RS1

Summary

RS1 (retinoschisin 1, HGNC:10457) is a protein-coding gene on chromosome Xp22.13, encoding Retinoschisin (O15537). Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision.

Source: NCBI Gene 6247 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked retinoschisis (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 190 total — 57 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 22
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000330

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10457
Approved symbol	RS1
Name	retinoschisin 1
Location	Xp22.13
Locus type	gene with protein product
Status	Approved
Aliases	XLRS1
Ensembl gene	ENSG00000102104
Ensembl biotype	protein_coding
OMIM	300839
Entrez	6247

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000379984, ENST00000476595

RefSeq mRNA: 1 — MANE Select: NM_000330 NM_000330

CCDS: CCDS14187

Canonical transcript exons

ENST00000379984 — 6 exons

Exon	Start	End
ENSE00000666224	18656653	18656758
ENSE00001346220	18657640	18657665
ENSE00001346228	18672017	18672108
ENSE00001483277	18639688	18642156
ENSE00003659988	18647191	18647332
ENSE00003683885	18644430	18644625

Expression profiles

Bgee: expression breadth broad, 34 present calls, max score 85.06.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1127 / max 91.5243, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198591	0.1127	6

Top tissues by expression

274 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	85.06	gold quality
oocyte	CL:0000023	77.26	silver quality
secondary oocyte	CL:0000655	73.19	silver quality
upper lobe of left lung	UBERON:0008952	65.38	gold quality
upper lobe of lung	UBERON:0008948	65.14	gold quality
tendon of biceps brachii	UBERON:0008188	62.26	gold quality
endometrium epithelium	UBERON:0004811	61.80	gold quality
lower lobe of lung	UBERON:0008949	61.08	gold quality
buccal mucosa cell	CL:0002336	60.09	gold quality
right lung	UBERON:0002167	59.19	gold quality
lung	UBERON:0002048	57.82	gold quality
decidua	UBERON:0002450	56.55	gold quality
prefrontal cortex	UBERON:0000451	55.21	gold quality
gingival epithelium	UBERON:0001949	55.17	gold quality
pigmented layer of retina	UBERON:0001782	54.11	gold quality
endothelial cell	CL:0000115	53.84	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
quadriceps femoris	UBERON:0001377	51.38	gold quality
vastus lateralis	UBERON:0001379	51.04	gold quality
gingiva	UBERON:0001828	50.79	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
myocardium	UBERON:0002349	49.80	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cerebellar vermis	UBERON:0004720	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
oviduct epithelium	UBERON:0004804	49.08	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	21.20
E-ANND-3	no	3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting RS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-7157-5P	99.66	69.33	1829

