regulatory subunit. J. Biol. Chem. 272, 16343–16350 (1997).

    CAS  PubMed  Google Scholar 

  44. Gibson, R. M. & Taylor, S. S. Dissecting the cooperative reassociation of the regulatory and catalytic subunits of cAMP-dependent protein kinase. Role of Trp-196 in the catalytic subunit. J. Biol. Chem. 272, 31998–32005 (1997).

    CAS  PubMed  Google Scholar 

  45. Groussin, L. et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am. J. Hum. Genet. 71, 1433–1442 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Perlick, H. A., Medghalchi, S. M., Spencer, F. A., Kendzior, R. J. Jr & Dietz, H. C. Mammalian orthologues of a yeast regulator of nonsense transcript stability. Proc. Natl Acad. Sci. USA 93, 10928–10932 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Frischmeyer, P. A. & Dietz, H. C. Nonsense-mediated mRNA decay in health and disease. Hum. Mol. Genet. 8, 1893–1900 (1999).

    CAS  PubMed  Google Scholar 

  48. Mabuchi, T. et al. PRKAR1A gene mutation in patients with cardiac myxoma. Int. J. Cardiol. 102, 273–277 (2005).

    CAS  PubMed  Google Scholar 

  49. Stratakis, C. A. Mutations of the gene encoding the protein kinase A type I-α regulatory subunit (PRKAR1A) in patients with the 'complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas' (Carney complex). Ann. NY Acad. Sci. 968, 3–21 (2002).

    CAS  PubMed  Google Scholar 

  50. Taymans, S. E., Kirschner, L. S., Giatzakis, C. & Stratakis, C. A. Characterization of the adrenal gland pathology of Carney complex, and molecular genetics of the disease. Endocr. Res. 24, 863–864 (1998).

    PubMed  Google Scholar 

  51. Irvine, A. D. et al. Evidence for a second genetic locus in Carney complex. Br. J. Dermatol. 139, 572–576 (1998).

    CAS  PubMed  Google Scholar 

  52. Maldonado, F. & Hanks, S. K. A cDNA clone encoding human cAMP-dependent protein kinase catalytic subunit Cα. Nucleic Acids Res. 16, 8189–8190 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Beebe, S. J. et al. Molecular cloning of a tissue-specific protein kinase (Cγ) from human testis — representing a third isoform for the catalytic subunit of cAMP-dependent protein kinase. Mol. Endocrinol. 4, 465–475 (1990).

    CAS  PubMed  Google Scholar 

  54. Tasken, K. et al. The gene encoding the catalytic subunit C-α of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1. Genomics 36, 535–538 (1996).

    CAS  PubMed  Google Scholar 

  55. Berube, D. et al. Assignment of the gene encoding the catalytic subunit Cβ of cAMP-dependent protein kinase to the p36 band on chromosome 1. Cytogenet. Cell. Genet. 58, 1850 (1991).

    Google Scholar 

  56. Boshart, M., Weih, F., Nichols, M. & Schutz, G. The tissue-specific extinguisher locus TSE1 encodes a regulatory subunit of cAMP-dependent protein kinase. Cell 66, 849–859 (1991).

    CAS  PubMed  Google Scholar 

  57. Tasken, K., Naylor, S. L., Solberg, R. & Jahnsen, T. Mapping of the gene encoding the regulatory subunit RII-α of cAMP-dependent protein kinase (locus PRKAR2A) to human chromosome region 3p21.3–p21.2. Genomics 50, 378–381 (1998).

    CAS  PubMed  Google Scholar 

  58. Solberg, R. et al. Mapping of the regulatory subunits RI-β and RII-β of cAMP-dependent protein kinase genes on human chromosome 7. Genomics 14, 63–69 (1992).

    CAS  PubMed  Google Scholar 

  59. Skalhegg, B. S. & Tasken, K. Specificity in the cAMP–PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Front. Biosci. 5, D678–D693 (2000).

    CAS  PubMed  Google Scholar 

  60. Corbin, J. D., Keely, S. L. & Park, C. R. The distribution and dissociation of cyclic adenosine 3′:5′-monophosphate-dependent protein kinases in adipose, cardiac, and other tissues. J. Biol. Chem. 250, 218–225 (1975).

