Alternative titles; symbols
HGNC Approved Gene Symbol: GNAL
SNOMEDCT: 719516000;
Cytogenetic location: 18p11.21 Genomic coordinates (GRCh38) : 18:11,689,264-11,885,685 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18p11.21 | Dystonia 25 | 615073 | Autosomal dominant | 3 |
The GNAL gene encodes a stimulatory G-alpha subunit of the G protein receptor. It was first identified as a G protein subunit that mediates odorant signaling in the olfactory epithelium and is thus expressed in the brain (summary by Fuchs et al., 2013).
The G protein alpha subunit involved in olfaction was cloned in the rat by Jones and Reed (1989).
Although GNAL was first identified in the olfactory epithelium, it is also highly expressed in certain areas of the brain and appears to be coupled to the dopamine D1 receptor (DRD1; 126449) (Herve et al., 1993; Sakagami et al., 1995).
By Northern blot analysis, Vuoristo et al. (2000) found an approximately 6-kb GNAL transcript in human brain. Highest expression was detected in caudate nucleus and amygdala. Sequencing the 3-prime UTR revealed that this transcript utilizes the most 3-prime polyadenylation signal at about 4.5 kb beyond the termination codon.
Corradi et al. (2005) identified a transcriptional variant of GNAL, designated XLG(olf). XLG(olf) uses an alternate first exon, designated exon 1a, that is 5-prime to the originally identified start site and encodes a longer functional protein. G(olf) and XLG(olf) displayed different expression patterns in the central nervous system when heterologously expressed in Sf9 cells, and both functionally coupled to the dopamine D1 receptor.
Although GNAL was first identified in the olfactory epithelium, it is also highly expressed in certain areas of the brain and appears to be coupled to the dopamine D1 receptor (DRD1; 126449) (Herve et al., 1993; Sakagami et al., 1995).
Ronnett and Snyder (1992) reviewed the molecular messengers of olfaction. Molecular cloning has revealed a large family of putative odorant receptors localized to olfactory epithelium that display a 7-transmembrane-domain motif suggesting an association with G proteins. Very potent and rapid enhancement of both adenylyl cyclase and phosphoinositide turnover has been demonstrated in response to odorants both in isolated olfactory cilia and in primary olfactory receptor neuronal cultures. A Ca(2+)-calmodulin-dependent phosphodiesterase has been localized to olfactory cilia. Also, odorants have been shown to affect the levels of cGMP in olfactory receptor neurons. The involvement of multiple second messengers may provide mechanisms for both fine-tuning and desensitization of olfaction.
Mombaerts et al. (1996), Buck (1996), and Reed (1996) reviewed the molecular biology and molecular genetics of mammalian olfaction.
Corradi et al. (2005) stated that there are CpG islands in the vicinity of the alternative first exons of the GNAL variants that are differentially methylated. They noted that genetic studies implicating the 18p11.2 region in susceptibility to bipolar disorder and schizophrenia (see 603206) have observed parent-of-origin effects that may be explained by genomic imprinting. Corradi et al. (2005) suggested that GNAL and possibly other genes in the region are subject to epigenetic regulation of potential significance in the etiology of schizophrenia.
G-alpha(olf) is highly expressed in striatal neurons in the basal ganglia. Using mutant mouse studies, Corvol et al. (2001) found that G-alpha(olf) has an obligatory role in the coupling of adenylyl cyclase responses to dopamine and adenosine in the basal ganglia via the Drd1 and Adora2a (102776) receptors. ADCY5 (600293) is the adenylyl cyclase expressed in the brain (summary by Fuchs et al., 2013).
Vuoristo et al. (2000) determined that the GNAL gene contains 12 coding exons and spans over 80 kb. The promoter region has no consensus CCAAT or TATA boxes, and the 5-prime UTR contains multiple transcription start sites. The 3-prime UTR contains 2 Alu elements and 3 polyadenylation sequences, the most 5-prime of which is between the 2 Alu repeats. Intron 5 contains a CA repeat that may be useful for linkage analysis since there are at least 11 alleles.
Vuoristo et al. (2001) identified the C18ORF2 gene (606486) within intron 5 of the GNAL gene.