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Novel and known missense mutations of XLRS1 gene in the diagnosis retinoschisis. (PMID:12055472)
• Two novel point mutations of the XLRS1 gene in two Japanese patients with X-linked juvenile retinoschisis. One novel splice donor site mutation (IVS2 + 1g to a) and one missense mutation of exon 6 (Ala211Thr) were found. (PMID:12383832)
• Basis of RS1 is intracellular retention of mutant proteins, which may explain why disease severity is not mutation-specific. (PMID:12417531)
• Electroretinographic findings in three family members with X-linked juvenile retinoschisis associated with a novel Pro192Thr missense mutation of the XLRS1 gene. (PMID:12457918)
• X-linked retinoschisis is caused by defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin (PMID:12746437)
• analysis of folding of mutant RS1 protein (PMID:12782284)
• Each family had a different mutation, Trp96stop, 522+1g–>a, and Lys167Asn in the XLRS1 gene. (PMID:12920343)
• four base pair deletion (375- 378 del AGAT) in exon 5 of the XLRS1 gene was found in all affected males. (PMID:12967815)
• Molecular testing revealed a novel 473-bp deletion including exon 4 in the XLRS1 gene in both siblings. This resulted in a frameshift mutation and a premature termination at codon 78. (PMID:14986011)
• One patient with more severe clinical presentation had a RS1 exon 1 deletion and a P193S mutation was found in the other patient with mild macular involvement (PMID:15281981)
• In three patients, we identified three different missense mutations (p.S73P, p.Y89C, p.R209C) in the functionally important discoidin domain of the RS1 gene. (PMID:15531314)
• assembly of RS1 into a disulfide-linked homo-octamer appears to be critical for its function as a retinal cell adhesion protein (PMID:15644328)
• A novel Leu103Phe mutation is an additional missense mutation which is responsible for the pathogenesis of X-linked retinoschisis. (PMID:16768192)
• We identified a novel point mutation (1A>T transversion) in the initiation codon of the XLRS1 gene in affected males (PMID:17031297)
• Retinoschisin protein(RS) is expressed in the pinealocytes but not in interstitial glial cells. The lack of structural abnormalities in the RS1(-/Y) mice suggests that RS serves a different function in the pineal gland than in the retina. (PMID:17093404)
• Review. Many mutations have been found in RS1, which encodes a 224-AA secreting retinal protein, retinoschisin. Retinoschisin octamerisation is implicated in cell-cell interactions & cell adhesion perhaps by interacting with beta2 laminin. (PMID:17172462)
• We describe a novel nonsense mutation in the conserved region of Rs1 in a Japanese XLRS family. (PMID:17295148)
• Multiple fine white dots at the macula may be the initial fundus feature in RS1 mutation. (PMID:17296904)
• Mutations in RS1 to be associated with XLRS in the Indian population. (PMID:17515881)
• Severe X linked juvenile retinoschisis phenotypes are associated with the frameshift mutation 26 del T, splice donor site mutation (IVS1+2T to C), and Arg102Gln, Asp145His, Arg209His, and Arg213Gln mutations. (PMID:17615541)
• We identified unusual presentations of X-linked retinoschisis with the help of electroretinography, optical coherence tomography, family screening, and genetic analysis (PMID:17631851)
• confirmed the co-localization of retinoschisin with Na/K ATPase and SARM1 in photoreceptors and bipolar cells of retina tissue (PMID:17804407)
• We found there are five different mutations with four containing missense point mutations and one having a frame-shift deletion (PMID:17852193)
• In clinically suspected X-linked congenital retinoschisis (RS), a combination of ERG, FAF, OCT, and molecular-genetic testing is advised to verify the diagnosis. (PMID:17987333)
• RS1 gene mutations caused X-linked juvenile retinoschisis in these Chinese families. (PMID:18369700)
• The ocular findings of a Hungarian family with X-linked juvenile retinoschisis (XLRS) reveals a novel putative splice mutation leading to serious truncation of retinoschisin (RS1) protein. (PMID:18728755)
• This study showed that the response of macular cysts to dorzolamide in patients with XLRS may be observed independent of the mechanism responsible for retinoschisin protein dysfunction. (PMID:18834580)
• This report describes a novel mutation in a family in which consanguinity has led to XLRS in 4 females. (PMID:18982040)
• The prevalent p.Gln154Arg mutation is first reported in this work and presents a common origin in Spanish patients with X-linked juvenile retinoschisis. (PMID:19324861)
• characterization of the mutational spectrum of the RS1 gene in Korean patients with X-linked retinoschisis (XLRS); a missense mutation was the predominant type & common or founder mutations were not observed in the Korean patients in this study with XLRS (PMID:19390641)
• hemizygous 371 A/G missense mutation and hemizygous 214 G/A missense mutation in exon 5 in juvenile retinoschisis (PMID:19393523)
• The c354del1-ins18 mutation caused an RS1-null biochemical phenotype and a progressive clinical phenotype in a 5-year-old boy, whereas the older XLRS relatives had macular atrophy. (PMID:19474399)
• Results show that missense mutations of retinoschisin which cause intracellular retention also lead to an unfolded protein response. (PMID:19849666)
• A novel p.D126G mutation appeared to be associated with a severe phenotype with vitreous hemorrhage developing in infancy. (PMID:20151283)
• Clinical follow-up of ten young XLRS (X-linked retinoschisis) patients with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. (PMID:20569020)
• The R213W mutation in RS1 causes various severities of retinoschisis in a large Chinese family. (PMID:20806044)
• analyzed the biochemical consequences of several RS1 signal-sequence mutants (c.1A>T, c.35T>A, c.38T>C, and c.52G>A) in X-linked retinoschisis disease (PMID:20809529)
• Retinoschisin, the protein involved in the pathogenesis of X-linked juvenile retinoschisis, membrane association is severely impaired in the absence of ATP1A3 and ATP1B2. (PMID:21196491)
• Two novel mutations (W112X and S134P) and three previously identified missense mutations (R102Q, R200H, and R213W) were found. (PMID:21701876)
• Data suggest that retinoschisin secretion is regulated by the F-actin cytoskeleton, that cGMP or inhibition of ROCK alters F-actin structure enhancing the secretion, and that the microtubule cytoskeleton is also involved in this process. (PMID:21738583)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rs1	ENSMUSG00000031293
rattus_norvegicus	Rs1	ENSRNOG00000030434