    CAS  PubMed  Google Scholar 

  61. Clegg, C. H., Cadd, G. G. & McKnight, G. S. Genetic characterization of a brainspecific form of the type I regulatory subunit of cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA 85, 3703–3707 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Wong, W. & Scott, J. D. AKAP signalling complexes: focal points in space and time. Nature Rev. Mol. Cell Biol. 5, 959–970 (2004).

    CAS  Google Scholar 

  63. Feliciello, A., Gottesman, M. E. & Avvedimento, E. V. The biological functions of A-kinase anchor proteins. J. Mol. Biol. 308, 99–114 (2001).

    CAS  PubMed  Google Scholar 

  64. Rubin, C. S. A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP. Biochim. Biophys. Acta. 1224, 467–479 (1994).

    PubMed  Google Scholar 

  65. Imaizumi-Scherrer, T., Faust, D. M., Barradeau, S., Hellio, R. & Weiss, M. C. Type I protein kinase a is localized to interphase microtubules and strongly associated with the mitotic spindle. Exp. Cell Res. 264, 250–265 (2001).

    CAS  PubMed  Google Scholar 

  66. Coghlan, V. M., Bergeson, S. E., Langeberg, L., Nilaver, G. & Scott, J. D. A-kinase anchoring proteins: a key to selective activation of cAMP-responsive events? Mol. Cell. Biochem. 127–128, 309–319 (1993).

    PubMed  Google Scholar 

  67. Lin, R. Y., Moss, S. B. & Rubin, C. S. Characterization of S-AKAP84, a novel developmentally regulated A kinase anchor protein of male germ cells. J. Biol. Chem. 270, 27804–27811 (1995).

    CAS  PubMed  Google Scholar 

  68. Trendelenburg, G., Hummel, M., Riecken, E. O. & Hanski, C. Molecular characterization of AKAP149, a novel A kinase anchor protein with a KH domain. Biochem. Biophys. Res. Commun. 225, 313–319 (1996).

    CAS  PubMed  Google Scholar 

  69. Huang, L. J., Durick, K., Weiner, J. A., Chun, J. & Taylor, S. S. D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain. Proc. Natl Acad. Sci. USA 94, 11184–11189 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, L. et al. Cloning and mitochondrial localization of full-length D-AKAP2, a protein kinase A anchoring protein. Proc. Natl Acad. Sci. USA 98, 3220–3225 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Alto, N., Carlisle Michel, J. J., Dodge, K. L., Langeberg, L. K. & Scott, J. D. Intracellular targeting of protein kinases and phosphatases. Diabetes 51 (Suppl.), S385–S388 (2002).

    CAS  PubMed  Google Scholar 

  72. Perkins, G. A. et al. PKA, PKC, and AKAP localization in and around the neuromuscular junction. BMC Neurosci. 2, 17 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lester, L. B. & Scott, J. D. Anchoring and scaffold proteins for kinases and phosphatases. Recent. Prog. Horm. Res. 52, 409–429 (1997).

    CAS  PubMed  Google Scholar 

  74. Fan, G., Shumay, E., Wang, H. & Malbon, C. C. The scaffold protein gravin (cAMP-dependent protein kinase-anchoring protein 250) binds the β2-adrenergic receptor via the receptor cytoplasmic Arg-329 to Leu-413 domain and provides a mobile scaffold during desensitization. J. Biol. Chem. 276, 24005–24014 (2001).

    CAS  PubMed  Google Scholar 

  75. Skalhegg, B. S. et al. Mutation of the Cα subunit of PKA leads to growth retardation and sperm dysfunction. Mol. Endocrinol. 16, 630–639 (2002).

    CAS  PubMed  Google Scholar 

  76. Brandon, E. P. et al. Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RIβ subunit of cAMP-dependent protein kinase. Proc. Natl Acad. Sci. USA. 92, 8851–8855 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Cummings, D. E. et al. Genetically lean mice result from targeted disruption of the RIIβ subunit of protein kinase A. Nature 382, 622–626 (1996).

    CAS  PubMed  Google Scholar 

  78. Burton, K. A., Treash-Osio, B., Muller, C. H., Dunphy, E. L. & McKnight, G. S. Deletion of type IIα regulatory subunit delocalizes protein kinase A in mouse sperm without affecting motility or fertilization. J. Biol. Chem. 274, 24131–24136 (1999).

    CAS  PubMed  Google Scholar 

  79. Rao, Y. et al. Reduced ocular dominance plasticity and long-term potentiation in the developing visual cortex of protein kinase A RIIα mutant mice. Eur. J. Neurosci. 20, 837–842 (2004).

