ARR3

Summary

ARR3 (arrestin 3, HGNC:710) is a protein-coding gene on chromosome Xq13.1, encoding Arrestin-C (P36575). May play a role in an as yet undefined retina-specific signal transduction.

The protein encoded by this gene is a non-visual arrestin which binds to agonist-activated, phosphorylated G protein-coupled receptors. This binding uncouples the receptor from the heterotrimeric G protein, resulting in termination of the G protein-coupled receptor signaling. The encoded protein also is a part of the centrosome, interacting with gamma-tubulin to help regulate proper centrosome function.

Source: NCBI Gene 407 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia 26, X-linked, female-limited (Strong, GenCC)
• Clinical variants (ClinVar): 135 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 2
• MANE Select transcript: NM_004312

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:710
Approved symbol	ARR3
Name	arrestin 3
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	ARRX
Ensembl gene	ENSG00000120500
Ensembl biotype	protein_coding
OMIM	301770
Entrez	407

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 retained_intron

ENST00000307959, ENST00000374495, ENST00000477379, ENST00000480877

RefSeq mRNA: 1 — MANE Select: NM_004312 NM_004312

CCDS: CCDS14399

Canonical transcript exons

ENST00000307959 — 17 exons

Exon	Start	End
ENSE00000672304	70278504	70278641
ENSE00000672305	70278066	70278138
ENSE00000672306	70277716	70277800
ENSE00000672307	70277394	70277529
ENSE00000672308	70276669	70276736
ENSE00000672309	70276433	70276492
ENSE00001041353	70269662	70269692
ENSE00001275540	70281676	70281840
ENSE00001275564	70280766	70280818
ENSE00001329160	70280559	70280582
ENSE00001329678	70280195	70280278
ENSE00001725604	70281099	70281108
ENSE00001851989	70268334	70268372
ENSE00003527551	70269843	70269903
ENSE00003624004	70269356	70269393
ENSE00003654142	70276082	70276281
ENSE00003682099	70270100	70270144

Expression profiles

Bgee: expression breadth ubiquitous, 160 present calls, max score 82.51.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1776 / max 144.1508, expressed in 8 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196619	0.1729	8
196618	0.0047	3

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.51	gold quality
sperm	CL:0000019	73.81	gold quality
male germ cell	CL:0000015	73.01	gold quality
pancreatic ductal cell	CL:0002079	71.94	silver quality
tibialis anterior	UBERON:0001385	69.60	silver quality
retina	UBERON:0000966	68.33	gold quality
pigmented layer of retina	UBERON:0001782	68.33	silver quality
vena cava	UBERON:0004087	67.41	gold quality
triceps brachii	UBERON:0001509	66.78	gold quality
body of tongue	UBERON:0011876	66.73	gold quality
gluteal muscle	UBERON:0002000	66.58	gold quality
ventral tegmental area	UBERON:0002691	66.39	gold quality
nipple	UBERON:0002030	66.18	gold quality
deltoid	UBERON:0001476	66.12	gold quality
saphenous vein	UBERON:0007318	66.08	gold quality
substantia nigra pars reticulata	UBERON:0001966	65.89	gold quality
thymus	UBERON:0002370	65.80	gold quality
tongue	UBERON:0001723	65.76	gold quality
pericardium	UBERON:0002407	65.70	gold quality
cardia of stomach	UBERON:0001162	65.65	gold quality
subthalamic nucleus	UBERON:0001906	65.56	gold quality
inferior vagus X ganglion	UBERON:0005363	65.43	gold quality
synovial joint	UBERON:0002217	65.37	gold quality
superior surface of tongue	UBERON:0007371	65.35	gold quality
dorsal plus ventral thalamus	UBERON:0001897	65.29	gold quality
trigeminal ganglion	UBERON:0001675	65.27	gold quality
cerebellar vermis	UBERON:0004720	65.25	gold quality
substantia nigra pars compacta	UBERON:0001965	65.22	gold quality
pylorus	UBERON:0001166	65.21	gold quality
pons	UBERON:0000988	65.16	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	5591.38
E-MTAB-7316	yes	5463.62
E-MTAB-11121	yes	3875.25
E-ANND-3	no	3.55

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, RORA, ZNF513

Literature-anchored findings (GeneRIF, showing 27)

