Alternative titles; symbols
HGNC Approved Gene Symbol: GNAT2
Cytogenetic location: 1p13.3 Genomic coordinates (GRCh38): 1:109,603,091-109,619,616 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p13.3 | Achromatopsia 4 | 613856 | 3 |
In photoreceptors, light-activated photopigment (see, e.g., red cone pigment, 300822) interacts with transducin, a 3-subunit G protein, stimulating the exchange of bound GDP for GTP (Morris and Fong, 1993). The transducin alpha-subunit, bound to GTP, is then released from its beta/gamma-subunits and activates cGMP-phosphodiesterase by removing the inhibitory gamma-subunits therefrom. The cGMP-PDE lowers the concentration of cGMP, causing the closure of cGMP-dependent cation channels and hyperpolarization of the photoreceptor. The transducin alpha-subunits are different in rods and cones, being encoded by different genes, GNAT1 (139330) in rods and GNAT2 in cones.
Morris and Fong (1993) isolated human GNAT2 genomic and cDNA clones. They demonstrated that the GNAT2 transcriptional unit is 9,967 basepairs long. The 354-amino acid protein shares 97% and 83% identity, respectively, with bovine GNAT2 and human GNAT1. Northern blot analysis of human retinal and WERI-RB1 RNA revealed a major transcript of 1.7 kb.
Morris and Fong (1993) demonstrated that the GNAT2 gene contains 8 exons. The gene has 7 initiation sites spanning 31 bp. The sequence upstream shows a TATA box consensus sequence at -29, a CCAAT box consensus sequence at -58 (reverse orientation), and a sequence (CCATAT) similar to the CCAAT box consensus at -76. The GNAT2 upstream sequence shows no significant identity with the upstream region of the human rod transducin alpha-subunit gene (GNAT1) or with the upstream regions of the color visual pigment genes (300824), indicating that the expression of GNAT2 may be regulated differently from these other rod- and cone-specific proteins.
Sparkes et al. (1987) and Blatt et al. (1988) used a cDNA probe to assign the alpha-transducing-2 polypeptide to chromosome 1 in man and to chromosome 17 in the mouse. By in situ hybridization, Wilkie et al. (1992) demonstrated that the GNAT2 gene is on human 1p13. By the study of RFLVs in an interspecific backcross, they demonstrated that the corresponding gene is on mouse chromosome 3 rather than on chromosome 17 as had previously been suggested.
Kohl et al. (2002) reported 5 families with achromatopsia, with 4 showing homozygosity for protein-truncation mutations in the GNAT2 gene (139340.0001; 139340.0003-139340.0004) (ACHM4; 613856).
Aligianis et al. (2002) used autozygosity mapping and positional candidate gene analysis in a large consanguineous Pakistani family containing 6 members with autosomal recessive complete achromatopsia. After excluding linkage to the 2 known achromatopsia genes, CNGA3 (600053) and CNGB3 (605080), they performed a genomewide linkage screen and detected an autozygous 12-cM segment on 1p13. Direct sequence analysis of the candidate gene located within this region, GNAT2, identified a frameshift mutation in exon 7 (139340.0002).
Rosenberg et al. (2004) researched the molecular genetic basis of a congenital stationary cone dysfunction characterized by congenital nystagmus, moderate visual impairment, and markedly disparate color vision deficiencies between 2 affected cousins. The phenotype of the proband was described as incomplete achromatopsia or extreme protanopia (303900) and that of her cousin as a mild protanomalous trichromacy (see 303900) (oligocone trichromacy). Whereas the proband was found to carry a homozygous frameshift mutation in GNAT2 (139340.0003), her cousin was a compound heterozygote for the frameshift mutation and a novel intronic mutation (139340.0004). Heterologous expression in COS-7 cells showed that the intronic mutation resulted in a splicing defect that caused early translation termination. However, this mutation was 'leaky,' giving rise to small amounts of correctly spliced transcripts and offered an explanation for the diverging clinical findings in the cousins. The authors concluded that these patients broadened the phenotypic spectrum of GNAT2 mutations and underscored the increasing importance of molecular genetics in the clinical diagnosis of atypical ophthalmic phenotypes.
Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 genes in 16 unrelated patients with autosomal recessive ACHM: 10 patients had mutations in CNGB3, 3 had mutations in CNGA3, and no coding region mutations were found in 3 patients. The authors concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia.
Kennedy et al. (2007) identified in vivo a 3.2-kb promoter fragment from zebrafish transducin-alpha that specifically directed robust transgene expression in retinal and pineal photoreceptors. Achromatopsia in the nof mutant was rescued using the identified promoter fragment to direct transgenic expression of wildtype cone transducin in mutant cones.
In a patient with achromatopsia-4 (ACHM4; 613856), Kohl et al. (2002) identified a C-to-T transition at nucleotide 235 in the GNAT2 gene causing a gln79-to-ter (Q79X) mutation resulting in truncation of the gene product.
In a consanguineous Pakistani family with achromatopsia-4 (ACHM4; 613856), Aligianis et al. (2002) used autozygosity mapping and positional candidate gene analysis to identify a 4-bp insertion (842insTCAG) in exon 7 of the GNAT2 gene that segregated with the disease.
In a patient with achromatopsia-4 (ACHM4; 613856), Kohl et al. (2002) detected a homozygous deletion/insertion mutation in exon 3 of the GNAT2 gene, 285_291del7insCTGTAT. The mutation resulted in frameshift and subsequent translation termination after 61 deviant codons (Tyr95fsTer61). Rosenberg et al. (2004) extended the molecular analysis to include the proband's less severely affected paternal first cousin. The cousin was compound heterozygous for the ins/del mutation, inherited from his mother, and a novel substitution in intron 4 of GNAT2 (139340.0004).
In an individual with achromatopsia-4 (ACHM4; 613856), Kohl et al. (2002) detected an intronic substitution in the GNAT2 gene, an A-to-G substitution at position +24 in intron 4 (461+24G-A). This substitution activated a cryptic splice donor site, resulting in a 21-bp insertion between exons 4 and 5 and a premature stop codon at the genuine exon-intron boundary. That the mutation was 'leaky,' giving rise to small amounts of correctly spliced transcripts, offered an explanation for the divergent clinical findings in the cousins.
Aligianis, I. A., Forshew, T., Johnson, S., Michaelides, M., Johnson, C. A., Trembath, R. C., Hunt, D. M., Moore, A. T., Maher, E. R. Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). J. Med. Genet. 39: 656-660, 2002. [PubMed: 12205108] [Full Text: https://doi.org/10.1136/jmg.39.9.656]
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]
Kennedy, B. N., Alvarez, Y., Brockerhoff, S. E., Stearns, G. W., Sapetto-Rebow, B., Taylor, M. R., Hurley, J. B. Identification of a zebrafish cone photoreceptor-specific promoter and genetic rescue of achromatopsia in the nof mutant. Invest. Ophthal. Vis. Sci. 48: 522-529, 2007. [PubMed: 17251445] [Full Text: https://doi.org/10.1167/iovs.06-0975]
Kohl, S., Baumann, B., Rosenberg, T., Kellner, U., Lorenz, B., Vadala, M., Jacobson, S. G., Wissinger, B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am. J. Hum. Genet. 71: 422-425, 2002. [PubMed: 12077706] [Full Text: https://doi.org/10.1086/341835]
Morris, T. A., Fong, S.-L. Characterization of the gene encoding human cone transducin alpha-subunit (GNAT2). Genomics 17: 442-448, 1993. [PubMed: 8406495] [Full Text: https://doi.org/10.1006/geno.1993.1345]
Rosenberg, T., Baumann, B., Kohl, S., Zrenner, E., Jorgensen, A. L., Wissinger, B. Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest. Ophthal. Vis. Sci. 45: 4256-4262, 2004. [PubMed: 15557429] [Full Text: https://doi.org/10.1167/iovs.04-0317]
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]
Wiszniewski, W., Lewis, R. A., Lupski, J. R. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of a uniparental disomy 14. Hum. Genet. 121: 433-439, 2007. [PubMed: 17265047] [Full Text: https://doi.org/10.1007/s00439-006-0314-y]