HGNC Approved Gene Symbol: GNB3
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:6,840,925-6,847,393 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | {Hypertension, essential, susceptibility to} | 145500 | Multifactorial | 3 |
| Night blindness, congenital stationary, type 1H | 617024 | Autosomal recessive | 3 |
Levine et al. (1990) cloned a third form of the G protein beta-subunit polypeptide. Also see GNB1 (139380) and GNB2 (139390). The GNB3 cDNA corresponds to a 2.0-kb mRNA expressed in all tissues and clonal cell lines examined. The encoded peptide consists of 340 amino acid residues.
Rosskopf et al. (2003) identified a splice variant of GNB3, designated GNB3v, that is generated by alternative splicing parts of intron 9 as a novel exon 10a. GNB3v retains 4 WD domains, but the protein has a novel C terminus. RT-PCR detected GNB3v in a wide variety of cells and tissues, including fibroblasts, B lymphoblasts, retinoblastoma cells, retina, brain, umbilical cord, and colon.
Modi et al. (1989) mapped the GNB3 gene to 12p13 by use of somatic cell hybrids and in situ hybridization. Levine et al. (1990) mapped the gene to 12pter-p12.3 by Southern analysis of somatic cell hybrids and by in situ hybridization.
By somatic cell hybrid analysis, Danciger et al. (1992) mapped the mouse Gnb3 gene to chromosome 6, distal to the Raf1 gene (164760).
Rosskopf et al. (2003) determined that the GNB3v variant could form dimers with the G protein gamma-3 and gamma-12 subunits, but they were unable to demonstrate functional association between the subunits in an activation assay.
Vertebrate retinas have distinct light-on (ON) and light-off (OFF) channels that originate at the level of the retinal bipolar cells. For the conversion from OFF to ON, ON bipolar cells use the GNAO1 (139311)-coupled glutamate receptor-6 (GRIK2; 138244) such that binding of glutamate suppresses a cation current rather than activating it. Using immunohistochemical analysis and single-cell PCR, Huang et al. (2003) showed that the gamma subunit Gng13 (607298) was coexpressed with the beta subunits Gnb3 and Gnb4 (610863), but no other beta subunits, in dissociated mouse ON bipolar cells. Huang et al. (2003) hypothesized that these G protein subunits selectively participate in signal transduction in ON bipolar cells.
Essential Hypertension, Susceptibility to
Siffert et al. (1995) and Pietruck et al. (1996) demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. They speculated that structural changes in the alpha, beta, or gamma subunit of heterotrimeric G proteins could be responsible for the enhanced G-protein reactivity in hypertensive cells. In studies of the GNB3 gene, they demonstrated an 825C-T polymorphism (139130.0001). Although the polymorphism did not affect the amino acid sequence of the beta-3 subunit, the T allele was associated with deletion of nucleotides 498-620 of exon 9. This was found to be an example of alternative splicing caused by a nucleotide change outside the splice donor and acceptor sites. Other examples include the alternative splicing of the platelet membrane glycoprotein IIIa (173470), as reported by Jin et al. (1996), in Glanzmann thrombasthenia (273800), in the human growth hormone receptor (600946) by Stallings-Mann et al. (1996), and in the fibrillin-1 gene (134797) in Marfan syndrome by Liu et al. (1997).
Congenital Stationary Night Blindness, Type 1H
In 3 patients from a Lebanese-Armenian kindred with congenital stationary night blindness type 1H (CSNB1H; 617024), Vincent et al. (2016) identified homozygosity or compound heterozygosity for mutations in the GNB3 gene: 2 affected Lebanese-Armenian brothers were compound heterozygous for a nonsense mutation (W339X; 139130.0002) inherited from their unaffected Armenian mother, and an in-frame 3-bp deletion (K57del; 139130.0003) inherited from their unaffected Lebanese father, whereas their affected maternal aunt was homozygous for the nonsense mutation. Analysis of GNB3 in 58 additional CSNB cases revealed a 65-year-old French woman from a consanguineous family who was negative for mutation in known CSNB genes but carried a missense mutation in GNB3 (S67F; 139130.0004) that was believed to be homozygous; family members were unavailable for testing.
