Alternative titles; symbols
HGNC Approved Gene Symbol: SAG
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:233,307,816-233,347,055 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | Oguchi disease-1 | 258100 | Autosomal recessive | 3 |
| Retinitis pigmentosa 47, autosomal recessive | 613758 | Autosomal recessive | 3 | |
| Retinitis pigmentosa 96, autosomal dominant | 620228 | Autosomal dominant | 3 |
The S-antigen, or arrestin, is a photoreceptor-specific soluble protein that plays an important role in quenching the phototransduction cascade by inactivating phosphorylation-activated rhodopsin (180380) (summary by Nakazawa et al., 1998).
S-antigen, a soluble protein of 405 amino acids with a molecular weight of 45 kD, is a rod photoreceptor protein implicated in the recovery phase of light transduction (Ngo et al., 1990, Yamaki et al., 1990). It is found in the retina and in the pineal gland. S-antigen has also been called 48-kD protein or arrestin and is known to have an inhibitory role in the activated phototransduction cascade. Additionally, S-antigen is highly antigenic and is capable of inducing experimental autoimmune uveoretinitis. The sequence of S-antigen cDNA shows homology with bovine alpha-transducin.
Using somatic cell hybrids, Ngo et al. (1990) mapped SAG to chromosome 2. In situ hybridization confirmed this assignment and regionally mapped the gene to 2q24-q37. Calabrese et al. (1994) confirmed the assignment and narrowed the regionalization to 2q37 by fluorescence in situ hybridization. Valverde et al. (1994) demonstrated tight linkage to the microsatellite marker D2S172.
Yamaki et al. (1990) isolated the SAG gene and demonstrated that it is approximately 50 kb long, containing 16 exons and 15 introns. The length of most exons was less than 100 bp and the smallest one was only 10 bp. In contrast, the length of most introns was larger than 2 kb, and the gene comprised 97% intron and 3% exon. The splice sites for donor and acceptor were in agreement with the GT/AG rule. The S-antigen protein was translated from an mRNA of 1.9 kb. Yamaki et al. (1990) demonstrated that there is only 1 copy of the SAG gene per haploid genome and that the S-antigen in the retina photoreceptor rod cells and pinealocytes is a single gene product. It has some structural similarity to beta-arrestin (107940).
In eye bank eyes with age-related macular degeneration (ARMD; see 153800), Ethen et al. (2005) determined that a significant linear decline in both arrestin and rhodopsin (180380) content correlated with progressive worsening of ARMD in the macula. In contrast, the peripheral region showed no significant correlation between degree of ARMD and the content of either protein.
Oguchi Disease 1
In 5 of 6 unrelated Japanese patients with Oguchi disease (CSNBO1; 258100), Fuchs et al. (1995) identified a homozygous deletion of nucleotide 1147 in codon 309 (181031.0001), predicting a shift in the reading frame and a premature termination of translation, resulting in 'functional null alleles.'
In 2 Indian brothers with Oguchi disease, Maw et al. (1998) identified homozygosity for a nonsense mutation in the SAG gene (R193X; 181031.0002). One of the brothers exhibited pigmentary retinal degeneration; the authors suggested that similar molecular pathologic events might be responsible for pigment formation in both Oguchi disease and some cases of retinitis pigmentosa.
In 2 unrelated Japanese men with Oguchi disease, Nakamura et al. (2004) identified compound heterozygosity and homozygosity, respectively, for mutations in the SAG gene (258100.0001, 258100.0006, and 258100.0004). The authors noted that all of the known arrestin gene mutations associated with Oguchi disease were nonsense mutations or frameshift mutations with premature terminations that are likely null alleles, suggesting that only critical mutations cause the disorder.
In a 15-year-old Pakistani girl with typical Oguchi disease, Waheed et al. (2012) identified homozygosity for a nonsense mutation in the SAG gene (E306X; 181031.0005) that was present in heterozygosity in her unaffected mother and 4 other unaffected relatives and was not found in a healthy control panel from the same population. The authors stated that this was the first Pakistani patient with Oguchi disease due to a SAG mutation.
In 9 Japanese patients from 7 families with Oguchi disease, Nishiguchi et al. (2019) identified homozygosity for the previously reported recurrent 1-bp deletion in the SAG gene (c.924A; 181031.0001), including 1 family (J98-32) in which a brother and sister had Oguchi disease but another brother had retinitis pigmentosa. The authors also identified homozygosity for the same 1-bp deletion in 12 patients with retinitis pigmentosa, and noted that it was unclear what determined the range of phenotypes attributed to the same SAG mutation. In addition, a 68-year-old Japanese woman with Oguchi disease was homozygous for a different 1-bp deletion in SAG (181031.0008).