Paralogs (1): DCBLD1 (ENSG00000164465)

Protein

Protein identifiers

Retinoschisin — O15537 (reviewed: O15537)

Alternative names: X-linked juvenile retinoschisis protein

All UniProt accessions (1): O15537

UniProt curated annotations — full annotation on UniProt →

Function. Binds negatively charged membrane lipids, such as phosphatidylserine and phosphoinositides. May play a role in cell-cell adhesion processes in the retina, via homomeric interaction between octamers present on the surface of two neighboring cells. Required for normal structure and function of the retina.

Subunit / interactions. Homooctamer of 4 homodimers; disulfide-linked. The homooctamer has a flat, cogwheel structure with a diameter of about 14 nm. Two stacked octamers can assemble to form a hexadecamer.

Subcellular location. Secreted. Cell membrane.

Tissue specificity. Restricted to the retina (at protein level). Detected in the inner segment of the photoreceptors, the inner nuclear layer, the inner plexiform layer and the ganglion cell layer (at protein level). At the macula, expressed in both the outer and inner nuclear layers and in the inner plexiform layer (at protein level). Detected in retina. Detected only within the photoreceptor cell layer, most prominently within the inner segments of the photoreceptors. Undetectable in the inner plexiform layers and the inner nuclear layer.

Disease relevance. Retinoschisis juvenile X-linked 1 (XLRS1) [MIM:312700] A vitreo-retinal dystrophy characterized by macular pathology and by splitting of the superficial layer of the retina. Macular changes are present in almost all cases. In the fundi, radially oriented intraretinal foveomacular cysts are seen in a spoke-wheel configuration, with the absence of foveal reflex in most cases. In addition, approximately half of cases have bilateral peripheral retinoschisis in the inferotemporal part of the retina. Aside from the typical fundus appearance, strabismus, nystagmus, axial hyperopia, defective color vision and foveal ectopy can be present. The most important complications are vitreous hemorrhage, retinal detachment, and neovascular glaucoma. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_000321* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000421	FA58C	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR050633	Neuropilin_MCO_CoagFactor	Family

Pfam: PF00754

UniProt features (77 total): sequence variant 69, disulfide bond 5, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3JD6	ELECTRON MICROSCOPY	4.1
5N6W	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15537-F1	73.69	0.30

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (5): 40, 59, 63–219, 110–142, 223

