DO: 0112010;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20q13.32 | Pituitary adenoma 3, multiple types, somatic | 617686 | 3 | GNAS | 139320 |
A number sign (#) is used with this entry because multiple types of pituitary adenomas (PITA3) are caused by somatic mutation in the GNAS gene (139320) on chromosome 20q13.
Somatic mutations in the GNAS gene have been found predominantly in GH-secreting pituitary adenomas but also in ACTH-secreting adenomas.
Mutations in the GNAS gene have been found in about 40% of sporadic somatotrophin adenomas (summary by Mete and Lopes, 2017).
For a general description and a discussion of genetic heterogeneity of pituitary adenomas, see PITA1 (102200).
Barlier et al. (1998) found that GNAS-mutant GH-secreting pituitary adenomas secreted significantly more growth hormone relative to tumor size compared to adenomas without GNAS mutations. In vitro and in vivo studies found that the mutant adenomas showed better sensitivity to octreotide; the GH nadir was significantly lower in the mutant adenomas compared to the nonmutant adenomas (85% of maximal inhibition vs 52%). In 18 acromegalic patients treated with octreotide for at least 3 months before surgery, the percent inhibition of GH hypersecretion was higher in those with somatic GNAS-mutant adenomas compared to nonmutant adenomas (76% vs 47%). GH hypersecretion was controlled in all patients with GNAS-mutant adenomas during 2 years of postoperative follow-up, even in those in whom tumor tissue remained after surgery. In contrast, patients with GNAS-negative adenomas did not respond as well to octreotide treatment.
Ballare et al. (2001) reported a mutation in the SSTR5 gene (182455.0001) that abrogated the antiproliferative action of somatostatin and activated mitogenic pathways in a patient with acromegaly resistant to treatment with octreotide who carried an activating GNAS mutation (R201C; 139320.0008).
Thakker et al. (1993) found somatic mutations in the GNAS1 gene in 2 non-MEN1 somatotropinomas, one of which also demonstrated allele loss of chromosome 11 (see, e.g., 139320.0009).
In a series of 32 corticotroph adenomas of the pituitary, Williamson et al. (1995) found 2 with somatic mutations in the GNAS1 gene at codon 227 (139320.0010; 139320.0012). One of the patients was a 35-year-old male who presented with severe Cushing disease complicated by psychosis.
Hayward et al. (2001) noted that approximately 40% of growth hormone-secreting pituitary adenomas harbor somatic mutations in the GNAS1 gene. Mutations at arg201 or glu227 (see, e.g., 139320.0008 and 139320.0010, respectively) constitutively activate the alpha subunit of GNAS1.
Lania et al. (1998) found that 8 GH (139250)-secreting adenomas with activating GNAS mutations (gsp+) had similar intracellular cAMP levels as 10 GH-secreting adenomas without GNAS mutations (gsp-). However, pharmacologic inhibition of phosphodiesterase (PDE; see 171885) induced a marked increase in cAMP in all but 1 mutation-positive adenomas (77 to 2900% increase) and a slight rise in only 2 mutation-negative adenomas. PDE blockade caused a further increase in 3 of 5 mutation-positive adenomas but not in negative tumors. By direct measurement, PDE activity was about 7-fold higher in mutation-positive adenomas. Mutation-positive adenomas also had significantly higher GH release compared to mutation-negative adenomas (315 vs 82 micro g/well; P less than 0.01). Lania et al. (1998) concluded that activating mutations of the Gs-alpha gene in pituitary adenomas are associated with increased PDE activity that might partially counteract the constitutive activation of the cAMP-dependent pathway.
Barlier et al. (1999) found that somatotroph adenomas with GNAS mutations (gsp+) had decreased expression of the Gs-alpha gene compared to GNAS-negative (gsp-) tumors, suggesting the existence of a negative feedback of the oncogenic protein upon its own mRNA. In contrast, Gi2-alpha (GNAI2; 139360), PIT1 (POU1F1; 173110), and GH mRNAs were not significantly different between the 2 groups. There was a positive correlation between octreotide-induced inhibition of GH secretion and the expression of SSTR2 (182452) mRNA, although the expression of the SSTR2 gene did not differ between gsp+ and gsp- adenomas. SSTR2 gene expression was significantly correlated to that of Gi2-alpha and PIT1, and Gs-alpha mRNA expression was positively correlated with that of Gi2-alpha and PIT1. The authors concluded there is a concerted dysregulation of the expression of these genes, which are involved in secretory activity, in both categories of adenomas.