    PubMed  Google Scholar 

  80. Amieux, P. S. et al. Increased basal cAMP-dependent protein kinase activity inhibits the formation of mesoderm-derived structures in the developing mouse embryo. J. Biol. Chem. 277, 27294–27304 (2002). Initial description of a Prkar1a -null mouse that demonstrates the key role of Prkar1a in early embryogenesis.

    CAS  PubMed  Google Scholar 

  81. Bertherat, J. et al. Molecular and functional analysis of PRKAR1A and its locus (17q22–24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res. 63, 5308–5319 (2003).

    CAS  PubMed  Google Scholar 

  82. Tsilou, E. T. et al. Eyelid myxoma in Carney complex without PRKAR1A allelic loss. Am. J. Med. Genet. 130, 395–397 (2004).

    Google Scholar 

  83. Seizinger, B. R. et al. Report of the committee on chromosome and gene loss in neoplasia. Cytogenet. Cell Genet. 58, 1080–1096 (1991).

    Google Scholar 

  84. Molnar, J., Weiss, J. S. & Rosenthal, J. E. Does heart rate identify sudden death survivors? Assessment of heart rate, QT interval, and heart rate variability. Am. J. Ther. 9, 99–110 (2002).

    PubMed  Google Scholar 

  85. Guzzetti, S. et al. Different spectral components of 24h heart rate variability are related to different modes of death in chronic heart failure. Eur. Heart J. 26, 357–362 (2005).

    PubMed  Google Scholar 

  86. Villareal, R. P., Liu, B. C. & Massumi, A. Heart rate variability and cardiovascular mortality. Curr. Atheroscler. Rep. 4, 120–127 (2002).

    PubMed  Google Scholar 

  87. Griffin, K. J. et al. A mouse model for Carney complex. Endocr. Res. 30, 903–911 (2004).

    CAS  PubMed  Google Scholar 

  88. Kirschner, L. S. et al. A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res. 65, 4506–4514 (2005).

    CAS  PubMed  Google Scholar 

  89. Groussin, L. et al. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J. Clin. Endocrinol. Metab. 87, 4324–4329 (2002).

    CAS  PubMed  Google Scholar 

  90. Rosenberg, D. et al. Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann. NY Acad. Sci. 968, 65–74 (2002).

    CAS  PubMed  Google Scholar 

  91. Ghosh, S. & Baltimore, D. Activation in vitro of NF-κB by phosphorylation of its inhibitor IκB. Nature 344, 678–682 (1990).

    CAS  PubMed  Google Scholar 

  92. Collins, S. P., Reoma, J. L., Gamm, D. M. & Uhler, M. D. LKB1, a novel serine/threonine protein kinase and potential tumour suppressor, is phosphorylated by cAMP-dependent protein kinase (PKA) and prenylated in vivo. Biochem. J. 345, 673–680 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lania, A. G. et al. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res. 64, 9193–9198 (2004).

    CAS  PubMed  Google Scholar 

  94. Gordge, P. C., Hulme, M. J., Clegg, R. A. & Miller, W. R. Elevation of protein kinase A and protein kinase C activities in malignant as compared with normal human breast tissue. Eur. J. Cancer 32A, 2120–2126 (1996).

    CAS  PubMed  Google Scholar 

  95. Bradbury, A. W. et al. Protein kinase A (PK-A) regulatory subunit expression in colorectal cancer and related mucosa. Br. J. Cancer 69, 738–742 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. McDaid, H. M. et al. Increased expression of the RIα subunit of the cAMP-dependent protein kinase A is associated with advanced stage ovarian cancer. Br. J. Cancer 79, 933–939 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Fossberg, T. M., Doskeland, S. O. & Ueland, P. M. Protein kinases in human renal cell carcinoma and renal cortex. A comparison of isozyme distribution and of responsiveness to adenosine 3′:5′-cyclic monophosphate. Arch. Biochem. Biophys. 189, 272–281 (1978).

    CAS  PubMed  Google Scholar 

  98. Nakajima, F., Imashuku, S., Wilimas, J., Champion, J. E. & Green, A. A. Distribution and properties of type I and type II binding proteins in the cyclic adenosine 3′:5′-monophosphate-dependent protein kinase system in Wilms' tumor. Cancer Res. 44, 5182–5187 (1984).

