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PRKAR1A  -  protein kinase, cAMP-dependent, regulatory...

Homo sapiens

Synonyms: ACRDYS1, ADOHR, CAR, CNC, CNC1, ...
 
 
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Disease relevance of PRKAR1A

 

Psychiatry related information on PRKAR1A

 

High impact information on PRKAR1A

  • Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome [9].
  • In CNC families mapping to 17q, we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (RIalpha), including a polymorphic site within its 5' region [10].
  • Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas [10].
  • Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas [10].
  • We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease [10].
 

Chemical compound and disease context of PRKAR1A

  • Somatic inactivating mutations of PRKAR1A have been observed in macronodules of PPNAD and in sporadic cortisol secreting adrenal adenomas [11].
  • PJS and CNC share manifestations with Cowden syndrome (or Cowden disease) (CS, OMIM#158350) and Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM#153480) [12].
  • A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD) [13].
  • Clinical experience of CNC-milled titanium frameworks supported by implants in the edentulous jaw: a 3-year interim report [14].
 

Biological context of PRKAR1A

 

Anatomical context of PRKAR1A

  • The mutant protein was present in patients' leukocytes and tumors, and in vitro studies indicated that the mutant PRKAR1A activated cAMP-dependent protein kinase A (PKA) signaling at the nuclear level [18].
  • The mRNA produced by the PRKAR1A undergoes decay if it codes for a truncated protein; we therefore also determined PRKAR1A mRNA levels in the tumours, and compared them with known mutant PRKAR1A-carrying lymphocyte samples [19].
  • Expression of the two alternatively spliced PRKAR1A RNAs in human endocrine glands [4].
  • OBJECTIVE: Carney complex (CNC) is an autosomal dominant multiple neoplasia syndrome featuring cardiac, endocrine, cutaneous and neural tumours, as well as a variety of pigmented lesions of the skin and mucosa [19].
  • PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex [20].
 

Associations of PRKAR1A with chemical compounds

  • 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 [18].
  • PPNAD and/or CNC patients with and without mutations leading to protein kinase A activation demonstrated in vitro and/or in vivo paradoxical dexamethasone responses and GR expression, indicating that PRKAR1A alterations are not necessary for these phenomena [21].
  • We conclude that PKA activity in CNC cells is increased and that its stimulation by forskolin or isoproterenol increases LPA-induced ERK1/2 phosphorylation, cell metabolism and proliferation [1].
  • The endocrine tumors of CS and PJS, which could classify these disorders as variant types of multiple endocrine neoplasias (MENs), are not present in most CS and BRR patients, but lentigines are shared by PJS, CNC and BRR [12].
  • These tissues are also targets of Carney complex (CNC), a multiple neoplasia syndrome caused by germline inactivating PRKAR1A mutations (PRKAR1A-mut) and associated with primary pigmented nodular adrenocortical disease (PPNAD) and increased steroid synthesis [22].
 

Regulatory relationships of PRKAR1A

  • We have shown previously that patients with the autosomal dominant tumor predisposition Carney complex carry inactivating mutations in the PRKAR1A gene, which encodes the type 1A regulatory subunit of protein kinase A (PKA), the cyclic AMP-dependent protein kinase [23].
 

Other interactions of PRKAR1A

  • Using duplex polymerase chain reaction (PCR) with the PRKAR1A and the "housekeeping" gene GAPDH, we determined the relative expression of the PRKAR1A gene in the unknown as well as in the positive control samples [19].
  • Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2 [1].
  • METHODS: We extracted RNA from a series of pituitary tumours, reverse transcribed it to cDNA, and directly sequenced the PRKAR1A coding sequence in 17 GH-secreting, three prolactin-secreting, three ACTH-secreting, one FSH-secreting and 10 nonfunctioning pituitary tumours [19].
  • PAP7 and PRKAR1A expression were studied in PPNAD and in lymphoblasts from patients bearing PRKAR1A-mut [22].
  • PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia [24].
 

