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ARRESTIN 3, RETINAL; ARR3

ARRESTIN 3, RETINAL; ARR3

Alternative titles; symbolsX-ARRESTIN; ARRXCONE ARRESTINARRESTIN 4; ARR4HGNC Approved Gene Symbol: ARR3Cytogenetic location: Xq13.1 Genomic coordinates (GRCh...

Alternative titles; symbols

  • X-ARRESTIN; ARRX
  • CONE ARRESTIN
  • ARRESTIN 4; ARR4

HGNC Approved Gene Symbol: ARR3

Cytogenetic location: Xq13.1 Genomic coordinates (GRCh38): X:70,268,333-70,281,839 (from NCBI)

▼ Cloning and Expression
Using a differential cDNA cloning approach to isolate human retina-specific and retina-enriched genes, Murakami et al. (1993) isolated a 1,314-bp cDNA, representing a highly retina-specific message encoding a 388-amino acid protein showing 58%, 50%, and 49% homology to bovine beta-arrestin (107940, 107941) and bovine and human retinal arrestin (S-antigen; SAG; 181031), respectively. Studies of the tissue distribution by in situ hybridization demonstrated expression of the gene in the inner and outer segments and the inner plexiform regions of the retina. Murakami et al. (1993) designated the gene X-arrestin. Compared to fly arrestins, X-arrestin showed the highest homology (37%) to that in Drosophila miranda, which is also encoded by a gene on the X chromosome. Murakami et al. (1993) speculated that X-arrestin may be involved in inactivation of rhodopsin, or, alternatively, may play a role in an as yet undefined retina-specific signal transduction.

Using several independent methods, Zhang et al. (2003) identified the antigen recognized by monoclonal antibody 7G6, a widely used cone-specific marker, as cone arrestin, a regulatory component of the cone cascade. The 7G6 epitope was contained in a divergent loop, the sequence of which was conserved in bovines and primates but not other vertebrate species, consistent with the specificity of the antibody.

▼ Gene Structure
Sakuma et al. (1998) determined that the ARRX gene contains 17 exons and spans approximately 20 kb.

▼ Mapping
By hybridization to panels of DNA from somatic cell hybrids containing specific human chromosomes and specific parts of the human X chromosome, Murakami et al. (1993) mapped the ARRX gene to Xcen-q21.

▼ Gene Function
Wang et al. (2004) reported that the multidomain protein spinophilin (603325) antagonizes the multiple arrestin functions associated with G protein-coupled receptor (GPCR)-mediated signaling and trafficking. Through blocking G protein receptor kinase-2 (GRK2; 109635) association with receptor-G-beta-gamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wildtype mice to sedation elicited by stimulation of alpha-2 adrenergic receptors (see 104210) whereas arrestin-3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. Wang et al. (2004) concluded that reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.

Zhang et al. (2003) found that cone arrestin translocated in bovine retina depending on illumination. In the light, it accumulated in the cone outer segments; in the dark, it accumulated in the inner segment. The light-dependent translocation of cone arrestin suggested a role in light-dark adaptation of cones. Zhang et al. (2003) concluded that cone arrestin is a candidate gene for X-linked cone dystrophies.

▼ Molecular Genetics
In 3 large Chinese families with female-limited early-onset high myopia (MYP26; 301010), Xiao et al. (2016) identified heterozygous mutations in the ARR3 gene (301770.0001-301770.0003) that segregated with disease and were not found in controls or public variant databases. Hemizygous and obligate carrier males were unaffected.

▼ Animal Model
Deming et al. (2015) found that, in comparison with wildtype mice, 2-month-old Arr4 -/- mice had diminished visual acuity and contrast sensitivity, yet enhanced ERG flicker response and higher phototopic ERG b-wave amplitudes. In contrast, in older Arr4 -/- mice, all ERG amplitudes were significantly reduced in magnitude compared to age-matched controls. Also, in older Arr4 -/- mice, the total cone numbers decreased and cone opsin protein immunoreactive expression levels were significantly reduced, while overall photoreceptor outer nuclear layer thickness was unchanged. Deming et al. (2015) concluded that ARR4 modulates essential functions in high acuity vision and downstream cellular signaling pathways that are not fulfilled or substituted by the coexpression of ARR1 (SAG; 181031). They suggested that Arr4 -/- mice are a model for the study of age-related cone dystrophy.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 MYOPIA 26, X-LINKED, FEMALE-LIMITED
ARR3, ALA298ASP
In affected members of a large 6-generation Chinese family (XF1) with female-limited early-onset high myopia (MYP26; 301010), Xiao et al. (2016) identified heterozygosity for a c.893C-A transversion in the AAR3 gene, resulting in an ala298-to-asp (A298D) substitution. The mutation segregated fully with disease in the family and was not found in 192 controls or in the HGMD, Exome Variant Server, ExAC, or 1000 Genomes Project databases. Two hemizygous male family members and 1 obligate male carrier were unaffected.

.0002 MYOPIA 26, X-LINKED, FEMALE-LIMITED
ARR3, ARG100TER
In affected members of a large 4-generation Chinese family (XF2) with female-limited early-onset high myopia (MYP26; 301010), Xiao et al. (2016) identified heterozygosity for a c.298C-T transition in the ARR3 gene, resulting in an arg100-to-ter (R200X) substitution. The mutation segregated fully with disease in the family and was not found in 192 controls or in the HGMD, Exome Variant Server, ExAC, or 1000 Genomes Project databases.

.0003 MYOPIA 26, X-LINKED, FEMALE-LIMITED
ARR3, LEU80PRO
In affected members of a large 4-generation Chinese family (XF3) with female-limited early-onset high myopia (MYP26; 301010), Xiao et al. (2016) identified heterozygosity for a c.239T-C transition in the ARR3 gene, resulting in a leu80-to-pro (L80P) substitution. The mutation segregated fully with disease in the family and was not found in 192 controls or in the HGMD, Exome Variant Server, ExAC, or 1000 Genomes Project databases. A hemizygous male family member was unaffected.

Tags: Xq13.1