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 137 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, GOCC_CELL_SURFACE, TGACCTY_ERR1_Q2, GOBP_NEURAL_RETINA_DEVELOPMENT, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_RETINA_LAYER_FORMATION, GOBP_SENSORY_PERCEPTION, GOBP_PROTEIN_HOMOOLIGOMERIZATION, GOBP_SENSORY_ORGAN_DEVELOPMENT, MODULE_287, GOBP_SENSORY_ORGAN_MORPHOGENESIS, GOBP_RETINA_DEVELOPMENT_IN_CAMERA_TYPE_EYE, GOBP_CAMERA_TYPE_EYE_MORPHOGENESIS

GO Biological Process (5): eye development (GO:0001654), cell adhesion (GO:0007155), visual perception (GO:0007601), retina layer formation (GO:0010842), protein homooligomerization (GO:0051260)

GO Molecular Function (4): phosphatidylserine binding (GO:0001786), phosphatidylinositol-3,4-bisphosphate binding (GO:0043325), protein-containing complex binding (GO:0044877), lipid binding (GO:0008289)

GO Cellular Component (9): photoreceptor inner segment (GO:0001917), obsolete extracellular space (GO:0005615), external side of plasma membrane (GO:0009897), protein-containing complex (GO:0032991), neuron to neuron synapse (GO:0098984), extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
binding	2
sensory organ development	1
visual system development	1
cellular process	1
sensory perception of light stimulus	1
neural retina development	1
anatomical structure formation involved in morphogenesis	1
retina morphogenesis in camera-type eye	1
protein complex oligomerization	1
phospholipid binding	1
anion binding	1
modified amino acid binding	1
phosphatidylinositol bisphosphate binding	1
plasma membrane	1
cell surface	1
side of membrane	1
cellular_component	1
synapse	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1312 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RS1	ABCA4	P78363	754
RS1	SARM1	Q6SZW1	691
RS1	NR2E3	Q9Y5X4	656
RS1	CDKL5	O76039	647
RS1	PRPH2	P23942	636
RS1	RPE65	Q16518	523
RS1	TIMP3	P35625	518
RS1	CACNA1F	O60840	507
RS1	BBS4	Q96RK4	505
RS1	NR2E1	Q9Y466	495
RS1	LACTBL1	A8MY62	472
RS1	PRDX6	P30041	468
RS1	GNAT2	P19087	460
RS1	CNGB3	Q9NQW8	448
RS1	RHO	P08100	445

IntAct

3 interactions, top by confidence:

A	B	Type	Score
RS1	ATP1A3	psi-mi:“MI:0914”(association)	0.350
RS1	SARM1	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): CASP4 (Affinity Capture-Western), RS1 (Reconstituted Complex)

ESM2 similar proteins: O15537, O35276, O35375, O35474, O42163, O42596, O43405, O43854, O60242, O60462, O75077, O75882, O95970, P15209, P21956, P24786, P26012, P51641, P70490, P79385, P84552, Q03351, Q16288, Q16620, Q1EGL2, Q5EA64, Q5IS37, Q5IS82, Q5R7K9, Q5R945, Q5VV63, Q62507, Q63604, Q63769, Q6A051, Q6IS24, Q7TT15, Q80ZF8, Q91044, Q91987

Diamond homologs: A0A182C2Z2, A2RUV9, B3EWZ5, B3EWZ6, B8V7S0, B8VIV4, F1RWC3, O08628, O08859, O14786, O15537, O18806, O35276, O35375, O35474, O43854, O43897, O57382, O57460, O60462, O60494, O70244, O88783, P00451, P12259, P12263, P13497, P21956, P25723, P28824, P48740, P60755, P60756, P60882, P70490, P79385, P79795, P85171, P97333, P98063

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CRX	“up-regulates quantity by expression”	RS1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	57
Likely pathogenic	16
Uncertain significance	54
Likely benign	41
Benign	5

