Alternative titles; symbols
HGNC Approved Gene Symbol: GNAT1
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:50,191,610-50,197,696 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Night blindness, congenital stationary, autosomal dominant 3 | 610444 | Autosomal dominant | 3 |
| Night blindness, congenital stationary, type 1G | 616389 | Autosomal recessive | 3 |
By physical cloning methodologies and bioinformatic computational analyses, Lerman and Minna (2000) identified a number of genes, including GNAT1, in a region of chromosome 3p21.3 that is associated with a putative lung cancer tumor suppressor gene. The deduced 350-amino acid transducin protein, which is 100% identical to the mouse protein, contains a G-alpha domain and an ARF domain. Northern blot analysis revealed abundant expression of a 1.5-kb transcript in retina and fetal heart and in T-cell lines. No expression was detected in lung or lung cancer cell lines, and no mutations were found in any lung cancer cell lines. Lerman and Minna (2000) concluded that GNAT1 is an unlikely candidate for functional tumor suppressor gene studies.
Using rhodopsin mRNA levels as a molecular marker for photoreceptor development, Naeem et al. (2012) investigated the quantitative expression of Gnat1 transcript levels in mouse ocular tissues at various postnatal intervals. Neither Gnat1 nor rhodopsin expression was detected before postnatal day 5 (P5); however, their expression increased exponentially from P7, indicating that Gnat1 is present in photoreceptors. Comparison of expression levels of Gnat1 in different ocular tissues suggested that GNAT1 is highly expressed in the retina, followed by the ciliary body, iris, and retinal pigment epithelium.
By genomic sequence analysis, Lerman and Minna (2000) determined that the 3.5-kb GNAT1 gene contains 7 exons.
Bourne et al. (1991) analyzed the conserved structure of the GTPase superfamily which includes the 21-kD (relative molecular mass, 21,000) products of the ras oncogenes (e.g., 190020, 190070) and the alpha subunits of the heterotrimeric signal-transducing G proteins. All such GTPases go through the same unidirectional cycle, in which exchange of GDP for GTP turns on the switch and GTP hydrolysis turns it off. Structures of the GTPases resemble one another not only in overall design, but also in detail.
Sparkes et al. (1987) and Blatt et al. (1988) hybridized cDNA probes for subunits of different G proteins against a mouse/human somatic cell hybrid panel. This permitted assignment of the gene for the alpha-transducing G protein, polypeptide-1, to human chromosome 3. Sparkes et al. (1987) mapped the corresponding gene in the mouse to chromosome 9. Using a cDNA clone for the alpha subunit of bovine rod transducin, Danciger et al. (1989) also mapped the corresponding gene, Gnat1, to mouse chromosome 9 with a panel of Chinese-hamster somatic cell hybrid DNAs. By in situ hybridization, Wilkie et al. (1992) demonstrated that the GNAT1 gene is on 3p21. They confirmed that the mouse equivalent is on chromosome 9. Transducin is involved in the stimulation of cGMP-phosphodiesterase when light hits the rod photoreceptors. Danciger et al. (1989) concluded that the primary defect in the retinal degeneration of mice, called rd, cannot reside in this gene inasmuch as the disease maps to mouse chromosome 5. Ngo et al. (1993) placed GNAT1 on 3p22 by in situ hybridization. In conjunction with earlier work, the localization could be said to be 3p22-p21.3.
Bourne et al. (1991) noted that the GNAT1 and GNAI2 (139360) genes are closely situated on human 3p21 and on mouse chromosome 9, consistent with the notion that they were generated by tandem gene duplication that occurred prior to the divergence of rodents and primates. Similarly, GNAI3 (139370) and GNAT2 (139340) are apparently closely linked on human 1p13 and murine chromosome 3.
Wilkie et al. (1992) pointed out that in mammals, 15 G protein alpha-subunit genes can be grouped by sequence and functional similarities into 4 classes: Gs, Gi, Gq, and G12. From the chromosomal location of these 15 genes, in combination with mapping studies in humans, they proposed a phylogenetic tree for the genes.
Lerman and Minna (2000) identified the human GNAT1 gene in a region of chromosome 3p21.3 that is associated with a putative lung cancer tumor suppressor gene.
Ruiz-Avila et al. (1995) demonstrated that rod transducin is not limited to retinal cells but is also present in vertebrate taste cells, where it specifically activates a phosphodiesterase isolated from taste tissue. Other results suggested that rod transducin transduces bitter taste by coupling a taste receptor(s) to taste-cell phosphodiesterase. Gustducin (139395), a G protein specific to taste receptor cells, is closely related to the transducins. Taste can be divided into 4 primary sensations: salty, sour, sweet, and bitter. Salty and sour are directly transduced by apical channels, whereas sweet and bitter utilize cyclic nucleotide second messengers. The role of rod transducin in bitter taste is an example of the latter mechanism.
