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HGNC Approved Gene Symbol: RGS9Cytogenetic location: 17q24.1 Genomic coordinates (GRCh38): 17:65,137,369-65,227,702 (from NCBI)▼ DescriptionMembers of the RG...

HGNC Approved Gene Symbol: RGS9

Cytogenetic location: 17q24.1 Genomic coordinates (GRCh38): 17:65,137,369-65,227,702 (from NCBI)

▼ Description
Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation.

▼ Cloning and Expression
He et al. (1998) identified RGS9 as the mammalian rod outer segment phototransduction GAP (GTPase-accelerating protein).

Burchett et al. (1998) isolated rat striatum cDNAs encoding several RGS proteins, including RGS9.

By searching an EST database for homologs of rat RGS9, Granneman et al. (1998) identified a human cDNA encoding an RGS9 isoform that they called RGS9L. The predicted 674-amino acid human RGS9L protein contains an N-terminal DEP (dishevelled, egl10, pleckstrin) domain, an RGS domain, and a C-terminal region highly enriched in proline and serine residues. Granneman et al. (1998) reported that the mouse and bovine retinal forms of RGS9 isolated by He et al. (1998) represent an alternatively spliced isoform, which they designated RGS9S. RGS9S lacks the C-terminal proline-rich domain found in RGS9L. Northern blot analysis and nuclease protection assays indicated that forebrain regions receiving dopamine innervation, such as striatum, hypothalamus, and nucleus accumbens, express RGS9L, while retina and pineal gland express RGS9S almost exclusively. This tissue-specific splicing pattern appeared to be highly conserved between human and rodents, suggesting cell-specific differences in the function of these isoforms. RGS9S and RGS9L are encoded by 9- and 2.5-kb mRNAs, respectively.

Zhang et al. (1999) cloned RGS9 variants, which they designated RGS9-1 and RGS9-2, from a retina cDNA library. Northern blot analysis indicated that the major transcript in retina is a 9.5-kb mRNA encoding RGS9-1, and the major transcript in brain is a 2.5-kb mRNA encoding RGS9-2. PCR analysis of retina detected RGS9-2 at a much lower level than RGS9-1. The RGS9-1 and RGS9-2 variants result from alternative splicing of exon 17 and encode proteins of 484 and 671 amino acids, respectively. Both proteins share DEP, GGL (G protein gamma subunit-like), and RGS domains, but RGS9-1 has an 18-residue C terminus, whereas RGS9-2 has a 205-residue, proline-rich C terminus. Zhang et al. (1999) also cloned RGS9-1 and RGS9-2 variants with a 9-bp insertion at the 3-prime end of exon 6, resulting in 3 additional amino acids in the proteins. Western blot analysis of retina detected RGS9-1 at an apparent molecular mass of 58 kD, and Western blot analysis of brain detected RGS9-2 at an apparent molecular mass of 70 kD, both in line with their expected masses. Immunocytochemical analysis of bovine and human retina found strong RGS9 staining of cones, weak staining of rods, and punctate staining of photoreceptor cell bodies. Weak staining was also detected in the inner retina, possibly in amacrine cells.

▼ Gene Function
He et al. (1998) found that the RGS domain of RGS9 accelerated GTP hydrolysis by transducin, the visual G protein (see 189970).

Granneman et al. (1998) showed that, when expressed in mammalian cells, RGS9L suppressed signaling mediated by Gi, the inhibitory GTP-binding regulator of adenylate cyclase (see 139310). They stated that this was probably due to RGS9L acting as a GAP.

Makino et al. (1999) reported that the GAP for transducin in rod photoreceptors is a tight complex between RGS9 and the long splice variant of G protein beta-5 (GNB5; 604447).