Analytical, diagnostic and therapeutic context of PRKAR1A

References

  1. Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. Robinson-White, A., Hundley, T.R., Shiferaw, M., Bertherat, J., Sandrini, F., Stratakis, C.A. Hum. Mol. Genet. (2003) [Pubmed]
  2. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. Groussin, L., Jullian, E., Perlemoine, K., Louvel, A., Leheup, B., Luton, J.P., Bertagna, X., Bertherat, J. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  3. Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (PRKAR1A) in odontogenic myxomas. Perdigão, P.F., Stergiopoulos, S.G., De Marco, L., Matyakhina, L., Boikos, S.A., Gomez, R.S., Pimenta, F.J., Stratakis, C.A. Genes Chromosomes Cancer (2005) [Pubmed]
  4. Expression of the two alternatively spliced PRKAR1A RNAs in human endocrine glands. Peverelli, E., Mantovani, G., Bondioni, S., Pellegrini, C., Bosari, S., Lania, A.G., Beck-Peccoz, P., Spada, A. Mol. Cell. Endocrinol. (2005) [Pubmed]
  5. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit (PRKAR1A) in patients with the "complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas" (Carney complex). Stratakis, C.A. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  6. Large deletions of the PRKAR1A gene in Carney complex. Horvath, A., Bossis, I., Giatzakis, C., Levine, E., Weinberg, F., Meoli, E., Robinson-White, A., Siegel, J., Soni, P., Groussin, L., Matyakhina, L., Verma, S., Remmers, E., Nesterova, M., Carney, J.A., Bertherat, J., Stratakis, C.A. Clin. Cancer Res. (2008) [Pubmed]
  7. Genomic mapping of chromosomal region 2p15-p21 (D2S378-D2S391): integration of Genemap'98 within a framework of yeast and bacterial artificial chromosomes. Kirschner, L.S., Taymans, S.E., Pack, S., Pak, E., Pike, B.L., Chandrasekharappa, S.C., Zhuang, Z., Stratakis, C.A. Genomics (1999) [Pubmed]
  8. Effects of insertion depth of cochlear implant electrodes upon speech perception. Yukawa, K., Cohen, L., Blamey, P., Pyman, B., Tungvachirakul, V., O'Leary, S. Audiol. Neurootol. (2004) [Pubmed]
  9. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Horvath, A., Boikos, S., Giatzakis, C., Robinson-White, A., Groussin, L., Griffin, K.J., Stein, E., Levine, E., Delimpasi, G., Hsiao, H.P., Keil, M., Heyerdahl, S., Matyakhina, L., Libè, R., Fratticci, A., Kirschner, L.S., Cramer, K., Gaillard, R.C., Bertagna, X., Carney, J.A., Bertherat, J., Bossis, I., Stratakis, C.A. Nat. Genet. (2006) [Pubmed]
  10. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Kirschner, L.S., Carney, J.A., Pack, S.D., Taymans, S.E., Giatzakis, C., Cho, Y.S., Cho-Chung, Y.S., Stratakis, C.A. Nat. Genet. (2000) [Pubmed]
  11. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Cazabat, L., Ragazzon, B., Groussin, L., Bertherat, J. Pituitary (2006) [Pubmed]
  12. Genetics of Peutz-Jeghers syndrome, Carney complex and other familial lentiginoses. Stratakis, C.A. Horm. Res. (2000) [Pubmed]
  13. A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex. Cignarelli, M., Picca, G., Campo, M., Margaglione, M., Marino, A., Logoluso, F., Giorgino, F. J. Endocrinol. Invest. (2005) [Pubmed]
  14. Clinical experience of CNC-milled titanium frameworks supported by implants in the edentulous jaw: a 3-year interim report. Ortorp, A., Jemt, T. Clinical implant dentistry and related research. (2002) [Pubmed]
