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Gene Review

GNAS  -  GNAS complex locus

Homo sapiens

Synonyms: AHO, C20orf45, GNAS1, GNASXL, GPSA, ...
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Disease relevance of GNAS


Psychiatry related information on GNAS

  • Association of the GNAS1 gene variant with hypertension is dependent on alcohol consumption [6].
  • In this report, we describe two unrelated patients with mental retardation and brachydactyly E classified as patients suffering from Albright hereditary osteodystrophy-like (AHO-like) syndrome [7].
  • As a result of the potential relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence using genomic DNA pools from autistic disorder, obsessive-compulsive disorder (OCD) probands and control subjects [8].
  • The results demonstrated that framing paradigms and methods can be usefully applied to the study of cognitive processes in social phobia and indicated that research to examine how GSP patients process specific types of social information is needed [9].
  • Individuals with Generalized Social Phobia (GSP, N = 25) and community controls (N = 26) participated in a social interaction task [10].

High impact information on GNAS

  • Epigenetic defects in the imprinted GNAS cluster are associated with pseudohypoparathyroidism type Ib [11].
  • In two kindreds with this disorder, we now report deletions that remove the differentially methylated region encompassing exon NESP55 and exons 3 and 4 of the antisense transcript [11].
  • Hence, XL alpha s may mediate the effects of cholera toxin on secretory vesicle formation [12].
  • XL alpha s is specifically associated with the trans-Golgi network and occurs selectively in cells containing both the regulated and the constitutive pathway of protein secretion [12].
  • Interestingly, paternal transmission of GNAS1 mutations leads to the AHO phenotype alone (pseudopseudohypoparathyroidism), while maternal transmission leads to AHO plus resistance to several hormones (e.g., PTH, TSH) that activate G(s) in their target tissues (pseudohypoparathyroidism type IA) [13].

Chemical compound and disease context of GNAS


Biological context of GNAS

  • We have now performed a detailed analysis of the GNAS methylation profile in 20 unrelated PHPIB probands [3].
  • Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein [19].
  • PHP-Ia is caused by heterozygous mutations affecting one of the 13 GNAS exons encoding Gsalpha or by large intragenic deletions [20].
  • However, an imprinted autosomal dominant form of PHP-Ib (AD-PHP-Ib) has been mapped to a region of chromosome 20q13.3 containing GNAS [21].
  • MAS is caused by sporadic, postzygotic, activating mutations in the GNAS gene, which codes for the cAMP-regulating protein, G(s)alpha (gsp oncogene) [22].

Anatomical context of GNAS

  • Instead, the region of overlap between the two microdeletions likely harbors a cis-acting imprinting control element that is necessary for establishing and/or maintaining methylation at GNAS exon A/B, thus allowing normal G alpha(s) expression in the proximal renal tubules [23].
  • Well-described GNAS mutations like fibrous dysplasia or Albright hereditary osteodystrophy are linked to abnormality in osteoblast function, and numerous evidences showed that Gsalpha coupled adrenergic receptors increase the expression of osteotrophic factors and regulate bone mass [24].
  • We therefore used PNA-clamping to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with McCune-Albright syndrome and fibrous dysplasia [25].
  • Nevertheless, his circulating fibroblast growth factor 23 (FGF-23) level was elevated, likely functioning as a "phosphatonin," yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune-Albright syndrome were detected in his leukocytes or affected skin [26].
  • Because in MAS patients, tissues as diverse as melanocytes, gonads and bone are affected, it is generally accepted that the GNAS mutation in this disease must have occurred early in development [27].

Associations of GNAS with chemical compounds

  • Purity, as assessed by GCMS, was shown to be greater than 95% for SNAS, SaMT, and GaMT and to be 88% for GNAS [28].
  • Accordingly, here we investigated the effect of GSP on mitogenic signaling and regulators of cell cycle and apoptosis as molecular targets for the growth arrest, apoptotic death, and/or differentiation of estrogen-independent MDA-MB468 human breast carcinoma cells [29].
  • Additional studies assessing the biological fate of GSP-treated cells showed that they do not undergo apoptotic death, as evidenced by a lack of DNA fragmentation, poly (ADP ribose) polymerase cleavage, and apoptotic morphology of the cells [29].
  • Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study [30].
  • The GNAS1 gene encodes the alpha subunit of the G protein Gs, which couples receptor binding by several hormones to activation of adenylate cyclase [31].

Regulatory relationships of GNAS


Other interactions of GNAS

  • All five probands with familial disease had a deletion mutation within the closely linked STX16 gene and a GNAS imprinting defect involving only the exon 1A region [3].
  • Several human disorders that result from genetic G-protein abnormalities involve the imprinted GNAS gene, which encodes Gs alpha, the ubiquitously expressed alpha-subunit that couples receptors to adenylyl cyclase and cAMP generation [2].
  • PHP-Ia and PPHP are caused by heterozygous inactivating mutations in those exons of GNAS encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsalpha), and the autosomal dominant form of PHP-Ib (AD-PHP-Ib) is caused by heterozygous mutations disrupting a long-range imprinting control element of GNAS [33].
  • In FRTL5, expression of GSP or mutant (m) TSHR induced a 2 - 3-fold increase in basal levels of cAMP [34].
  • In primary cultures, expression of mTSHR, but not GSP, consistently induced formation of colonies with epithelial morphology and thyroglobulin expression, capable of 10 - 15 population doublings (PD) compared to less than three in controls [34].