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068998	NC_000023.10:g.(?18674761)(18675795_?)del	Pathogenic
1073512	NM_000330.4(RS1):c.26dup (p.Leu9fs)	Pathogenic
1076978	NC_000023.10:g.(?18690137)(18690188_?)del	Pathogenic
1076979	NC_000023.10:g.(?18675740)(18675805_?)del	Pathogenic
1380589	NM_000330.4(RS1):c.98G>A (p.Trp33Ter)	Pathogenic
1419115	NM_000330.4(RS1):c.149G>A (p.Trp50Ter)	Pathogenic
1433834	NM_000330.4(RS1):c.178_181del (p.Ile60fs)	Pathogenic
1456120	NM_000330.4(RS1):c.179_180del (p.Ile60fs)	Pathogenic
1723073	NM_000330.4(RS1):c.78+2T>C	Pathogenic
1805017	NM_000330.4(RS1):c.103C>T (p.Gln35Ter)	Pathogenic
1997459	NM_000330.4(RS1):c.53-1G>C	Pathogenic
2095068	NM_000330.4(RS1):c.79-1G>A	Pathogenic
2112217	NM_000330.4(RS1):c.69_72del (p.Ser24fs)	Pathogenic
2138482	NM_000330.4(RS1):c.97del (p.Trp33fs)	Pathogenic
2159556	NM_000330.4(RS1):c.175T>G (p.Cys59Gly)	Pathogenic
2422903	NC_000023.10:g.(?18690117)(18690188_?)del	Pathogenic
2422905	NC_000023.10:g.(?18674753)(18675805_?)del	Pathogenic
2422907	NC_000023.10:g.(?18674753)(18674898_?)del	Pathogenic
2709070	NM_000330.4(RS1):c.65T>G (p.Leu22Ter)	Pathogenic
3244282	NC_000023.10:g.(?18525053)(18662765_?)del	Pathogenic
3244304	NC_000023.10:g.(?18593454)(18690188_?)del	Pathogenic
3249711	NC_000023.11:g.(18656759_18657639)(18672069?)del	Pathogenic
3249747	NM_000330.4:c.(52+1_53-1)_(184+1_185-1)del	Pathogenic
3249784	NM_000330.4(RS1):c.124del (p.Cys42fs)	Pathogenic
3249812	NM_000330.4(RS1):c.183_184+12del	Pathogenic
3249914	NC_000023.11:g.(18657666_18672016)(18672069?)del	Pathogenic
3249949	NM_000330.4:c.(184+1_185-1)_(522+1_523-1)del	Pathogenic
3250194	NM_000330.4:c.(78+1_79-1)_(184+1_185-1)del	Pathogenic
3250229	NC_000023.11:g.(?18641623)(18641623_18644.669)del	Pathogenic
3250265	NC_000023.11:g.(18657652_18672110)(18672110?)del	Pathogenic

SpliceAI

875 predictions. Top by Δscore:

Variant	Effect	Δscore
X:18642152:AAGAC:A	acceptor_gain	1.0000
X:18642153:AGAC:A	acceptor_gain	1.0000
X:18642154:GAC:G	acceptor_gain	1.0000
X:18642155:AC:A	acceptor_gain	1.0000
X:18642155:ACC:A	acceptor_loss	1.0000
X:18642156:CC:C	acceptor_gain	1.0000
X:18642157:C:CC	acceptor_gain	1.0000
X:18644425:CTTA:C	donor_loss	1.0000
X:18644426:TTACC:T	donor_loss	1.0000
X:18644427:TACCC:T	donor_loss	1.0000
X:18644428:A:AC	donor_gain	1.0000
X:18644428:A:C	donor_loss	1.0000
X:18644428:AC:A	donor_gain	1.0000
X:18644428:ACC:A	donor_gain	1.0000
X:18644429:C:A	donor_loss	1.0000
X:18644429:C:CA	donor_gain	1.0000
X:18644429:CC:C	donor_gain	1.0000
X:18644429:CCC:C	donor_gain	1.0000
X:18644429:CCCG:C	donor_gain	1.0000
X:18644429:CCCGG:C	donor_gain	1.0000
X:18647185:GCTTA:G	donor_loss	1.0000
X:18647186:CTTAC:C	donor_loss	1.0000
X:18647187:TTA:T	donor_loss	1.0000
X:18647188:TAC:T	donor_loss	1.0000
X:18647189:A:AC	donor_gain	1.0000
X:18647189:AC:A	donor_gain	1.0000
X:18647190:C:CC	donor_gain	1.0000
X:18647190:CC:C	donor_gain	1.0000
X:18647193:AAAG:A	donor_gain	1.0000
X:18647328:GCATT:G	acceptor_gain	1.0000