• Regulation of arrestin-3 phosphorylation by casein kinase II. (PMID:11877451)
• The light-dependent translocation of cone arrestin suggests a role in light-dark adaptation of cones. (PMID:12824223)
• association of arrestin-3 with the FSHR is dependent on receptor phosphorylation, however phosphorylation of the third intracellular loop residues is not needed for arrestin-3 association. (PMID:12850288)
• Autoimmunity to this antigen and retinal vasculitis is not altered in patients with Behcet’s disease (PMID:12918707)
• Arrestin in all conformations binds JNK3 comparably, whereas Mdm2 preferentially binds cone arrestin ‘frozen’ in the basal state. (PMID:17680991)
• Arrestin 3 but not arrestin 2 is required for internalization of C-C chemokine receptor CCR7 when bound to C-C chemokine ligand CCL19. In contrast, arrestins are not required for internalization of CCR7/CCL21. (PMID:18802075)
• the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2 (PMID:19001375)
• two non-visual arrestins, arrestin2 and arrestin3, localize to the centrosome, a key organelle involved in microtubule nucleation and bipolar mitotic spindle assembly (PMID:20056609)
• The agonist-induced internalization of GPR109A receptors is regulated by GRK2 and arrestin3 in a pertussis toxin-sensitive manner and that internalized receptor recycling is independent of endosomal acidification. (PMID:20460384)
• upon ligand activation, CysLT(1)R is tyrosine-phosphorylated and released from heterodimers with CysLT(2)R and, subsequently, internalizes from the plasma membrane to the nuclear membrane in a clathrin-, arrestin-3-, and Rab-5-dependent manner (PMID:21203429)
• PP2A inhibits association between the Na+,K+-ATPase and arrestin, and diminishes the effect of arrestin on Na+,K+-ATPase trafficking. (PMID:22242112)
• the TGN acts as a checkpoint for both the recycling and down-regulation of beta1AR and arrestin-3 not only mediates beta1AR endocytosis but also its recycling through the TGN (PMID:22378779)
• Silent scaffolds: inhibition OF c-Jun N-terminal kinase 3 activity in cell by dominant-negative arrestin-3 mutant. (PMID:22523077)
• These data suggest cell type- and subcellular compartment-dependent differences in GRK/arrestin-mediated desensitization and signaling. (PMID:23139825)
• arrestin-3 regulates the activity of multiple JNK isoforms, suggesting that it might play a role in survival and apoptosis of all cell types. (PMID:24292834)
• The 25-amino acid N-domain element of arrestin 3 has the highest affinity for JNK3alpha2, suggesting that it is the key site for JNK3alpha2 docking. (PMID:24412749)
• Identification of receptor binding-induced conformational changes in non-visual arrestins. (PMID:24867953)
• In the cell membrane, arrestin-3 dissociates quickly and almost completely from the Beta2-adrenoceptor. (PMID:25425623)
• These data suggest that heterozygous mutations in ARR3 might be responsible for X-linked female-limited early onset high myopia in the three families, a pattern contrary to the standard X-linked recessive trait. (PMID:27829781)
• These data highlight a novel arrestin-mediated modulation of CREB signalling, suggesting a reciprocal relationship between arrestin2 and arrestin3, wherein recruitment of arrestin3 restricts the ability of beta2AR to activate prolonged CREB phosphorylation by precluding recruitment of an arrestin2/Src/p38 complex. (PMID:28733084)
• The Y1R is able to bind Galpha0 protein as well as arr-3 simultaneously and internalizes as a supercomplex. (PMID:29944985)

• 15-fold higher affinity for inactive JNK3 than for active JNK3; shift in the binding site following JNK3 activation (PMID:30591558)

• Early onset X-linked female limited high myopia in three multigenerational families caused by novel mutations in the ARR3 gene. (PMID:35001458)
• Genetic and clinical landscape of ARR3-associated MYP26: the most common cause of Mendelian early-onset high myopia with a unique inheritance. (PMID:36180177)
• Cannabinoid 1 (CB1) receptor arrestin subtype-selectivity and phosphorylation dependence. (PMID:36250246)
• Pathogenic variant in the X-linked ARR3 gene associated with variable early-onset myopia. (PMID:37795829)
• Novel Splicing Variants in the ARR3 Gene Cause the Female-Limited Early-Onset High Myopia. (PMID:38517428)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	arr3a	ENSDARG00000056511
danio_rerio	arr3b	ENSDARG00000098475
mus_musculus	Arr3	ENSMUSG00000060890
rattus_norvegicus	Arr3	ENSRNOG00000002904
drosophila_melanogaster	krz	FBGN0040206
caenorhabditis_elegans		WBGENE00000195