Siffert et al. (1998) described an 825C-T polymorphism in exon 10 of the gene encoding the beta-3 subunit of heterotrimeric G proteins. The T allele was associated with a splice variant in which nucleotides 498-620 of exon 9 were deleted. This in-frame deletion caused the loss of 41 amino acids and 1 WD repeat domain of the beta subunit. Increased activity of the splice variant was thought to be responsible for the previously observed enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. The T allele in homozygous or heterozygous state were found in 44% of normotensive subjects and in 53.1% of hypertensive subjects.
Hegele et al. (1999) found an increased body mass index among Canadian Inuits who were homozygous for the 825T allele. Siffert et al. (1999) found increased body mass index in 825T homozygotes of Caucasian, Chinese, and black-African ethnicity. Hocher et al. (2000) found an association between maternal G protein beta-3 825T allele and low birth weight in babies born to women without other risks for reduced fetal growth. Gutersohn et al. (2000) found that sedentary primiparous women homozygous for the 825T allele retained more weight after delivery, as compared with women with at least 1 825C allele. Feldman and Hegele (2000) commented on the aforementioned studies.
Lindemann et al. (2001) demonstrated that the C825T allele influences cellular immune responses toward recall antigens and interleukin-2 (IL2; 147680) stimulation. Responses were increased 2- to 4-fold in homozygous 825T peripheral blood mononuclear cells compared with cells from homozygous 825C individuals. Furthermore, lymphocyte chemotaxis and CD4 (186940)-positive T-cell counts were significantly enhanced in individuals homozygous or heterozygous for the 825T allele. Lindemann et al. (2001) concluded that 825T allele status is predictive of immunocompetence and that GNB3 could be a candidate gene in disorders associated with inadequate immune response.
The 825C-T polymorphism has been associated with obesity in several ethnic groups (Siffert et al., 1999), and with body mass index (BMI) the first year after pregnancy (Gutersohn et al., 2000), as well as with low birth weight (Hocher et al., 2000). Dishy et al. (2003) showed that the women homozygous for the T allele (TT) gained significantly more weight than women carrying the C allele (CC and CT groups) (P = 0.006) and had a significantly higher prepregnancy BMI (p = 0.02).
In 2 Lebanese-Armenian brothers with congenital stationary night blindness type 1H (CSNB1H; 617024), Vincent et al. (2016) identified compound heterozygosity for mutations in the GNB3 gene: a c.1017G-A transition (c.1017G-A, NM_002075.3) in exon 10, resulting in a trp339-to-ter (W339X) substitution at a highly conserved residue between the first and last beta sheets of the beta-propeller structure, and an in-frame 3-bp deletion (c.170_172delAGA; 139130.0003) in exon 4, predicted to cause deletion of a highly conserved lys57 residue (K57del) located within a surface loop. The nonsense mutation was inherited from their unaffected Armenian mother and the 3-bp deletion from their unaffected Lebanese father. Their affected maternal aunt was homozygous for the nonsense mutation, which was present in heterozygosity in the unaffected maternal grandparents and an unaffected maternal uncle. Neither mutation was found in the ExAc, Exome Variant Server, or 1000 Genomes Project databases.
For discussion of the in-frame 3-bp deletion (c.170_172delAGA, NM_002075.3) in exon 4 of the GNB3 gene, predicted to cause deletion of lys57 (K57del), that was found in compound heterozygous state in 2 brothers with congenital stationary night blindness type 1H (CSNB1H; 617024) by Vincent et al. (2016), see 139130.0002.
In a 65-year-old woman from a consanguineous French family with congenital stationary night blindness type 1H (CSNB1H; 617024), Vincent et al. (2016) identified a c.200C-T transition (c.200C-T, NM_002075.3) in exon 4 of the GNB3 gene, resulting in a ser67-to-phe (S67F) substitution at a conserved residue at the top ridge of the overall beta-barrel structure. The mutation was believed to be present in homozygosity, but the authors noted that compound heterozygosity with a deletion of GNB3 on the other allele could not be completely excluded, since family members were unavailable for testing. The S67F variant was found at a low frequency in the ExAC and ESP databases (minor allele frequencies, 0.00004 and 0.0002, respectively), but never in homozygous state.