Wilkie et al. (1992) used a rat probe to identify restriction fragment length variants in the mouse for mapping the Gnal gene to mouse chromosome 18 in an interspecific backcross of C57BL/6J and Mus spretus. Schwab et al. (1998) stated that the human GNAL gene is located on chromosome 18p, between D18S53 distally and D18S71 proximally.
By genomic sequence analysis, Vuoristo et al. (2000) mapped the GNAL gene to chromosome 18p11.
By exome sequencing of 2 large families with autosomal dominant dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified 2 different heterozygous mutations in the GNAL gene (139312.0001 and 139312.0002) that segregated with the disorder in each family. Screening of the GNAL gene identified heterozygous pathogenic mutations (see, e.g., 139312.0003-139312.0006) in 6 of 39 additional families with a similar disorder. In vitro functional expression studies in a cell-based bioluminescence reporter system indicated that a nonsense mutation (S293X; 139312.0002) did not support any DRD1-driven responses, whereas wildtype GNAL caused a rapid increase in the signal. A V137M missense mutation (139312.0001) showed an intermediate phenotype, consistent with impaired association of G(s)-olf with the G-beta-gamma subunits. The findings suggested that the mutations resulted in a loss of function. The identification of GNAL mutations indicated that primary abnormalities in postsynaptic DRD1 and/or ADORA2A transmission in the basal ganglia may lead to dystonia.
Belluscio et al. (1998) found that mice homozygous for a null mutation in G(olf) show a striking reduction in the electrophysiologic response of primary olfactory sensory neurons to a wide variety of odors. Despite this profound diminution in response to odors, the topographic map of primary sensory projections to the olfactory bulb remained unaltered in G(olf) mutants. Greater than 75% of the G(olf) mutant mice were unable to nurse and died within 2 days after birth. Rare surviving homozygotes mated and were fertile, but mutant females exhibited inadequate maternal behaviors. Surviving homozygous mutant mice also exhibited hyperactive behaviors. These behavioral phenotypes, taken together with the pattern of G(olf) expression, suggested that G(olf) is required for olfactory signal transduction and may also function as an essential signaling molecule more centrally in the brain.
In 7 affected members of a family with autosomal dominant dystonia-25 (DYT25; 615073) originally reported by Bressman et al. (1994), Fuchs et al. (2013) identified a heterozygous 409G-A transition in the GNAL gene, resulting in a val137-to-met (V137M) substitution at a highly conserved residue. The mutation, which was identified by exome sequencing, was not found in 572 control chromosomes or in 3,500 European exomes.
In 6 affected members of a family with dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified a heterozygous 878C-A transversion in the GNAL gene, resulting in a ser293-to-ter (S293X) substitution. The mutation, which was found by exome sequencing, was not found in 572 control chromosomes or in 3,500 European exomes.
In 2 sibs with dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified a heterozygous 463G-A transition in the GNAL gene, resulting in a glu155-to-lys (E155K) substitution at a highly conserved residue.
In 4 members of a family with dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified a heterozygous 1-bp insertion (283insT) in the GNAL gene, resulting in a frameshift and premature termination (Ser95fsTer110).
In 3 members of a family with dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified a heterozygous 1-bp insertion (591insA) in the GNAL gene, resulting in a frameshift and premature termination (Arg198fsTer210).
In 3 sibs with dystonia-25 (DYT25; 615073), Fuchs et al. (2013) identified a heterozygous 61C-T transition in the GNAL gene, resulting in an arg21-to-ter (R21X) substitution.
