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CNC2  -  Carney complex type 2, multiple neoplasia...

Homo sapiens

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Disease relevance of CNC

  • Carney complex (CNC) is a familial multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and cutaneous myxomas, and endocrine tumors [1].
  • Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of cortisol production to glucocorticoids) and multi-tissue involvement [2].
  • So far, half of the patients with CNC have germline inactivating mutations in the PRKAR1A gene; in their pituitary tumors, the normal allele of the PRKAR1A gene is lost [3].
  • These data provide evidence for a PRKAR1A-induced somatomammotroph hyperpasia in the pituitary tissue of CNC patients; hyperplasia, in turn may lead to additional genetic changes at the somatic level, which then cause the formation of adenomas in some, but not all, patients [3].
  • Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2 [4].

Psychiatry related information on CNC


High impact information on CNC

  • 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 [8].
  • 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 PRKAR1alpha deletion revealed that the myxoma cells retain both the wild-type and the mutant PRKAR1alpha alleles and that wild-type R1alpha protein is stably expressed [9].
  • Our linkage analysis mapped a Carney complex gene defect to chromosome 17q24 [9].
  • Furthermore, we show that PRKAR1alpha frameshift mutations in three unrelated families result in haploinsufficiency of R1alpha and cause Carney complex [9].
  • The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex [4].

Chemical compound and disease context of CNC


Biological context of CNC

  • We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC patients, including those with germline, inactivating PRKAR1A mutations [14].
  • To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs) [14].
  • Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex [15].
  • Chromosome 2 (2p16) abnormalities in Carney complex tumours [14].
  • Histochemistry of tissues from CNC patients is indicative of autophagic deficiency and this led us to investigate the relationship between RIalpha and mammalian autophagy [16].

Anatomical context of CNC


Associations of CNC with chemical compounds

  • 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].
  • 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 [22].
  • 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 [23].
  • Substitution of all 4 non-activation loop tyrosine residues significantly attenuated, but did not abolish, TDII transforming activity [24].
  • Furthermore, following TDII transfection, signal transducer and activator of transcription 1 (STAT1) is phosphorylated in the absence of FGFR3 ligand and brefeldin A does not inhibit its activation [25].

Regulatory relationships of CNC

  • 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 [26].
  • The congenital gene defects of Carney complex or of Peutz-Jeghers syndrome might trigger a cascade of intracellular events that leads to overexpression of aromatase in Sertoli cells, favoring the development of a LCCSCT [27].