Nair et al. (2005) identified the presence of leu-gly-asn repeat-enriched protein (LGN; 609245), a putative binding partner of transducin, in rod photoreceptors.
Using immunofluorescence and Western blot analyses of mouse and rat retina cross-sections, Sinha et al. (2013) found that Unc119 (604011) localized predominantly to rod inner segments under all levels of illumination. In contrast, with illumination, the majority of Gnat1 translocated from the rod outer segment to other rod cellular compartments, where it colocalized with Unc119. Western blot analysis showed that mouse retina contained an approximately 1 to 4 molar ratio of Unc119 to Gnat1. Analysis of Gnat1 -/- mouse retina revealed that expression of the Unc119 and Gnat1 proteins was codependent, suggesting that Gnat1 interacts with Unc119 to stabilize it via complex formation.
Cheguru et al. (2015) examined the solution structure of the complex formed by myristoylated chimeric GNAT1 and amino acids 50 to 240 of UNC119. They found that upon binding of GNAT1 to UNC119, the N-terminal alpha helix of GNAT1 rotated 45 degrees at the hinge residues 27 to 29 and bent around residues 8 to 9. The analysis also suggested the involvement of a novel interaction interface between the 2 proteins. The effector binding site of GNAT1 was occluded in the complex with UNC119.
Autosomal Dominant Congenital Stationary Night Blindness 3
Dryja et al. (1996) reported that descendants of Jean Nougaret (1637-1719) with congenital stationary night blindness (CSNBAD3; 610444) carry a missense mutation in the GNAT1 gene. Sequence analysis in 2 affected sibs revealed a point mutation in codon 38 (139330.0001) resulting in a G38D amino acid change. No other changes in the coding region or flanking intron sequences were found by SSCP. Dryja et al. (1996) reported that subsequent analysis of 27 relatives revealed that the mutation was present only in affected family members. Dryja et al. (1996) noted that gly38 is a highly conserved residue among heteromeric G proteins including p21(RAS) (see 190020).
In a 3-generation Danish family with autosomal dominant CSNB mapping to chromosome 3p, Szabo et al. (2007) identified a heterozygous missense mutation in the GNAT1 gene (Q200E; 139330.0002) that segregated with disease.
Autosomal Recessive Congenital Stationary Night Blindness 1G
In affected members of a consanguineous Pakistani family segregating autosomal recessive CSNB (CSNB1G; 616389), Naeem et al. (2012) identified homozygosity for a missense mutation (D129G; 139330.0003) in the GNAT1 gene. Heterozygotes in the family were unaffected.
In an 80-year-old Irish man with lifelong nonprogressive night blindness, who also exhibited late-onset mild localized retinitis pigmentosa, Carrigan et al. (2016) identified homozygosity for a nonsense mutation in the GNAT1 gene (Q302X; 139330.0004). The authors noted similarities between electroretinographic responses in the patient and in Gnat1 -/- mice (see ANIMAL MODEL).
Calvert et al. (2000) generated Gnat1 -/- mice and observed mild retinal degeneration with age. By 13 weeks, the rod outer-segment length had shortened in the null mice, and the thickness of the outer nuclear layer had decreased by about 1 row of nuclei, indicating a loss of approximately 10% of rods. At 51 weeks, there was little further change in the outer nuclear layer or outer-segment length, but the inner nuclear layer was somewhat thinner, perhaps due to secondary loss of neurons downstream from the photoreceptors. Electroretinographic (ERG) analysis revealed that the Gnat1 -/- mice did not produce a detectable rod b-wave, indicating a major defect in the rods and/or in the rod bipolar cells. Noting that the a-wave in mice is generated almost exclusively by suppression of the rod circulating current, the authors stated that its absence in Gnat1 -/- mice indicated that the rod circulating current was absent or unresponsive to light. Nevertheless, dark-adapted Gnat1 -/- mice did exhibit responses to intense flashes; however, the responses consisted only of corneal-positive signals that closely resembled mouse cone b-waves. Superposition of a bright probe flash on a background suppressing over 95% of the rod circulating current yielded ERGs in wildtype and null mice that closely resembled each other and also resembled the tracings in the dark-adapted null mice, which supported the hypothesis that the Gnat1 -/- responses originated from cone-driven cells. Analysis of phototransduction in single cells showed that the vast majority (213 rods from 4 null mice) failed to respond to flashes delivering 600 times the number of photons required for a half-maximal response in a wildtype rod. Because 1 cell did respond, Calvert et al. (2000) suggested that perhaps phototransduction in a small population of rods could be supported by a G protein other than, or in addition to, Gnat1.