Analytical, diagnostic and therapeutic context of GNAS


  1. 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]
  2. Genetic diseases associated with heterotrimeric G proteins. Weinstein, L.S., Chen, M., Xie, T., Liu, J. Trends Pharmacol. Sci. (2006) [Pubmed]
  3. Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB. Liu, J., Nealon, J.G., Weinstein, L.S. Hum. Mol. Genet. (2005) [Pubmed]
  4. Pseudohypoparathyroidism type 1a with congenital hypothyroidism. Pinsker, J.E., Rogers, W., McLean, S., Schaefer, F.V., Fenton, C. J. Pediatr. Endocrinol. Metab. (2006) [Pubmed]
  5. Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study. Terra, S.G., McGorray, S.P., Wu, R., McNamara, D.M., Cavallari, L.H., Walker, J.R., Wallace, M.R., Johnson, B.D., Bairey Merz, C.N., Sopko, G., Pepine, C.J., Johnson, J.A. International journal of obesity (2005) (2005) [Pubmed]
  6. Association of the GNAS1 gene variant with hypertension is dependent on alcohol consumption. Chen, Y., Nakura, J., Jin, J.J., Wu, Z., Yamamoto, M., Abe, M., Tabara, Y., Yamamoto, Y., Igase, M., Bo, X., Kohara, K., Miki, T. Hypertens. Res. (2003) [Pubmed]
  7. Two further AHO-like syndrome patients with deletion of glypican 1 gene region in 2q37.2-q37.3. Polityko, A., Maltseva, O., Rumyantseva, N., Khurs, O., Seidel, J., Claussen, U., Weise, A., Liehr, T., Starke, H. Int. J. Mol. Med. (2004) [Pubmed]
  8. Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1. Kim, S.J., Gonen, D., Hanna, G.L., Leventhal, B.L., Cook, E.H. Mol. Cell. Probes (2000) [Pubmed]
  9. Framing social information and generalized social phobia. Alden, L.E., Mellings, T.M., Laposa, J.M. Behaviour research and therapy. (2004) [Pubmed]
  10. Generalized Social Phobia and social judgments: the salience of self- and partner-information. Alden, L.E., Mellings, T.M. Journal of anxiety disorders. (2004) [Pubmed]
  11. Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib. Bastepe, M., Fröhlich, L.F., Linglart, A., Abu-Zahra, H.S., Tojo, K., Ward, L.M., Jüppner, H. Nat. Genet. (2005) [Pubmed]
  12. XL alpha s is a new type of G protein. Kehlenbach, R.H., Matthey, J., Huttner, W.B. Nature (1994) [Pubmed]
  13. Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting. Weinstein, L.S., Yu, S., Warner, D.R., Liu, J. Endocr. Rev. (2001) [Pubmed]
  14. Perillyl alcohol as a chemopreventive agent in N-nitrosomethylbenzylamine-induced rat esophageal tumorigenesis. Liston, B.W., Nines, R., Carlton, P.S., Gupta, A., Aziz, R., Frankel, W., Stoner, G.D. Cancer Res. (2003) [Pubmed]
  15. Perillyl alcohol as a radio-/chemosensitizer in malignant glioma. Rajesh, D., Stenzel, R.A., Howard, S.P. J. Biol. Chem. (2003) [Pubmed]
  16. Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Ripple, G.H., Gould, M.N., Arzoomanian, R.Z., Alberti, D., Feierabend, C., Simon, K., Binger, K., Tutsch, K.D., Pomplun, M., Wahamaki, A., Marnocha, R., Wilding, G., Bailey, H.H. Clin. Cancer Res. (2000) [Pubmed]
  17. The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome. Hahn, S., Frey, U.H., Siffert, W., Tan, S., Mann, K., Janssen, O.E. Eur. J. Endocrinol. (2006) [Pubmed]
  18. Monoterpenes inhibit proliferation of human colon cancer cells by modulating cell cycle-related protein expression. Bardon, S., Foussard, V., Fournel, S., Loubat, A. Cancer Lett. (2002) [Pubmed]
  19. Neuroendocrine secretory protein 55 (NESP55): alternative splicing onto transcripts of the GNAS gene and posttranslational processing of a maternally expressed protein. Weiss, U., Ischia, R., Eder, S., Lovisetti-Scamihorn, P., Bauer, R., Fischer-Colbrie, R. Neuroendocrinology (2000) [Pubmed]
  20. Autosomal-dominant pseudohypoparathyroidism type Ib is caused by different microdeletions within or upstream of the GNAS locus. Jüppner, H., Linglart, A., Fröhlich, L.F., Bastepe, M. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  21. Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS. Bastepe, M., Fröhlich, L.F., Hendy, G.N., Indridason, O.S., Josse, R.G., Koshiyama, H., Körkkö, J., Nakamoto, J.M., Rosenbloom, A.L., Slyper, A.H., Sugimoto, T., Tsatsoulis, A., Crawford, J.D., Jüppner, H. J. Clin. Invest. (2003) [Pubmed]
