Alternative titles; symbols
HGNC Approved Gene Symbol: GNAI2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:50,227,068-50,263,358 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Pituitary adenoma, ACTH-secreting, somatic | 3 | ||
| Ventricular tachycardia, idiopathic | 192605 | Autosomal dominant | 3 |
Magovcevic et al. (1992) isolated a cDNA for the GNAI2 gene from a human T-cell library.
Itoh et al. (1988) demonstrated 3 distinct human G-alpha inhibitory proteins. Southern blot analysis indicated that a single copy of each gene is present in the haploid human genome.
Itoh et al. (1988) determined that the GNAI2 and GNAI3 (139380) genes contain 8 coding exons and possess identical exon-intron organization.
Sparkes et al. (1987, 1987) and Blatt et al. (1988) used a cDNA probe with a mouse/human somatic cell hybrid panel to assign the alpha-2 inhibitory polypeptide to chromosome 3 in man and chromosome 9 in mouse. Blatt et al. (1988) also assigned the GNAI2 gene to chromosome 3 by hybridization of cDNA clones with DNA from human-mouse somatic cell hybrids. Magovcevic et al. (1992) mapped the GNAI2 gene to 3p21 by chromosomal in situ hybridization. A related sequence, GNAI2L (139180), was mapped by the same method to 12p13-p12. The assignment to chromosome 3 was supported by PCR amplification of GNAI2-specific sequences in a human/rodent somatic cell hybrid containing only human chromosome 3. Wilkie et al. (1992) assigned the corresponding gene to mouse chromosome 9.
Hermouet et al. (1991) demonstrated that activating and inactivating mutations of the GNAI2 gene have opposite effects on proliferation of NIH 3T3 cells.
Jiang et al. (2011) found that microRNA-138 (MIR138; see 613394) was downregulated in tongue squamous cell carcinoma (TSCC) compared with normal tissue. Using microarray-based differential expression analysis on human TSCC cells transfected with an MIR138 mimic or a control mimic, followed by bioinformatic analysis, Jiang et al. (2011) identified GNAI2 and 4 other genes as high-confidence candidate targets of MIR138. They observed a reverse correlation between MIR138 and GNAI2 levels in a TSCC cell line panel and identified 2 MIR138 target sequences in the 3-prime UTR of GNAI2 mRNA. Reporter gene assays confirmed that both putative target sequences were inhibited by MIR138. Knockdown of MIR138 in TSCC cells enhanced the expression of GNAI2 at the mRNA and protein levels. In contrast, transfection of MIR138 or an MIR138 mimic reduced GNAI2 mRNA and protein expression, which was associated with reduced cell proliferation and enhanced apoptosis.
Since somatic mutations in some growth hormone-secreting pituitary tumors convert the gene for the alpha polypeptide chain of G(s) into a putative oncogene, referred to as GSP (139320), Lyons et al. (1990) considered the likelihood that similar mutations would activate other G proteins. They found mutations of the GNAI2 gene that replaced arginine-179 with either cysteine or histidine in tumors of the adrenal cortex and endocrine tumors of the ovary. They referred to this mutant GNAI2 gene as the GIP2 oncogene. Williamson et al. (1995) studied 32 adrenocorticotrophin hormone-secreting pituitary adenomas for the presence of GSP and GIP mutations. GSP mutations were demonstrated in 2 tumors at codon 227 (139320.0012) and a GIP mutation was identified in 1 tumor at codon 179 (139360.0003).
Idiopathic ventricular tachycardia is a generic term that describes the various forms of ventricular arrhythmias that occur in patients without structural heart disease and in the absence of the long QT syndrome. Many of these tachycardias are focal in origin, localize to the right ventricular outflow tracts, terminate in response to beta-blockers, verapamil, vagal maneuvers, and adenosine, and are thought to result from cAMP-mediated triggered activity. Lerman et al. (1998) prepared DNA from biopsy samples obtained from myocardial tissue from a patient with adenosine-insensitive idiopathic ventricular tachycardia arising from the right ventricular outflow tracts. Genomic sequences of the GNAI2B gene showed a point mutation (phe200 to leu; 139360.0004) in the GTP-binding domain of the inhibitory G protein, as identified in a biopsy sample from the arrhythmogenic focus. This mutation was shown to increase intracellular cAMP concentration and inhibit suppression of cAMP by adenosine. No mutations were detected in the GNAI2B gene from myocardial tissue sampled from regions remote from the origin of tachycardia, or from peripheral lymphocytes. The findings suggested that somatic cell mutations in the cAMP-dependent signal transduction pathway occurring during myocardial development may be responsible for some forms of idiopathic ventricular tachycardia.
Rudolph et al. (1995) generated mice deficient in the G protein subunit alpha-i2 by homologous recombination in embryonic stem cells. The deficient mice displayed growth retardation and developed a lethal diffuse colitis with clinical and histopathologic features closely resembling ulcerative colitis (see 266600) in humans, including the development of adenocarcinoma of the colon. Before clinical symptoms, the mice showed profound alterations in thymocyte maturation and function. Elevated immunoglobulin levels, particularly IgG in the large bowel, were observed. Bowel disease developed even when mice were raised in a specific-pathogen-free facility.
In 3 of 11 tumors of the adrenal cortex and in 3 of 10 endocrine tumors of the ovary, Lyons et al. (1990) found mutations that replaced arginine-179 with either cysteine or histidine. Two of the ovarian tumors were granulosa cell tumors and 1 was a thecoma.