Hattar et al. (2003) investigated whether photoreceptor systems besides rod-cone and melanopsin participate in pupillary reflex, light-induced phase delays of the circadian clock, and period lengthening of the circadian rhythm in constant light. Using mice lacking rods and cones, Hattar et al. (2003) measured the action spectrum for phase-shifting the circadian rhythm of locomotor behavior. This spectrum matched that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. Hattar et al. (2003) also generated triple-knockout mice (for Gnat, Cnga3, 600053, and Opn4, 606665) in which the rod-cone and melanopsin systems were both silenced. These animals had an intact retina but failed to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, Hattar et al. (2003) concluded that the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
Inactivating mutations in the RPE65 gene (180069) and LRAT gene (604863) cause forms of Leber congenital amaurosis (LCA). Maeda et al. (2009) investigated human RPE65-LCA patients and mice with visual cycle abnormalities to determine the impact of chronic chromophore deprivation on cones. Young patients with RPE65 mutations showed foveal cone loss along with shortened inner and outer segments of remaining cones; cone cell loss also was dramatic in young mice lacking Rpe65 or Lrat gene function. To selectively evaluate cone pathophysiology, the authors eliminated the rod contribution to electroretinographic (ERG) responses by generating double-knockout mice lacking Lrat or Rpe65 together with an inactivated Gnat1 gene. Cone ERG responses were absent in Gnat1-null/Lrat-null mice, which also showed progressive degeneration of cones. Cone ERG responses in Gnat1-null/Rpe65-null mice were markedly reduced and declined over weeks. Treatment of these mice with an artificial chromophore prodrug, 9-cis-retinyl acetate, partially protected inferior retinal cones as evidenced by improved ERGs and retinal histochemistry. Gnat1-null mice chronically treated with retinylamine, a selective inhibitor of RPE65, also showed a decline in the number of cones that was ameliorated by 9-cis-retinyl acetate. Maeda et al. (2009) suggested that chronic lack of chromophore may lead to progressive loss of cones in mice and humans, and that therapy for LCA patients could be geared toward early adequate delivery of chromophore to cone photoreceptors.
In descendants of Jean Nougaret (1647-1719) with autosomal dominant congenital stationary night blindness (CSNBAD3; 610444), Dryja et al. (1996) identified heterozygosity for a G-A transition in exon 2 of the GNAT1 gene, resulting in a gly38-to-asp (G38D) substitution at a highly conserved residue within a small loop that forms hydrogen bonds with the alpha and beta phosphates of GTP/GDP. The mutation, which segregated with disease in the family, was not found in 75 controls.
In affected members of a 3-generation Danish family with autosomal dominant night blindness (CSNBAD3; 610444), Szabo et al. (2007) identified heterozygosity for a c.598C-G transversion (c.598C-G, NM_144499.1) in exon 6 of the GNAT1 gene, resulting in a gln200-to-glu (Q200E) substitution. The mutation segregated with disease in the family and was not found in 104 control alleles. Trypsin degradation studies indicated that Q200E-mutant transducin does not form a proper complex with GDP.A1F-/4.
In 4 affected members of a consanguineous Pakistani family with autosomal recessive congenital stationary night blindness mapping to chromosome 3p22.1-p14.3 (CSNB1G; 616389), Naeem et al. (2012) identified homozygosity for a c.386A-G transition in the GNAT1 gene, resulting in an asp129-to-gly (D129G) substitution at a highly conserved residue. Unaffected family members were heterozygous for the mutation, which was not found in 192 ethnically matched control chromosomes.
In an 80-year-old Irish man with lifelong nonprogressive night blindness (CSNB1G; 616389), who also exhibited late-onset mild localized retinitis pigmentosa, Carrigan et al. (2016) identified homozygosity for a c.904C-T transition in the GNAT1 gene, resulting in a gln302-to-ter (Q302X) substitution that eliminates 49 C-terminal amino acids, several of which are crucial to alpha-transducin protein function. The mutation was detected in heterozygosity in the proband's unaffected 56-year-old daughter, but was not found in 190 other Irish patients with inherited retinopathies or in the 1000 Genomes Project database; however, it was present at a low allele frequency of 5/66,210 in the ExAC database.