Belluscio, L., Gold, G. H., Nemes, A., Axel, R. Mice deficient in G(olf) are anosmic. Neuron 20: 69-81, 1998. [PubMed: 9459443] [Full Text: https://doi.org/10.1016/s0896-6273(00)80435-3]
Bressman, S. B., Heiman, G. A., Nygaard, T. G., Ozelius, L. J., Hunt, A. L., Brin, M. F., Gordon, M. F., Moskowitz, C. B., de Leon, D., Burke, R. E., Fahn, S., Risch, N. J., Beakefield, X. O., Kramer, P. L. A study of idiopathic torsion dystonia in a non-Jewish family: evidence for genetic heterogeneity. Neurology 44: 283-287, 1994. [PubMed: 8309575] [Full Text: https://doi.org/10.1212/wnl.44.2.283]
Buck, L. B. Information coding in the mammalian olfactory system. Cold Spring Harbor Symp. Quant. Biol. 61: 147-155, 1996. [PubMed: 9246443]
Corradi, J. P., Ravyn, V., Robbins, A. K., Hagan, K. W., Peters, M. F., Bostwick, R., Buono, R. J., Berrettini, W. H., Furlong, S. T. Alternative transcripts and evidence of imprinting of GNAL on 18p11.2. Molec. Psychiat. 10: 1017-1025, 2005. [PubMed: 16044173] [Full Text: https://doi.org/10.1038/sj.mp.4001713]
Corvol, J. C., Studler, J. M., Schonn, J. S., Girault, J. A., Herve, D. Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum. J. Neurochem. 76: 1585-1588, 2001. [PubMed: 11238742] [Full Text: https://doi.org/10.1046/j.1471-4159.2001.00201.x]
Fuchs, T., Saunders-Pullman, R., Masuho, I., Luciano, M. S., Raymond, D., Factor, S., Lang, A. E., Liang, T.-W., Trosch, R. M., White, S., Ainehsazan, E., Herve, D., Sharma, N., Ehrlich, M. E., Martemyanov, K. A., Bressman, S. B., Ozelius, L. J. Mutations in GNAL cause primary torsion dystonia. Nature Genet. 45: 88-92, 2013. [PubMed: 23222958] [Full Text: https://doi.org/10.1038/ng.2496]
Herve, D., Levi-Strauss, M., Marey-Semper, I., Verney, C., Tassin, J.-P., Glowinski, J., Girault, J.-A. G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. J. Neurosci. 13: 2237-2248, 1993. [PubMed: 8478697] [Full Text: https://doi.org/10.1523/JNEUROSCI.13-05-02237.1993]
Jones, D. T., Reed, R. R. Golf: an olfactory neuron specific G protein involved in odorant signal transduction. Science 244: 790-795, 1989. [PubMed: 2499043] [Full Text: https://doi.org/10.1126/science.2499043]
Mombaerts, P., Wang, F., Dulac, C., Vassar, R., Chao, S. K., Nemes, A., Mendelsohn, M., Edmondson, J., Axel, R. The molecular biology of olfactory perception. Cold Spring Harbor Symp. Quant. Biol. 61: 135-145, 1996. [PubMed: 9246442]
Reed, R. R. Genetic approaches to mammalian olfaction. Cold Spring Harbor Symp. Quant. Biol. 61: 165-172, 1996. [PubMed: 9246445]
Ronnett, G. V., Snyder, S. H. Molecular messengers of olfaction. Trends Neurosci. 15: 508-513, 1992. [PubMed: 1282752] [Full Text: https://doi.org/10.1016/0166-2236(92)90104-g]
Sakagami, H., Sawamura, Y., Kondo, H. Synchronous patchy pattern of gene expression for adenylyl cyclase and phosphodiesterase but discrete expression for G-protein in developing rat striatum. Brain Res. Molec. Brain Res. 33: 185-191, 1995. [PubMed: 8750876] [Full Text: https://doi.org/10.1016/0169-328x(95)00123-a]
Schwab, S. G., Hallmayer, J., Lerer, B., Albus, M., Borrmann, M., Honig, S., Strauss, M., Segman, R., Lichtermann, D., Knapp, M., Trixler, M., Maier, W., Wildenauer, D. B. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am. J. Hum. Genet. 63: 1139-1152, 1998. [PubMed: 9758604] [Full Text: https://doi.org/10.1086/302046]
Vuoristo, J. T., Berrettini, W. H., Ala-Kokko, L. C18orf2, a novel, highly conserved intronless gene within intron 5 of the GNAL gene on chromosome 18p11. Cytogenet. Cell Genet. 93: 19-22, 2001. [PubMed: 11474171] [Full Text: https://doi.org/10.1159/000056940]
Vuoristo, J. T., Berrettini, W. H., Overhauser, J., Prockop, D. J., Ferraro, T. N., Ala-Kokko, L. Sequence and genomic organization of the human G-protein Golf-alpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Molec. Psychiat. 5: 495-501, 2000. [PubMed: 11032382] [Full Text: https://doi.org/10.1038/sj.mp.4000758]
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]