Danciger, M., Chakraborti, A., Farber, D. B., Kozak, C. A. Localization of the gene for a third G protein beta-subunit to mouse chromosome 6 near Raf-1. Genomics 12: 688-692, 1992. [PubMed: 1572642] [Full Text: https://doi.org/10.1016/0888-7543(92)90295-4]
Dishy, V., Gupta, S., Landau, R., Xie, H.-G., Kim, R. B., Smiley, R. M., Byrne, D. W., Wood, A. J. J., Stein, C. M. G-protein beta-3 subunit 825 C/T polymorphism is associated with weight gain during pregnancy. Pharmacogenetics 13: 241-242, 2003. [PubMed: 12668921] [Full Text: https://doi.org/10.1097/00008571-200304000-00009]
Feldman, R. D., Hegele, R. A. G-protein polymorphisms and maternal/neonatal metabolism: still a weight for the answer. (Commentary) Lancet 355: 1201-1202, 2000. [PubMed: 10770297] [Full Text: https://doi.org/10.1016/S0140-6736(00)02081-X]
Gutersohn, A., Naber, C., Muller, N., Erbel, R., Siffert, W. G protein beta-3 subunit 825 TT genotype and post-pregnancy weight retention. Lancet 355: 1240-1241, 2000. [PubMed: 10770309] [Full Text: https://doi.org/10.1016/S0140-6736(00)02093-6]
Hegele, R. A., Anderson, C., Young, T. K., Connelly, P. W. G-protein beta-3 subunit gene splice variant and body fat distribution in Nunavut Inuit. Genome Res. 9: 972-977, 1999. [PubMed: 10523525] [Full Text: https://doi.org/10.1101/gr.9.10.972]
Hocher, B., Slowinski, T., Stolze, T., Pleschka, A., Neumayer, H.-H., Halle, H. Association of maternal G protein beta-3 subunit 825T allele with low birthweight. Lancet 355: 1241-1242, 2000. [PubMed: 10770310] [Full Text: https://doi.org/10.1016/S0140-6736(00)02094-8]
Huang, L., Max, M., Margolskee, R. F., Su, H., Masland, R. H., Euler, T. G protein subunit G-gamma-13 is coexpressed with G-alpha-o, G-beta-3, and G-beta-4 in retinal ON bipolar cells. J. Comp. Neurol. 455: 1-10, 2003. [PubMed: 12454992] [Full Text: https://doi.org/10.1002/cne.10396]
Jin, Y., Dietz, H. C., Montgomery, R. A., Bell, W. R., McIntosh, I., Coller, B., Bray, P. F. Glanzmann thrombasthenia: cooperation between sequence variants in Cis during splice site selection. J. Clin. Invest. 98: 1745-1754, 1996. [PubMed: 8878424] [Full Text: https://doi.org/10.1172/JCI118973]
Levine, M. A., Modi, W. S., O'Brien, S. J. Chromosomal localization of the genes encoding two forms of the G-protein beta polypeptide, beta-1 and beta-3, in man. Genomics 8: 380-386, 1990. [PubMed: 1979057] [Full Text: https://doi.org/10.1016/0888-7543(90)90296-7]
Levine, M. A., Smallwood, P. M., Moen, P. T., Jr., Helman, L. J., Ahn, T. G. Molecular cloning of beta-3 subunit, a third form of the G protein beta-subunit polypeptide. Proc. Nat. Acad. Sci. 87: 2329-2333, 1990. [PubMed: 2107550] [Full Text: https://doi.org/10.1073/pnas.87.6.2329]
Lindemann, M., Virchow, S., Ramann, F., Barsegian, V., Kreuzfelder, E., Siffert, W., Muller, N., Grosse-Wilde, H. The G protein beta-3 subunit 825T allele is a genetic marker for enhanced T cell response. FEBS Lett. 495: 82-86, 2001. [PubMed: 11322952] [Full Text: https://doi.org/10.1016/s0014-5793(01)02339-0]
Liu, W., Qian, C., Francke, U. Silent mutation induces exon skipping of fibrillin-1 gene in Marfan syndrome. (Letter) Nature Genet. 16: 328-329, 1997. [PubMed: 9241263] [Full Text: https://doi.org/10.1038/ng0897-328]
Modi, W. S., Levine, M. A., Seuanez, H., O'Brien, S. J. Chromosomal localization of the gene encoding a third form of the beta subunit of GTP-binding regulatory proteins. (Abstract) Cytogenet. Cell Genet. 51: 1046 only, 1989.