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]
Bourne, H. R., Sanders, D. A., McCormick, F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349: 117-127, 1991. [PubMed: 1898771] [Full Text: https://doi.org/10.1038/349117a0]
Calvert, P. D., Krasnoperova, N. V., Lyubarsky, A. L., Isayama, T., Nicolo, M., Kosaras, B., Wong, G., Gannon, K. S., Margolskee, R. F., Sidman, R. L., Pugh, R. N., Jr., Makino, C. L., Lem, J. Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha-subunit. Proc. Nat. Acad. Sci. 97: 13913-13918, 2000. Note: Erratum: Proc. Nat. Acad. Sci. 98: 10515 only, 2001. [PubMed: 11095744] [Full Text: https://doi.org/10.1073/pnas.250478897]
Carrigan, M., Duignan, E., Humphries, P., Palfi, A., Kenna, P. F., Farrar, G. J. A novel homozygous truncating GNAT1 mutation implicated in retinal degeneration. Brit. J. Ophthal. 100: 495-500, 2016. [PubMed: 26472407] [Full Text: https://doi.org/10.1136/bjophthalmol-2015-306939]
Cheguru, P., Majumder, A., Yadav, R., Gopalakrishna, K. N., Gakhar, L., Artemyev, N. O. The solution structure of the transducin-alpha-uncoordinated 11 protein complex suggests occlusion of the G-beta-1-gamma-1-binding sites. FEBS J. 282: 550-561, 2015. [PubMed: 25425538] [Full Text: https://doi.org/10.1111/febs.13161]
Danciger, M., Kozak, C. A., Farber, D. B. The gene for the alpha-subunit of retinal rod transducin is on mouse chromosome 9. Genomics 4: 215-217, 1989. [PubMed: 2737680] [Full Text: https://doi.org/10.1016/0888-7543(89)90303-0]
Dryja, T. P., Hahn, L. B., Reboul, T., Arnaud, B. Missense mutation in the gene encoding the alpha subunit of rod transducin in the Nougaret form of congenital stationary night blindness. Nature Genet. 13: 358-365, 1996. [PubMed: 8673138] [Full Text: https://doi.org/10.1038/ng0796-358]
Hattar, S., Lucas, R. J., Mrosovsky, N., Thompson, S., Douglas, R. H., Hankins, M. W., Lem, J., Biel, M., Hofmann, F., Foster, R. G., Yau, K.-W. Melanopsin and rod-cone photoreceptive systems account for all major accessory visual functions in mice. Nature 424: 76-81, 2003. [PubMed: 12808468] [Full Text: https://doi.org/10.1038/nature01761]
Lerman, M. I., Minna, J. D. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. Cancer Res. 60: 6116-6133, 2000. [PubMed: 11085536]
Maeda, T., Cideciyan, A. V., Maeda, A., Golczak, M., Aleman, T. S., Jacobson, S. G., Palczewski, K. Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. Hum. Molec. Genet. 18: 2277-2287, 2009. [PubMed: 19339306] [Full Text: https://doi.org/10.1093/hmg/ddp163]
Naeem, M. A., Chavali, V. R. M., Ali, S., Iqbal, M., Riazuddin, S., Khan, S. N., Husnain, T., Sieving, P. A., Ayyagari, R., Riazuddin, S., Hejtmancik, J. F., Riazuddin, S. A. GNAT1 associated with autosomal recessive congenital stationary night blindness. Invest. Ophthal. Vis. Sci. 53: 1353-1361, 2012. [PubMed: 22190596] [Full Text: https://doi.org/10.1167/iovs.11-8026]
Nair, K. S., Mendez, A., Blumer, J. B., Rosenzweig, D. H., Slepak, V. Z. The presence of a leu-gly-asn repeat-enriched protein (LGN) a putative binding partner of transducin, in ROD photoreceptors. Invest. Ophthal. Vis. Sci. 46: 383-389, 2005. [PubMed: 15623799] [Full Text: https://doi.org/10.1167/iovs.04-1006]
Ngo, J. T., Bateman, J. B., Klisak, I., Mohandas, T., Van Dop, C., Sparkes, R. S. Regional mapping of a human rod alpha-transducin (GNAT1) gene to chromosome 3p22. Genomics 18: 724-725, 1993. [PubMed: 8307584] [Full Text: https://doi.org/10.1016/s0888-7543(05)80384-2]
Ruiz-Avila, L., McLaughlin, S. K., Wildman, D., McKinnon, P. J., Robichon, A., Spickofsky, N., Margolskee, R. F. Coupling of bitter receptor to phosphodiesterase through transducin in taste receptor cells. Nature 376: 80-85, 1995. [PubMed: 7596440] [Full Text: https://doi.org/10.1038/376080a0]
Sinha, S., Majumder, A., Belcastro, M., Sokolov, M., Artemyev, N. O. Expression and subcellular distribution of UNC119a, a protein partner of transducin alpha subunit in rod photoreceptors. Cell. Signal. 25: 341-348, 2013. [PubMed: 23072788] [Full Text: https://doi.org/10.1016/j.cellsig.2012.10.005]
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, 1987.
Szabo, V., Kreienkamp, H.-J., Rosenberg, T., Gal, A. p.Gln200Glu, a putative constitutively active mutant of rod alpha-transducin (GNAT1) in autosomal dominant congenital stationary night blindness. (Abstract) Hum. Mutat. 28: 741-742, 2007. Note: Full article online. [PubMed: 17584859] [Full Text: https://doi.org/10.1002/humu.9499]
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]