Paralogs (3): SAG (ENSG00000130561), ARRB1 (ENSG00000137486), ARRB2 (ENSG00000141480)

Protein

Protein identifiers

Arrestin-C — P36575 (reviewed: P36575)

Alternative names: Cone arrestin, Retinal cone arrestin-3, X-arrestin

All UniProt accessions (2): P36575, D6RCT3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in an as yet undefined retina-specific signal transduction. Could bind to photoactivated-phosphorylated red/green opsins.

Subunit / interactions. Homodimer; disulfide-linked in response to retinal illumination. Interacts with CXCR4; the interaction is dependent on the C-terminal phosphorylation of CXCR4 and modulates the calcium ion mobilization activity of CXCR4. Interacts with GPR84.

Subcellular location. Photoreceptor inner segment. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Inner and outer segments, and the inner plexiform regions of the retina.

Disease relevance. Myopia 26, X-linked, female-limited (MYP26) [MIM:301010] A form of myopia, a refractive error of the eye, in which parallel rays from a distant object come to focus in front of the retina, vision being better for near objects than for far. MYP26 is characterized by typical tigroid fundus changes commonly seen in early onset high myopia, and an unusual pattern of X-linked female-limited inheritance. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the arrestin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P36575-1	1	yes
P36575-2	2

RefSeq proteins (1): NP_004303* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000698	Arrestin	Family
IPR011021	Arrestin-like_N	Domain
IPR011022	Arrestin-like_C	Domain
IPR014752	Arrestin-like_C_sf	Homologous_superfamily
IPR014753	Arrestin_N	Homologous_superfamily
IPR014756	Ig_E-set	Homologous_superfamily
IPR017864	Arrestin_CS	Conserved_site

Pfam: PF00339, PF02752

UniProt features (10 total): sequence variant 4, sequence conflict 4, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36575-F1	87.37	0.67

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, MEF2_02, GOBP_VESICLE_MEDIATED_TRANSPORT, PID_CONE_PATHWAY, PID_CXCR4_PATHWAY, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_RECEPTOR_INTERNALIZATION, AFFAR_YY1_TARGETS_UP, GOBP_SENSORY_PERCEPTION, GOMF_G_PROTEIN_COUPLED_RECEPTOR_BINDING, GOCC_NEURON_PROJECTION, GOMF_SIGNALING_RECEPTOR_BINDING, GOBP_IMPORT_INTO_CELL, CTAWWWATA_RSRFC4_Q2, GOBP_ENDOCYTOSIS

GO Biological Process (4): G protein-coupled receptor internalization (GO:0002031), signal transduction (GO:0007165), visual perception (GO:0007601), endocytosis (GO:0006897)

GO Molecular Function (4): G protein-coupled receptor binding (GO:0001664), opsin binding (GO:0002046), phosphoprotein binding (GO:0051219), protein binding (GO:0005515)

GO Cellular Component (5): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), cytoplasm (GO:0005737), synapse (GO:0045202), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
desensitization of G protein-coupled receptor signaling pathway	1
receptor internalization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception of light stimulus	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
signaling receptor binding	1
binding	1
photoreceptor cell cilium	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1232 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARR3	RHO	P08100	987
ARR3	OPN1SW	P03999	893
ARR3	GRK2	P25098	836
ARR3	MAP3K5	Q99683	788
ARR3	RBP3	P10745	769
ARR3	PPP1R9B	Q96SB3	753
ARR3	RCVRN	P35243	751
ARR3	ADRB2	P07550	737
ARR3	NR2E3	Q9Y5X4	729
ARR3	PDE6H	Q13956	702
ARR3	CRX	O43186	693
ARR3	LHCGR	P22888	693
ARR3	GNAT2	P19087	690
ARR3	APEH	P13798	684
ARR3	PDE6C	P51160	680

IntAct

27 interactions, top by confidence:

A	B	Type	Score
ZNF496	ARR3	psi-mi:“MI:0915”(physical association)	0.770
ARR3	ZNF496	psi-mi:“MI:0915”(physical association)	0.770
ARR3	PLK4	psi-mi:“MI:0915”(physical association)	0.560
ARR3	ZBTB43	psi-mi:“MI:0915”(physical association)	0.560
PLK4	ARR3	psi-mi:“MI:0915”(physical association)	0.560
ZBTB43	ARR3	psi-mi:“MI:0915”(physical association)	0.560
ARR3	GNMT	psi-mi:“MI:0915”(physical association)	0.550
ARR3	DVL2	psi-mi:“MI:0915”(physical association)	0.550
ARR3	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
ARRB1		psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
ARRB2	AHCYL1	psi-mi:“MI:0914”(association)	0.350
ARRB1	ARR3	psi-mi:“MI:0915”(physical association)	0.000
ARR3	CAPNS1	psi-mi:“MI:0915”(physical association)	0.000
ARR3	RNASE6	psi-mi:“MI:0915”(physical association)	0.000
ARR3	RCOR2	psi-mi:“MI:0915”(physical association)	0.000
ARR3	MAP2K7	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): PLK4 (Two-hybrid), ZBTB43 (Two-hybrid), ZNF496 (Two-hybrid), GNMT (Two-hybrid), DVL2 (Two-hybrid), ZNF496 (Two-hybrid), ZNF496 (Affinity Capture-Western), ARR3 (Two-hybrid), ARR3 (Affinity Capture-MS), ARR3 (Affinity Capture-MS), CAPNS1 (Two-hybrid), RNASE6 (Two-hybrid), ZNF496 (Two-hybrid), MARCH8 (Two-hybrid), RHO (Reconstituted Complex)

ESM2 similar proteins: A7YW45, O14744, P08168, P10523, P15372, P15887, P19107, P19108, P20443, P25455, P32122, P36575, P51432, P51477, P51478, P51479, P51481, P51482, P51483, P51484, P51485, P51486, P51487, P52566, P55274, P79260, Q0VCA2, Q1JQD4, Q28281, Q498D9, Q4R4K0, Q4R5M3, Q5DRQ4, Q5FWL4, Q5R5L7, Q5R698, Q61599, Q66KM2, Q6NUA1, Q6TXF1

Diamond homologs: P08168, P10523, P15372, P15887, P17870, P19107, P19108, P20443, P29066, P29067, P32120, P32121, P32122, P36575, P36576, P49407, P51466, P51467, P51468, P51477, P51478, P51479, P51481, P51482, P51483, P51484, P51485, P51486, P51487, P55274, P79260, Q28281, Q4R562, Q5DRQ4, Q5RCR4, Q7YS78, Q8BWG8, Q91YI4, Q95223, Q9EQP6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

135 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	50
Likely benign	14
Benign	4

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1697230	NM_004312.3(ARR3):c.214C>T (p.Arg72Ter)	Pathogenic
3234786	NM_004312.3(ARR3):c.193G>T (p.Glu65Ter)	Pathogenic
4071984	NM_004312.3(ARR3):c.905+2del	Pathogenic
4730264	NM_004312.3(ARR3):c.1A>G (p.Met1Val)	Pathogenic
478824	NM_004312.3(ARR3):c.893C>A (p.Ala298Asp)	Pathogenic
478825	NM_004312.3(ARR3):c.298C>T (p.Arg100Ter)	Pathogenic
478826	NM_004312.3(ARR3):c.239T>C (p.Leu80Pro)	Pathogenic
4839366	NM_004312.3(ARR3):c.824del (p.Leu275fs)	Pathogenic
154440	GRCh38/hg38 Xq13.1(chrX:69839596-70301821)x1	Likely pathogenic
3032603	NM_004312.3(ARR3):c.330C>A (p.Tyr110Ter)	Likely pathogenic
3345498	NM_004312.3(ARR3):c.917del (p.Gly306fs)	Likely pathogenic

SpliceAI

2051 predictions. Top by Δscore:

Variant	Effect	Δscore
X:70269394:G:GG	donor_gain	1.0000
X:70269908:G:GG	donor_gain	1.0000
X:70270143:GT:G	donor_gain	1.0000
X:70276080:A:AG	acceptor_gain	1.0000
X:70276081:G:GG	acceptor_gain	1.0000
X:70276081:GT:G	acceptor_gain	1.0000
X:70276249:C:G	donor_gain	1.0000
X:70276428:CCTAG:C	acceptor_loss	1.0000
X:70276429:CTAG:C	acceptor_loss	1.0000
X:70276430:TA:T	acceptor_loss	1.0000
X:70276431:A:AG	acceptor_gain	1.0000
X:70276431:AGAT:A	acceptor_gain	1.0000
X:70276432:G:GG	acceptor_gain	1.0000
X:70276432:GATG:G	acceptor_gain	1.0000
X:70276489:A:T	donor_gain	1.0000
X:70276667:A:AG	acceptor_gain	1.0000
X:70276668:G:GA	acceptor_gain	1.0000
X:70276668:GCCCT:G	acceptor_gain	1.0000
X:70276734:G:GT	donor_gain	1.0000
X:70276734:GAG:G	donor_gain	1.0000
X:70277527:G:T	donor_gain	1.0000
X:70277711:TTTA:T	acceptor_loss	1.0000
X:70277712:TTAGG:T	acceptor_loss	1.0000
X:70277714:A:AG	acceptor_gain	1.0000
X:70277715:G:A	acceptor_loss	1.0000
X:70277715:G:GG	acceptor_gain	1.0000
X:70277798:CAGG:C	donor_loss	1.0000
X:70277799:AGGT:A	donor_loss	1.0000
X:70277801:G:GG	donor_gain	1.0000
X:70277801:GTGA:G	donor_loss	1.0000

AlphaMissense

2520 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:70276105:T:C	F57L	0.989
X:70276107:T:A	F57L	0.989
X:70276107:T:G	F57L	0.989
X:70278066:T:A	V232D	0.989
X:70278634:A:C	S300R	0.989
X:70278636:C:A	S300R	0.989
X:70278636:C:G	S300R	0.989
X:70277417:G:C	R166P	0.988
X:70277744:T:A	V213D	0.988
X:70277750:T:A	V215D	0.987
X:70276696:A:C	S145R	0.986
X:70276698:T:A	S145R	0.986
X:70276698:T:G	S145R	0.986
X:70269870:T:C	F23L	0.985
X:70269872:C:A	F23L	0.985
X:70269872:C:G	F23L	0.985
X:70280241:T:G	Y318D	0.984
X:70277421:A:C	K167N	0.982
X:70277421:A:T	K167N	0.982
X:70280248:T:A	V320D	0.982
X:70280254:T:A	V322D	0.982
X:70276684:T:C	F141L	0.981
X:70276686:T:A	F141L	0.981
X:70276686:T:G	F141L	0.981
X:70277763:C:A	N219K	0.978
X:70277763:C:G	N219K	0.978
X:70276270:T:C	F112L	0.977
X:70276271:T:C	F112S	0.977
X:70276272:T:A	F112L	0.977
X:70276272:T:G	F112L	0.977

dbSNP variants (sampled 300 via entrez): RS1000410161 (X:70282104 C>T), RS1001150730 (X:70267503 C>T), RS1001267125 (X:70281398 G>A), RS1001517007 (X:70274492 C>A,T), RS1002046217 (X:70277208 G>A), RS1002929731 (X:70277699 C>G,T), RS1004057356 (X:70271484 T>C), RS1004121536 (X:70281292 T>C), RS1004917907 (X:70274118 T>C), RS1004950083 (X:70271993 C>T), RS1005280829 (X:70268868 C>T), RS1005731780 (X:70268117 C>T), RS1007006655 (X:70266655 G>A), RS1007039822 (X:70266877 C>G), RS1007611638 (X:70276970 G>A)

Disease associations

OMIM: gene MIM:301770 | disease phenotypes: MIM:301010

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia 26, X-linked, female-limited	Strong	X-linked

Mondo (1): myopia 26, X-linked, female-limited (MONDO:0049221)

Orphanet (1): Microphthalmia-anophthalmia-coloboma (Orphanet:98555)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0001417	X-linked inheritance
HP:0011003	High myopia

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	2
triphenyl phosphate	affects expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Silicon Dioxide	increases expression	1
Paclitaxel	decreases response to substance	1
Cadmium Chloride	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.