By coimmunoprecipitation analysis, Hu and Wensel (2002) determined that bovine Rgs9 was associated with a heterotetrameric complex containing R9ap (607814), Gnb5, and Gnat (see 139330) in detergent-solubilized rod outer segment (ROS) membranes. R9ap interacted specifically with the N-terminal domain of Rgs9. Hu and Wensel (2002) concluded that the C-terminal transmembrane domain of R9ap functions as the membrane anchor for the other largely soluble interacting partners. Hu et al. (2003) determined that the formation of a membrane-bound complex with bovine R9ap increased the GTPase-accelerating activity of Rgs9 by a factor of 4.

By single-cell RT-PCR and immunoprecipitation analysis, Cabrera-Vera et al. (2004) detected Rgs9-2 and Gnb5 mRNA and protein complexes in rat striatal cholinergic and gamma-aminobutyric acidergic neurons. Introduction of bovine Rgs9 constructs through a patch pipette in these cells showed that the RGS domain of Rgs9-2 modulated D2 dopamine receptor (DRD2; 126450)-mediated inhibition of Cav2.2 (CACNA1B; 601012) Ca(2+) channels. This modulation was blocked by the introduction of the DEP-GGL domain of Rgs9-2. Rgs9 did not modulate the M2 muscarinic receptor (CHRM2; 118493) linkage to Cav2.2 channels in the same cell.

▼ Gene Structure
Zhang et al. (1999) determined that the RGS9 gene contains 19 exons and spans more than 75 kb. The RGS9-1 transcript is derived from exons 1 through 17, and the RGS9-2 transcript is derived from exons 1 through 16, a short segment of exon 17, and exons 18 and 19. Exon 17 is alternatively spliced in a cell-specific manner. Alternative splicing of exon 6, resulting in a 9-bp insertion, occurs in some RGS9-1 and RGS9-2 variants.

Sierra et al. (2002) determined that the RGS9 gene contains 19 exons and spans 91 kb.

▼ Mapping
By analysis of a radiation hybrid panel and by FISH, Granneman et al. (1998) mapped the RGS9 gene to chromosome 17q23-q24. Zhang et al. (1999) confirmed this localization by somatic cell hybrid analysis and FISH.

▼ Molecular Genetics
Nishiguchi et al. (2004) identified 4 unrelated Dutch patients with bradyopsia (608415), each homozygous for a trp299-to-arg in the RGS9 gene (W299R; 604067.0001).

▼ Animal Model
Chen et al. (2000) generated mice deficient in Rgs9 by homologous recombination. The rod outer segment membranes from mice lacking Rgs9 hydrolyzed GTP more slowly than rod outer segment membranes from control mice. The G-beta-5-L protein that forms a complex with Rgs9 was absent from Rgs9 -/- retinas, although G-beta-5-L mRNA was still present. The flash responses of Rgs9 -/- rods rose normally, but recovered much more slowly than normal. Chen et al. (2000) concluded that Rgs9, probably in a complex with G-beta-5-L, is essential for acceleration of hydrolysis of GTP by the rod transducin alpha subunit (139330) and for normal recovery of the photoresponse.

▼ ALLELIC VARIANTS ( 1 Selected Example):

In 4 unrelated Dutch patients with prolonged electroretinal response suppression (PERRS; 608415), Nishiguchi et al. (2004) identified a homozygous T-to-C transition at cDNA nucleotide 895 of RGS9 that resulted in a tryptophan-to-arginine substitution at codon 299 (W299R). The segregation of the W299R allele in the 4 families was consistent with its pathogenicity. The electrophysiologic findings of W299R homozygotes were similar to those in rgs9 knockout mice. W299 is one of the most highly conserved residues in the catalytic RGS domain among RGS family members in species ranging from C. elegans to human. The substitution of a hydrophobic tryptophan with a positively charged arginine residue was expected to disrupt the hydrophobic interactions of the RGS domain. Nishiguchi et al. (2004) expressed the domain with the W299R mutation and evaluated its function. The mutant was much less soluble than the corresponding wildtype domain, and its ability to stimulate the GTPase activity of transducin (see 139340) was about 20-fold lower than that of the wildtype domain.

Tags: 17q24.1