See 139360.0001.
In an adrenocorticotrophic hormone-secreting pituitary adenoma, Williamson et al. (1995) found a CGC-to-GGC change in codon 179 of the GNAI2 gene converting arginine to glycine.
Lerman et al. (1998) found a somatic mutation of the GNAI2 gene in myocardial DNA biopsied from the arrhythmogenic focus in the right ventricular outflow tract of a 58-year-old man with idiopathic ventricular tachycardia (192605). The man developed sustained monomorphic ventricular tachycardia during an intense argument. The tachycardia was associated with chest pain, dyspnea, diaphoresis, and a systolic blood pressure of 60 mm Hg. The cycle length of tachycardia was 240 ms. Emergency medical services restored sinus rhythm with an electric shock. The resting ECG was normal, as was an echocardiogram. Cardiac catheterization demonstrated normal coronary anatomy and normal left ventricular function. There was no family history of ventricular tachycardia or sudden cardiac death. The mutation in this patient was a change of codon 200 from TTT (phe) to TTA (leu).
Blatt, C., Eversole-Cire, P., Cohn, V. H., Zollman, S., Fournier, R. E. K., Mohandas, L. T., Nesbitt, M., Lugo, T., Jones, D. T., Reed, R. R., Weiner, L. P., Sparkes, R. S., Simon, M. I. Chromosomal localization of genes encoding guanine nucleotide-binding protein subunits in mouse and human. Proc. Nat. Acad. Sci. 85: 7642-7646, 1988. [PubMed: 2902634] [Full Text: https://doi.org/10.1073/pnas.85.20.7642]
Hermouet, S., Merendino, J. J., Jr., Gutkind, J. S., Spiegel, A. M. Activating and inactivating mutations of the alpha subunit of G(i2) protein have opposite effects on proliferation of NIH 3T3 cells. Proc. Nat. Acad. Sci. 88: 10455-10459, 1991. [PubMed: 1660138] [Full Text: https://doi.org/10.1073/pnas.88.23.10455]
Itoh, H., Toyama, R., Kozasa, T., Tsukamoto, T., Matsuoka, M., Kaziro, Y. Presence of three distinct molecular species of G(i) protein alpha subunit: structure of rat cDNAs and human genomic DNAs. J. Biol. Chem. 263: 6656-6664, 1988. [PubMed: 2834384]
Jiang, L., Dai, Y., Liu, X., Wang, C., Wang, A., Chen, Z., Heidbreder, C. E., Kolokythas, A., Zhou, X. Identification and experimental validation of G protein alpha inhibiting activity polypeptide 2 (GNAI2) as a microRNA-138 target in tongue squamous cell carcinoma. Hum. Genet. 129: 189-197, 2011. [PubMed: 21079996] [Full Text: https://doi.org/10.1007/s00439-010-0915-3]
Lerman, B. B., Dong, B., Stein, K. M., Markowitz, S. M., Linden, J., Catanzaro, D. F. Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunit-alpha-i2. J. Clin. Invest. 101: 2862-2868, 1998. [PubMed: 9637720] [Full Text: https://doi.org/10.1172/JCI1582]
Lyons, J., Landis, C. A., Harsh, G., Vallar, L., Grunewald, K., Feichtinger, H., Duh, Q.-Y., Clark, O. H., Kawasaki, E., Bourne, H. R., McCormick, F. Two G protein oncogenes in human endocrine tumors. Science 249: 655-659, 1990. [PubMed: 2116665] [Full Text: https://doi.org/10.1126/science.2116665]
Magovcevic, I., Ang, S.-L., Seidman, J. G., Tolman, C. J., Neer, E. J., Morton, C. C. Regional localization of the human G protein alpha(i2) (GNAI2) gene: assignment to 3p21 and a related sequence (GNAI2L) to 12p12-p13. Genomics 12: 125-129, 1992. [PubMed: 1733849] [Full Text: https://doi.org/10.1016/0888-7543(92)90414-n]
Rudolph, U., Finegold, M. J., Rich, S. S., Harriman, G. R., Srinivasan, Y., Brabet, P., Boulay, G., Bradley, A., Birnbaumer, L. Ulcerative colitis and adenocarcinoma of the colon in G alpha(i2)-deficient mice. Nature Genet. 10: 143-150, 1995. [PubMed: 7663509] [Full Text: https://doi.org/10.1038/ng0695-143]
Sparkes, R. S., Cohn, V. H., Mohandas, T., Zollman, S., Cire-Eversole, P., Amatruda, T. T., Reed, R. R., Lochrie, M. A., Simon, M. I. Mapping of genes encoding the subunits of guanine nucleotide-binding protein (G-proteins) in humans. (Abstract) Cytogenet. Cell Genet. 46: 696 only, 1987.
Wilkie, T. M., Gilbert, D. J., Olsen, A. S., Chen, X.-N., Amatruda, T. T., Korenberg, J. R., Trask, B. J., de Jong, P., Reed, R. R., Simon, M. I., Jenkins, N. A., Copeland, N. G. Evolution of the mammalian G protein alpha subunit multigene family. Nature Genet. 1: 85-91, 1992. [PubMed: 1302014] [Full Text: https://doi.org/10.1038/ng0592-85]
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]