Other interactions of CNC


Analytical, diagnostic and therapeutic context of CNC


  1. Haploinsufficiency at the Protein Kinase A RI{alpha} Gene Locus Leads to Fertility Defects in Male Mice and Men. Burton, K.A., McDermott, D.A., Wilkes, D., Poulsen, M.N., Nolan, M.A., Goldstein, M., Basson, C.T., McKnight, G.S. Mol. Endocrinol. (2006) [Pubmed]
  2. Carney complex: pathology and molecular genetics. Boikos, S.A., Stratakis, C.A. Neuroendocrinology (2006) [Pubmed]
  3. Pituitary pathology in Carney complex patients. Stergiopoulos, S.G., Abu-Asab, M.S., Tsokos, M., Stratakis, C.A. Pituitary (2004) [Pubmed]
  4. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. Stratakis, C.A., Carney, J.A., Lin, J.P., Papanicolaou, D.A., Karl, M., Kastner, D.L., Pras, E., Chrousos, G.P. J. Clin. Invest. (1996) [Pubmed]
  5. 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]
  6. Behavioral differences among subjects with Prader-Willi syndrome and type I or type II deletion and maternal disomy. Butler, M.G., Bittel, D.C., Kibiryeva, N., Talebizadeh, Z., Thompson, T. Pediatrics (2004) [Pubmed]
  7. Expression of 4 genes between chromosome 15 breakpoints 1 and 2 and behavioral outcomes in prader-willi syndrome. Bittel, D.C., Kibiryeva, N., Butler, M.G. Pediatrics (2006) [Pubmed]
  8. 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]
  9. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. Casey, M., Vaughan, C.J., He, J., Hatcher, C.J., Winter, J.M., Weremowicz, S., Montgomery, K., Kucherlapati, R., Morton, C.C., Basson, C.T. J. Clin. Invest. (2000) [Pubmed]
  10. GH-secreting pituitary adenomas infrequently contain inactivating mutations of PRKAR1A and LOH of 17q23-24. Yamasaki, H., Mizusawa, N., Nagahiro, S., Yamada, S., Sano, T., Itakura, M., Yoshimoto, K. Clin. Endocrinol. (Oxf) (2003) [Pubmed]
  11. 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]
  12. Functional ion channels in pulmonary alveolar type I cells support a role for type I cells in lung ion transport. Johnson, M.D., Bao, H.F., Helms, M.N., Chen, X.J., Tigue, Z., Jain, L., Dobbs, L.G., Eaton, D.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  13. Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. Iwata, T., Li, C.L., Deng, C.X., Francomano, C.A. Hum. Mol. Genet. (2001) [Pubmed]
  14. Chromosome 2 (2p16) abnormalities in Carney complex tumours. Matyakhina, L., Pack, S., Kirschner, L.S., Pak, E., Mannan, P., Jaikumar, J., Taymans, S.E., Sandrini, F., Carney, J.A., Stratakis, C.A. J. Med. Genet. (2003) [Pubmed]
  15. 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]
  16. Depletion of type IA regulatory subunit (RI{alpha}) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Mavrakis, M., Lippincott-Schwartz, J., Stratakis, C.A., Bossis, I. Hum. Mol. Genet. (2006) [Pubmed]
  17. 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]
  18. 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]
  19. Pathology and molecular genetics of the pituitary gland in patients with the 'complex of spotty skin pigmentation, myxomas, endocrine overactivity and schwannomas' (Carney complex). Stratakis, C.A., Matyakhina, L., Courkoutsakis, N., Patronas, N., Voutetakis, A., Stergiopoulos, S., Bossis, I., Carney, J.A. Frontiers of hormone research. (2004) [Pubmed]
  20. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. Stratakis, C.A., Kirschner, L.S., Carney, J.A. J. Clin. Endocrinol. Metab. (2001) [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 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]
  23. 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]
  24. Constitutively activated FGFR3 mutants signal through PLCgamma-dependent and -independent pathways for hematopoietic transformation. Chen, J., Williams, I.R., Lee, B.H., Duclos, N., Huntly, B.J., Donoghue, D.J., Gilliland, D.G. Blood (2005) [Pubmed]
  25. The thanatophoric dysplasia type II mutation hampers complete maturation of fibroblast growth factor receptor 3 (FGFR3), which activates signal transducer and activator of transcription 1 (STAT1) from the endoplasmic reticulum. Lievens, P.M., Liboi, E. J. Biol. Chem. (2003) [Pubmed]
  26. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Nadella, K.S., Kirschner, L.S. Cancer Res. (2005) [Pubmed]
  27. High TGFbeta1, estrogen receptor, and aromatase gene expression in a large cell calcifying sertoli cell tumor (LCCSCT): implications for the mechanism of oncogenesis. Saraco, N., Berensztein, E., Sciara, M., de Davila, M.T., Ciaccio, M., Ferrari, P., Belgorosky, A., Rivarola, M.A. Pediatr. Dev. Pathol. (2006) [Pubmed]
  28. Growth hormone-secreting tumors: genetic aspects and data from animal models. Lytras, A., Tolis, G. Neuroendocrinology (2006) [Pubmed]
  29. Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity. So, A., Duffy, D.L., Gordon, R.D., Jeske, Y.W., Lin-Su, K., New, M.I., Stowasser, M. J. Hypertens. (2005) [Pubmed]
  30. Clinical phenotypes and molecular genetic mechanisms of Carney complex. Wilkes, D., McDermott, D.A., Basson, C.T. The lancet oncology. (2005) [Pubmed]
  31. Synaptophysin immunoreactivity in primary pigmented nodular adrenocortical disease: neuroendocrine properties of tumors associated with Carney complex. Stratakis, C.A., Carney, J.A., Kirschner, L.S., Willenberg, H.S., Brauer, S., Ehrhart-Bornstein, M., Bornstein, S.R. J. Clin. Endocrinol. Metab. (1999) [Pubmed]
  32. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. Veugelers, M., Bressan, M., McDermott, D.A., Weremowicz, S., Morton, C.C., Mabry, C.C., Lefaivre, J.F., Zunamon, A., Destree, A., Chaudron, J.M., Basson, C.T. N. Engl. J. Med. (2004) [Pubmed]
  33. 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]
  34. Carney complex: the first 20 years. Boikos, S.A., Stratakis, C.A. Current opinion in oncology (2007) [Pubmed]
  35. Melanotic nonpsammomatous trigeminal schwannoma as the first manifestation of Carney complex: case report. Carrasco, C.A., Rojas-Salazar, D., Chiorino, R., Venega, J.C., Wohllk, N. Neurosurgery (2006) [Pubmed]
  36. An implant-supported prosthesis with a CNC-milled framework for the rehabilitation of the edentulous jaw. Shor, A., Goto, Y. Practical procedures & aesthetic dentistry : PPAD. (2006) [Pubmed]
  37. Evaluation of equivalency in two recordings of monosyllabic words. Skinner, M.W., Holden, L.K., Fourakis, M.S., Hawks, J.W., Holden, T., Arcaroli, J., Hyde, M. Journal of the American Academy of Audiology. (2006) [Pubmed]
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