Retinitis Pigmentosa 47
Nakazawa et al. (1998) identified the 1147delA mutation in the SAG gene in 3 unrelated patients with retinitis pigmentosa (RP47; 613758). One of the patients had a sib with Oguchi disease associated with the same mutation.
In 12 Japanese patients from 9 families with retinitis pigmentosa, Nishiguchi et al. (2019) identified homozygosity for the previously reported recurrent 1-bp deletion in the SAG gene (c.924A; 181031.0001), including 1 family (J98-32) in which a brother had retinitis pigmentosa but another brother and sister had Oguchi disease. The authors also identified homozygosity for the same 1-bp deletion in 9 patients with Oguchi disease, and noted that it was unclear what determined the range of phenotypes attributed to the same SAG mutation.
Retinitis Pigmentosa 96
In 20 affected individuals from 12 families of Hispanic descent segregating autosomal dominant retinitis pigmentosa (RP96; 620228), Sullivan et al. (2017) identified heterozygosity for a missense mutation in the SAG gene (C147F; 181031.0007). The mutation, which segregated with disease in each family, was not found in more than 4,000 exomes from Hispanic controls, and was extremely rare on global databases. Haplotype analysis was consistent with a founder mutation event and that the 12 families were distantly related.
In affected members of a 3-generation Australian family segregating autosomal dominant retinitis pigmentosa, Pappalardo et al. (2021) identified heterozygosity for the previously reported C147F mutation in the SAG gene.
Chan et al. (2007) examined the biochemical characteristics of rod and cone arrestins with respect to their ability to quench the activity of light-activated rhodopsin (180380) in transgenic mice. The mouse rod opsin promoter was used to drive expression of mouse cone arrestin (301770) in rod photoreceptor cells of rod arrestin knockout (Arr1 -/-) mice. Two independent lines of transgenic mice were obtained that expressed cone arrestin in rod photoreceptors and each was bred into the Arr1 -/- background. Expression of mouse cone arrestin conferred dose-dependent protection against photoreceptor cell death caused by low light exposure to Arr1 -/- retinas, but did not appear to be as effective as rod arrestin. Cone arrestin could partially substitute for rod arrestin in Arr1 -/- rods, offering a degree of protection from light-induced damage and increasing the extent of rhodopsin deactivation in response to flashes of light. Although earlier work had shown that rod arrestin could bind and deactivate cone pigments efficiently, Chan et al. (2007) concluded that cone arrestin bound light-activated, phosphorylated rhodopsin less efficiently than did rod arrestin in vivo, and that the structural requirements for high-affinity binding are fundamentally distinct for rod and cone arrestins.
Oguchi Disease 1
In 5 of 6 unrelated Japanese patients with Oguchi disease-1 (CSNBO1; 258100), Fuchs et al. (1995) identified a homozygous deletion of nucleotide 1147A in codon 309 of the arrestin gene, predicted to cause a frameshift resulting in premature termination of translation after incorporation of 11 additional amino acids unrelated to SAG. Fuchs et al. (1995) noted that the numbering of the mutation was according to the sequence of Yamaki et al. (1990). Although no relationship was identified among the patients, a single founder mutation was suggested because all 5 patients were also homozygous for 3 intragenic S-antigen polymorphisms/rare sequence variants and carried the same S-antigen gene haplotypes.
In a 23-year-old Japanese man with Oguchi disease, Nakamura et al. (2004) identified compound heterozygosity for 2 mutations in the SAG gene: the 1147delA mutation, and a 744C-T transition in exon 8 resulting in an arg175-to-ter (R175X; 181031.0006) substitution. His unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 100 control alleles.
In 9 Japanese patients from 7 families with Oguchi disease, Nishiguchi et al. (2019) identified homozygosity for a recurrent 1-bp deletion in the SAG gene, c.924delA (c.924delA, NM_000541), previously reported as c.1147delA. In 1 family (J98-32), a brother and sister had Oguchi disease but another brother had RP; the authors also identified homozygosity for the same 1-bp deletion in 12 patients with retinitis pigmentosa, and noted that it was unclear what determined the range of phenotypes attributed to the same SAG mutation.
Retinitis Pigmentosa 47
Nakazawa et al. (1998) identified the 1147delA mutation in exon 11 of the SAG gene in homozygous state in 3 unrelated patients with retinitis pigmentosa (RP47; 613758). Patient 1 had a sib with Oguchi disease associated with the same mutation.