    CAS  PubMed  Google Scholar 

  99. Miller, W. R., Elton, R. A., Dixon, J. M., Chetty, U. & Watson, D. M. Cyclic AMP binding proteins and prognosis in breast cancer. Br. J. Cancer 61, 263–266 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Miller, W. R., Watson, D. M., Jack, W., Chetty, U. & Elton, R. A. Tumour cyclic AMP binding proteins: an independent prognostic factor for disease recurrence and survival in breast cancer. Breast Cancer Res. Treat. 26, 89–94 (1993).

    CAS  PubMed  Google Scholar 

  101. Simpson, B. J. et al. Cyclic adenosine 3′,5′-monophosphate-binding proteins in human ovarian cancer: correlations with clinicopathological features. Clin. Cancer Res. 2, 201–206 (1996).

    CAS  PubMed  Google Scholar 

  102. Nesterova, M. & Cho-Chung, Y. S. A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. Nature Med. 1, 528–533 (1995).

    CAS  PubMed  Google Scholar 

  103. Cho-Chung, Y. S., Pepe, S., Clair, T., Budillon, A. & Nesterova, M. cAMP-dependent protein kinase: role in normal and malignant growth. Crit. Rev. Oncol. Hematol. 21, 33–61 (1995).

    CAS  PubMed  Google Scholar 

  104. Cho-Chung, Y. S. et al. Antisense DNA-targeting protein kinase A-RIA subunit: a novel approach to cancer treatment. Front. Biosci. 4, D898–D907 (1999). Review of therapeutic applications for manipulation of R1α signalling in malignant tumours.

    CAS  PubMed  Google Scholar 

  105. Farrow, B. et al. Inhibition of pancreatic cancer cell growth and induction of apoptosis with novel therapies directed against protein kinase A. Surgery 134, 197–205 (2003).

    PubMed  Google Scholar 

  106. Tortora, G. & Ciardiello, F. Targeting of epidermal growth factor receptor and protein kinase A: molecular basis and therapeutic applications. Ann. Oncol. 11, 777–783 (2000).

    CAS  PubMed  Google Scholar 

  107. Nesterova, M. & Cho-Chung, Y. S. Oligonucleotide sequence-specific inhibition of gene expression, tumor growth inhibition, and modulation of cAMP signaling by an RNA–DNA hybrid antisense targeted to protein kinase A RIα subunit. Antisense Nucleic Acid Drug Dev. 10, 423–433 (2000).

    CAS  PubMed  Google Scholar 

  108. Cho, Y. S. et al. Protein kinase A RIα antisense inhibition of PC3M prostate cancer cell growth: Bcl-2 hyperphosphorylation, Bax up-regulation, and Bad-hypophosphorylation. Clin. Cancer Res. 8, 607–614 (2002).

    CAS  PubMed  Google Scholar 

  109. Wang, H. et al. Antitumor activity and pharmacokinetics of a mixed-backbone antisense oligonucleotide targeted to the RIα subunit of protein kinase A after oral administration. Proc. Natl Acad. Sci. USA 96, 13989–13994 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Michael Wolk Heart Foundation (C.T.B.), the Snart Cardiovascular Fund (C.T.B.) and the Hellenic Society of Cardiology (K.C.). C.T.B. is an Established Investigator of the American Heart Association and an Irma T. Hirschl Scholar.

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  1. Greenberg Division of Cardiology, Department of Medicine, Weill Medical College of Cornell University, 525 East 68th Street, New York, 10021, New York, USA

    David Wilkes, Konstantinos Charitakis & Craig T. Basson

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  1. David Wilkes
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  2. Konstantinos Charitakis
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  3. Craig T. Basson
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Correspondence to Craig T. Basson.

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A disorder that results from increased adrenocortical secretion of cortisol.

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Endocrine disorder that is marked by progressive enlargement of peripheral parts of the body, especially the head, face, hands and feet, owing to excessive secretion of somatotropin.

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Rare inherited disorder that is characterized by the inability to completely open the mouth (trismus) and/or the presence of abnormally short muscle-tendon units in the hands and feet, causing the digits to curve or bend when the hand or foot is dorsiflexed.

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Similar to handedness, people usually have a dominant right or left eye — this is referred to as ocular dominance. In some circumstances, this can be modified by genetic and/or environmental factors (plasticity).

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Wilkes, D., Charitakis, K. & Basson, C. Inherited disposition to cardiac myxoma development. Nat Rev Cancer 6, 157–165 (2006). https://doi.org/10.1038/nrc1798

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