  22. Pegvisomant for the treatment of gsp-mediated growth hormone excess in patients with McCune-Albright syndrome. Akintoye, S.O., Kelly, M.H., Brillante, B., Cherman, N., Turner, S., Butman, J.A., Robey, P.G., Collins, M.T. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  23. A novel STX16 deletion in autosomal dominant pseudohypoparathyroidism type Ib redefines the boundaries of a cis-acting imprinting control element of GNAS. Linglart, A., Gensure, R.C., Olney, R.C., Jüppner, H., Bastepe, M. Am. J. Hum. Genet. (2005) [Pubmed]
  24. Runx2 regulates the expression of GNAS on SaOs-2 cells. Bertaux, K., Broux, O., Chauveau, C., Hardouin, P., Jeanfils, J., Devedjian, J.C. Bone (2006) [Pubmed]
  25. A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. Lietman, S.A., Ding, C., Levine, M.A. The Journal of bone and joint surgery. American volume. (2005) [Pubmed]
  26. Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis? Heike, C.L., Cunningham, M.L., Steiner, R.D., Wenkert, D., Hornung, R.L., Gruss, J.S., Gannon, F.H., McAlister, W.H., Mumm, S., Whyte, M.P. Am. J. Med. Genet. A (2005) [Pubmed]
  27. A novel technique based on a PNA hybridization probe and FRET principle for quantification of mutant genotype in fibrous dysplasia/McCune-Albright syndrome. Karadag, A., Riminucci, M., Bianco, P., Cherman, N., Kuznetsov, S.A., Nguyen, N., Collins, M.T., Robey, P.G., Fisher, L.W. Nucleic Acids Res. (2004) [Pubmed]
  28. The isolation, purification, and characterisation of the principal urinary metabolites of melatonin. Leone, A.M., Francis, P.L., Silman, R.E. J. Pineal Res. (1987) [Pubmed]
  29. A polyphenolic fraction from grape seeds causes irreversible growth inhibition of breast carcinoma MDA-MB468 cells by inhibiting mitogen-activated protein kinases activation and inducing G1 arrest and differentiation. Agarwal, C., Sharma, Y., Zhao, J., Agarwal, R. Clin. Cancer Res. (2000) [Pubmed]
  30. Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Nieminen, T., Uusitalo, H., Mäenpää, J., Turjanmaa, V., Rane, A., Lundgren, S., Ropo, A., Rontu, R., Lehtimäki, T., Kähönen, M. Eur. J. Clin. Pharmacol. (2005) [Pubmed]
  31. The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins. Hayward, B.E., Kamiya, M., Strain, L., Moran, V., Campbell, R., Hayashizaki, Y., Bonthron, D.T. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  32. Coding GNAS mutations leading to hormone resistance impair in vitro agonist- and cholera toxin-induced adenosine cyclic 3',5'-monophosphate formation mediated by human XLalphas. Linglart, A., Mahon, M.J., Kerachian, M.A., Berlach, D.M., Hendy, G.N., Jüppner, H., Bastepe, M. Endocrinology (2006) [Pubmed]
  33. GNAS locus and pseudohypoparathyroidism. Bastepe, M., Jüppner, H. Horm. Res. (2005) [Pubmed]
  34. Contrasting effects of activating mutations of GalphaS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Ludgate, M., Gire, V., Crisp, M., Ajjan, R., Weetman, A., Ivan, M., Wynford-Thomas, D. Oncogene (1999) [Pubmed]
  35. Activating mutations of Gsalpha in kidney cancer. Kalfa, N., Lumbroso, S., Boulle, N., Guiter, J., Soustelle, L., Costa, P., Chapuis, H., Baldet, P., Sultan, C. J. Urol. (2006) [Pubmed]
  36. NESP55, a novel chromogranin-like peptide, is expressed in endocrine tumours of the pancreas and adrenal medulla but not in ileal carcinoids. Jakobsen, A.M., Ahlman, H., Kölby, L., Abrahamsson, J., Fischer-Colbrie, R., Nilsson, O. Br. J. Cancer (2003) [Pubmed]
  37. Mapping of the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase (GNAS1) to 20q13.2----q13.3 in human by in situ hybridization. Levine, M.A., Modi, W.S., O'Brien, S.J. Genomics (1991) [Pubmed]
  38. G protein polymorphisms do not predict weight loss and improvement of hypertension in severely obese patients. Potoczna, N., Wertli, M., Steffen, R., Ricklin, T., Lentes, K.U., Horber, F.F. J. Gastrointest. Surg. (2004) [Pubmed]
  39. Mutational analysis of the GNAS1 exons encoding the stimulatory G protein in five patients with pseudohypoparathyroidism type 1a. Lim, S.H., Poh, L.K., Cowell, C.T., Tey, B.H., Loke, K.Y. Journal of pediatric endocrinology & metabolism : JPEM. (2002) [Pubmed]
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