In 12 Japanese patients from 9 families with retinitis pigmentosa, Nishiguchi et al. (2019) identified homozygosity for a recurrent 1-bp deletion in the SAG gene, c.924delA (previously reported as c.1147delA) including in 1 family (J98-32) in which a brother had RP but another brother and sister had Oguchi disease. The authors noted that it was unclear what determined the range of phenotypes attributed to the same SAG mutation.
In 2 Indian brothers with Oguchi disease (CSNBO1; 258100), Maw et al. (1998) identified homozygosity for a 797C-T transition in exon 8 of the SAG gene, resulting in an arg193-to-ter (R193X) substitution. SSCP screening of the arrestin gene revealed a bandshift in exon 8 that was homozygous in the brothers, heterozygous in the unaffected parents and an unaffected sister, and absent in 80 Indian controls.
In a 30-year-old Japanese man with Oguchi disease (CSNBO1; 258100), Nakamura et al. (2004) identified homozygosity for a 1195C-T transition in exon 11 of the SAG gene, resulting in an arg292-to-ter (R292X) substitution. Family members were not available for testing; however, the mutation was not found in 100 control alleles.
In a 15-year-old Pakistani girl with typical Oguchi disease (CSNBO1; 258100), Waheed et al. (2012) identified homozygosity for a 916G-T transversion in exon 11 of the SAG gene, resulting in a glu306-to-ter (E306X) substitution. The mutation was present in heterozygosity in her unaffected mother and 4 other unaffected relatives but was not found in a healthy control panel from the same population. The authors noted that the patient was also diagnosed with dural sinus thrombosis, thrombocytopenia, and systemic lupus erythematosus, which were unlikely to be associated with the SAG variant. In addition, the patient, as well as 4 other family members, had hyperhomocysteinemia, which was found to segregate with the known 677C-T polymorphism in the MTHFR gene (607093.0003).
For discussion of the arg175-to-ter (R175X) mutation in the SAG gene that was found in compound heterozygous state in a patient with Oguchi disease-1 (CSNBO1; 258100) by Nakamura et al. (2004), see 181031.0001.
In 20 affected individuals from 12 families of Hispanic descent segregating autosomal dominant retinitis pigmentosa (RP96; 620228), Sullivan et al. (2017) identified heterozygosity for a c.440G-T transversion (c.440G-T, NM_000541.4) in the SAG gene, resulting in a cys147to-phe (C147F) substitution at a highly conserved residue. The mutation segregated fully with disease in all families, and was not found in more than 4,000 exomes from Hispanic controls; however, it was present once in the ExAC database, at a frequency of 1/120,594 alleles overall and in 1/11,566 Hispanic alleles.
In affected members of a 3-generation Australian family segregating autosomal dominant RP, Pappalardo et al. (2021) identified heterozygosity for the C147F mutation in the SAG gene. The mutation was present in the proband, his brother, and his affected son, as well as in the proband's asymptomatic 10-year-old nephew who had not been examined. The variant was not found in the proband's asymptomatic son, who had a normal retinal examination at age 35 years.
In a 68-year-old Japanese woman with Oguchi disease (CSNBO1; 258100), Nishiguchi et al. (2019) identified homozygosity for a 1-bp deletion (c.636delT, NM_000541) in the SAG gene. She showed diffuse retinal degeneration most prominent in the macula, with a few areas of bone spicule pigmentation in the temporal macula bilaterally, and only a circumferential gold sheen peripheral to the posterior pole with patchy dropouts. The authors suggested this might represent a phenotype intermediate between Oguchi disease and retinitis pigmentosa (see RP47, 613758).