Pietruck, F., Moritz, A., Montemurro, M., Sell, A., Busch, S., Rosskopf, D., Virchow, S., Esche, H., Brockmeyer, N., Jakobs, K. H., Siffert, W. Selectively enhanced cellular signaling by G(i) proteins in essential hypertension: G-alpha(i2), G-alpha(i3), G-beta(2) are not mutated. Circ. Res. 79: 974-983, 1996. [PubMed: 8888689] [Full Text: https://doi.org/10.1161/01.res.79.5.974]
Rosskopf, D., Kielbik, M., Manthey, I., Bilmen, G., Eisenhardt, A., Siffert, W. Characterization of the splice variant G-beta-3v of the human G-protein G-beta-3 subunit. Biochim. Biophys. Acta 1626: 33-42, 2003. [PubMed: 12697327] [Full Text: https://doi.org/10.1016/s0167-4781(03)00035-6]
Siffert, W., Forster, P., Jockel, K.-H., Mvere, D. A., Brinkmann, B., Naber, C., Crookes, R., Du P. Heyns, A., Epplen, J. T., Fridey, J., Freedman, B. I., Muller, N., and 15 others. Worldwide ethnic distribution of the G protein beta-3 subunit 825T allele and its association with obesity in Caucasian, Chinese, and black African individuals. J. Am. Soc. Nephrol. 10: 1921-1030, 1999. [PubMed: 10477144] [Full Text: https://doi.org/10.1681/ASN.V1091921]
Siffert, W., Rosskopf, D., Moritz, A., Wieland, T., Kaldenberg-Stasch, S., Kettler, N., Hartung, K., Beckmann, S., Jakobs, K. H. Enhanced G protein activation in immortalized lymphoblasts from patients with essential hypertension. J. Clin. Invest. 96: 759-766, 1995. [PubMed: 7635969] [Full Text: https://doi.org/10.1172/JCI118120]
Siffert, W., Rosskopf, D., Siffert, G., Busch, S., Moritz, A., Erbel, R., Sharma, A. M., Ritz, E., Wichmann, H.-E., Jakobs, K. H., Horsthemke, B. Association of a human G-protein beta-3 subunit variant with hypertension. Nature Genet. 18: 45-48, 1998. [PubMed: 9425898] [Full Text: https://doi.org/10.1038/ng0198-45]
Stallings-Mann, M. L., Ludwiczak, R. L., Klinger, K. W., Rottman, F. Alternative splicing of exon 3 of the human growth hormone receptor is the result of an unusual genetic polymorphism. Proc. Nat. Acad. Sci. 93: 12394-12399, 1996. [PubMed: 8901592] [Full Text: https://doi.org/10.1073/pnas.93.22.12394]
Vincent, A., Audo, I., Tavares, E., Maynes, J. T., Tumber, A., Wright, T., Li, S., Michiels, C., GNB3 Consortium, MacDonald, H., Verdet, R., Sahel, J.-A., Hamel, C. P., Zeitz, C., Heon, E. Biallelic mutations in GNB3 cause a unique form of autosomal-recessive congenital stationary night blindness. Am. J. Hum. Genet. 98: 1011-1019, 2016. [PubMed: 27063057] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.021]