  15. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Veugelers, M., Wilkes, D., Burton, K., McDermott, D.A., Song, Y., Goldstein, M.M., La Perle, K., Vaughan, C.J., O'Hagan, A., Bennett, K.R., Meyer, B.J., Legius, E., Karttunen, M., Norio, R., Kaariainen, H., Lavyne, M., Neau, J.P., Richter, G., Kirali, K., Farnsworth, A., Stapleton, K., Morelli, P., Takanashi, Y., Bamforth, J.S., Eitelberger, F., Noszian, I., Manfroi, W., Powers, J., Mochizuki, Y., Imai, T., Ko, G.T., Driscoll, D.A., Goldmuntz, E., Edelberg, J.M., Collins, A., Eccles, D., Irvine, A.D., McKnight, G.S., Basson, C.T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  16. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Kirschner, L.S., Sandrini, F., Monbo, J., Lin, J.P., Carney, J.A., Stratakis, C.A. Hum. Mol. Genet. (2000) [Pubmed]
  17. Minireview: PRKAR1A: normal and abnormal functions. Bossis, I., Stratakis, C.A. Endocrinology (2004) [Pubmed]
  18. 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. Groussin, L., Kirschner, L.S., Vincent-Dejean, C., Perlemoine, K., Jullian, E., Delemer, B., Zacharieva, S., Pignatelli, D., Carney, J.A., Luton, J.P., Bertagna, X., Stratakis, C.A., Bertherat, J. Am. J. Hum. Genet. (2002) [Pubmed]
  19. Sequence analysis of the PRKAR1A gene in sporadic somatotroph and other pituitary tumours. Kaltsas, G.A., Kola, B., Borboli, N., Morris, D.G., Gueorguiev, M., Swords, F.M., Czirják, S., Kirschner, L.S., Stratakis, C.A., Korbonits, M., Grossman, A.B. Clin. Endocrinol. (Oxf) (2002) [Pubmed]
  20. PRKAR1A Mutations and protein kinase A interactions with other signaling pathways in the adrenal cortex. Robinson-White, A., Meoli, E., Stergiopoulos, S., Horvath, A., Boikos, S., Bossis, I., Stratakis, C.A. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  21. Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor. Bourdeau, I., Lacroix, A., Schürch, W., Caron, P., Antakly, T., Stratakis, C.A. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  22. Molecular cloning, chromosomal localization of human peripheral-type benzodiazepine receptor and PKA regulatory subunit type 1A (PRKAR1A)-associated protein PAP7, and studies in PRKAR1A mutant cells and tissues. Liu, J., Matyakhina, L., Han, Z., Sandrini, F., Bei, T., Stratakis, C.A., Papadopoulos, V. FASEB J. (2003) [Pubmed]
  23. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Nadella, K.S., Kirschner, L.S. Cancer Res. (2005) [Pubmed]
  24. PECAM1, MPO and PRKAR1A at chromosome 17q21-q24 and susceptibility for multiple sclerosis in Sweden and Sardinia. Nelissen, I., Fiten, P., Vandenbroeck, K., Hillert, J., Olsson, T., Marrosu, M.G., Opdenakker, G. J. Neuroimmunol. (2000) [Pubmed]
  25. 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. Bertherat, J., Groussin, L., Sandrini, F., Matyakhina, L., Bei, T., Stergiopoulos, S., Papageorgiou, T., Bourdeau, I., Kirschner, L.S., Vincent-Dejean, C., Perlemoine, K., Gicquel, C., Bertagna, X., Stratakis, C.A. Cancer Res. (2003) [Pubmed]
  26. Ovarian lesions in Carney complex: clinical genetics and possible predisposition to malignancy. Stratakis, C.A., Papageorgiou, T., Premkumar, A., Pack, S., Kirschner, L.S., Taymans, S.E., Zhuang, Z., Oelkers, W.H., Carney, J.A. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
 
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