Calabrese, G., Sallese, M., Stornaiuolo, A., Stuppia, L., Palka, G., De Blasi, A. Chromosome mapping of the human arrestin (SAG), beta-arrestin 2 (ARRB2), and beta-adrenergic receptor kinase 2 (ADRBK2) genes. Genomics 23: 286-288, 1994. [PubMed: 7695743] [Full Text: https://doi.org/10.1006/geno.1994.1497]
Chan, S., Rubin, W. W., Mendez, A., Liu, X., Song, X., Hanson, S. M., Craft, C. M., Gurevich, V. V., Burns, M. E., Chen, J. Functional comparisons of visual arrestins in rod photoreceptors of transgenic mice. Invest. Ophthal. Vis. Sci. 48: 1968-1975, 2007. [PubMed: 17460248] [Full Text: https://doi.org/10.1167/iovs.06-1287]
Ethen, C. M., Feng, X., Olsen, T. W., Ferrington, D. A. Declines in arrestin and rhodopsin in the macula with progression of age-related macular degeneration. Invest. Ophthal. Vis. Sci. 46: 769-775, 2005. [PubMed: 15728529] [Full Text: https://doi.org/10.1167/iovs.04-0810]
Fuchs, S., Nakazawa, M., Maw, M., Tamai, M., Oguchi, Y., Gal, A. A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nature Genet. 10: 360-362, 1995. [PubMed: 7670478] [Full Text: https://doi.org/10.1038/ng0795-360]
Maw, M., Kumaramanickavel, G., Kar, B., John, S., Bridges, R., Denton, M. Two Indian siblings with Oguchi disease are homozygous for an arrestin mutation encoding premature termination. Hum. Mutat. Suppl. 1: S317-S319, 1998. [PubMed: 9452120] [Full Text: https://doi.org/10.1002/humu.1380110199]
Nakamura, M., Yamamoto, S., Okada, M., Ito, S., Tano, Y., Miyake, Y. Novel mutations in the arrestin gene and associated clinical features in Japanese patients with Oguchi's disease. Ophthalmology 111: 1410-1414, 2004. [PubMed: 15234147] [Full Text: https://doi.org/10.1016/j.ophtha.2003.11.006]
Nakazawa, M., Wada, Y., Tamai, M. Arrestin gene mutations in autosomal recessive retinitis pigmentosa. Arch. Ophthal. 116: 498-501, 1998. [PubMed: 9565049] [Full Text: https://doi.org/10.1001/archopht.116.4.498]
Ngo, J. T., Klisak, I., Sparkes, R. S., Mohandas, T., Yamaki, K., Shinohara, T., Bateman, J. B. Assignment of S-antigen gene to human chromosome 2q24-q37. Genomics 7: 84-87, 1990. [PubMed: 2335355] [Full Text: https://doi.org/10.1016/0888-7543(90)90521-u]
Nishiguchi, K. M., Ikeda, Y., Fujita, K., Kunikata, H., Akiho, M., Hashimoto, K., Hosono, K., Kurata, K., Koyanagi, Y., Akiyama, M., Suzuki, T., Kawasaki, R., Wada, Y., Hotta, Y., Sonoda, K.-H., Murakami, A., Nakazawa, M., Nakazawa, T., Abe, T. Phenotypic features of Oguchi disease and retinitis pigmentosa in patients with S-antigen mutations: a long-term follow-up study. Ophthalmology 126: 1557-1566, 2019. [PubMed: 31257036] [Full Text: https://doi.org/10.1016/j.ophtha.2019.05.027]
Pappalardo, J., Heath Jeffery, R. C., Thompson, J. A., Charng, J., Chelva, E. S., Constable, I. J., McLaren, T. L., Lamey, T. M., De Roach, J. N., Chen, F. K. Progressive sector retinitis pigmentosa due to c.440G>T mutation in SAG in an Australian family. Ophthalmic Genet. 42: 62-70, 2021. [PubMed: 33047631] [Full Text: https://doi.org/10.1080/13816810.2020.1832533]
Sullivan, L. S., Bowne, S. J., Koboldt, D. C., Cadena, E. L., Heckenlively, J. R., Branham, K. E., Wheaton, D. H., Jones, K. D., Ruiz, R. S., Pennesi, M. E., Yang, P., Davis-Boozer, D., Northrup, H., Gurevich, V. V., Chen, R., Xu, M., Li, Y., Birch, D. G., Daiger, S. P. A novel dominant mutation in SAG, the arrestin-1 gene, is a common cause of retinitis pigmentosa in Hispanic families in the southwestern United States. Invest. Ophthal. Vis. Sci. 58: 2774-2784, 2017. [PubMed: 28549094] [Full Text: https://doi.org/10.1167/iovs.16-21341]
Valverde, D., Bayes, M., Martinez, I., Grinberg, D., Vilageliu, L., Balcells, S., Gonzalez-Duarte, R., Baiget, M. Genetic fine localization of the arrestin (S-antigen) gene 4 cM distal from D2S172. Hum. Genet. 94: 193-194, 1994. [PubMed: 8045567] [Full Text: https://doi.org/10.1007/BF00202869]
Waheed, N. K., Qavi, A. H., Malik, S. N., Maria, M., Riaz, M., Cremers, F. P. M., Azam, M., Qamar, R. A nonsense mutation in S-antigen (p.glu306ter) causes Oguchi disease. Molec. Vis. 18: 1253-1259, 2012. [PubMed: 22665972]
Yamaki, K., Tsuda, M., Kikuchi, T., Chen, K.-H., Huang, K.-P., Shinohara, T. Structural organization of the human S-antigen gene: cDNA, amino acid, intron, exon, promoter, in vitro transcription, retina, and pineal gland. J. Biol. Chem. 265: 20757-20762, 1990. [PubMed: 2249983]