Persani et al. (2001) found that normal pituitary and gsp- GH-secreting adenomas showed similar PDE activities, whereas gsp+ tumors showed 7-fold higher PDE levels. In gsp+ tumors, the increased activity was mainly due to isobutyl-methyl-xanthine-sensitive phosphodiesterase-4 and to isobutyl-methyl-xanthine-insensitive isoforms. By semiquantitative RT-PCR, all phosphodiesterase-4 transcripts were expressed in the normal and tumoral pituitary. However, the levels of phosphodiesterase-4C (600128) and -4D (600129) mRNAs were significantly higher in gsp+ than in gsp- GH-secreting adenomas and normal pituitary. Expression of the thyroid-specific isobutyl-methyl-xanthine-insensitive phosphodiesterase-8B (603390) was absent in the normal pituitary but detectable in almost all GH-secreting adenomas and higher in gsp+ (P less than 0.02). The authors concluded that up-regulation of PDEs is a mechanism to counteract the constitutive activation of cAMP production and may have a significant impact on the phenotypic expression of gsp mutations such as the rates of GH secretion or tumor growth.
Ballare, E., Mantovani, S., Lania, A., Di Blasio, A. M., Vallar, L., Spada, A. Activating mutations of the GS-alpha gene are associated with low levels of GS-alpha protein in growth hormone-secreting tumors. J. Clin. Endocr. Metab. 83: 4386-4390, 1998. [PubMed: 9851782] [Full Text: https://doi.org/10.1210/jcem.83.12.5354]
Ballare, E., Persani, L., Lania, A. G., Filopanti, M., Giammona, E., Corbetta, S., Mantovani, S., Arosio, M., Beck-Peccoz, P., Faglia, G., Spada, A. Mutation of somatostatin receptor type 5 in an acromegalic patient resistant to somatostatin analog treatment. J. Clin. Endocr. Metab. 86: 3809-3814, 2001. [PubMed: 11502816] [Full Text: https://doi.org/10.1210/jcem.86.8.7787]
Barlier, A., Gunz, G., Zamora, A. J., Morange-Ramos, I., Figarella-Branger, D., Dufour, H., Enjalbert, A., Jaquet, P. Pronostic (sic) and therapeutic consequences of Gs-alpha mutations in somatotroph adenomas. J. Clin. Endocr. Metab. 83: 1604-1610, 1998. [PubMed: 9589663] [Full Text: https://doi.org/10.1210/jcem.83.5.4797]
Barlier, A., Pellegrini-Bouiller, I., Gunz, G., Zamora, A. J., Jaquet, P., Enjalbert, A. Impact of gsp oncogene on the expression of genes coding for Gs-alpha, Pit-1, Gi2-alpha, and somatostatin receptor 2 in human somatotroph adenomas: involvement in octreotide sensitivity. J. Clin. Endocr. Metab. 84: 2759-2765, 1999. [PubMed: 10443675] [Full Text: https://doi.org/10.1210/jcem.84.8.5919]
Hayward, B. E., Barlier, A., Korbonits, M., Grossman, A. B., Jacquet, P., Enjalbert, A., Bonthron, D. T. Imprinting of the G(s)-alpha gene GNAS1 in the pathogenesis of acromegaly. J. Clin. Invest. 107: R31-R36, 2001. [PubMed: 11254676] [Full Text: https://doi.org/10.1172/JCI11887]
Lania, A., Persani, L., Ballare, E., Mantovani, S., Losa, M., Spada, A. Constitutively active Gs-alpha is associated with an increased phosphodiesterase activity in human growth hormone-secreting adenomas. J. Clin. Endocr. Metab. 83: 1624-1628, 1998. [PubMed: 9589667] [Full Text: https://doi.org/10.1210/jcem.83.5.4814]
Mete, O., Lopes, M. B. Overview of the 2017 WHO classification of pituitary tumors. Endocr. Path. 28: 228-243, 2017. [PubMed: 28766057] [Full Text: https://doi.org/10.1007/s12022-017-9498-z]
Persani, L., Borgato, S., Lania, A., Filopanti, M., Mantovani, G., Conti, M., Spada, A. Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: effect of Gs-alpha mutations. J. Clin. Endocr. Metab. 86: 3795-3800, 2001. [PubMed: 11502813] [Full Text: https://doi.org/10.1210/jcem.86.8.7779]
Thakker, R. V., Pook, M. A., Wooding, C., Boscaro, M., Scanarini, M., Clayton, R. N. Association of somatotrophinomas with loss of alleles on chromosome 11 and with gsp mutations. J. Clin. Invest. 91: 2815-2821, 1993. [PubMed: 8514889] [Full Text: https://doi.org/10.1172/JCI116524]
Williamson, E. A., Ince, P. G., Harrison, D., Kendall-Taylor, P., Harris, P. E. G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. Europ. J. Clin. Invest. 25: 128-131, 1995. [PubMed: 7737262] [Full Text: https://doi.org/10.1111/j.1365-2362.1995.tb01537.x]