AlphaMissense

1456 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:18642041:C:G	R213P	1.000
X:18642080:C:G	R200P	1.000
X:18644536:T:G	Q139P	1.000
X:18642142:G:C	N179K	0.999
X:18642142:G:T	N179K	0.999
X:18642146:C:T	G178D	0.999
X:18644463:C:A	W163C	0.999
X:18644463:C:G	W163C	0.999
X:18644501:A:C	Y151D	0.999
X:18644511:C:A	W147C	0.999
X:18644511:C:G	W147C	0.999
X:18644530:C:G	R141P	0.999
X:18644534:C:A	G140W	0.999
X:18644534:C:G	G140R	0.999
X:18644534:C:T	G140R	0.999
X:18644581:T:G	Q124P	0.999
X:18644618:A:G	W112R	0.999
X:18644618:A:T	W112R	0.999
X:18642022:G:C	C219W	0.998
X:18642023:C:G	C219S	0.998
X:18642024:A:G	C219R	0.998
X:18642024:A:T	C219S	0.998
X:18642147:C:G	G178R	0.998
X:18642152:A:G	F176S	0.998
X:18644431:C:G	R174P	0.998
X:18644465:A:G	W163R	0.998
X:18644465:A:T	W163R	0.998
X:18644533:C:A	G140V	0.998
X:18644533:C:T	G140E	0.998
X:18644549:C:A	G135W	0.998

dbSNP variants (sampled 300 via entrez): RS1000041857 (X:18652644 G>A), RS1000072804 (X:18653211 T>C), RS1000310021 (X:18669499 A>G), RS1000365152 (X:18660938 A>C), RS1000406833 (X:18652050 G>A), RS1000418894 (X:18661263 C>T), RS1000507732 (X:18645229 T>C), RS1000564916 (X:18645633 C>T), RS1000660523 (X:18669281 G>A), RS1001030019 (X:18652388 G>T), RS1001274458 (X:18664686 T>A), RS1001510205 (X:18659364 C>T), RS1001788878 (X:18640972 G>A,C), RS1001930204 (X:18671284 G>A), RS1002035500 (X:18663490 C>T)

Disease associations

OMIM: gene MIM:300839 | disease phenotypes: MIM:300672, MIM:312700

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked retinoschisis	Definitive	X-linked
retinoschisis	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked retinoschisis	Definitive	XL

Mondo (4): developmental and epileptic encephalopathy, 2 (MONDO:0010396), X-linked retinoschisis (MONDO:0010725), inherited retinal dystrophy (MONDO:0019118), retinoschisis (MONDO:0004579)

Orphanet (5): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), West syndrome (Orphanet:3451), CDKL5-deficiency disorder (Orphanet:505652), X-linked retinoschisis (Orphanet:792), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

22 total (23 of 22 shown, HPO-id order):

HPO	Term
HP:0000486	Strabismus
HP:0000493	Abnormal foveal morphology
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000504	Abnormality of vision
HP:0000512	Abnormal electroretinogram
HP:0000529	Progressive visual loss
HP:0000540	Hypermetropia
HP:0000541	Retinal detachment
HP:0000546	Retinal degeneration
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001419	X-linked recessive inheritance
HP:0007401	Macular atrophy
HP:0007667	Peripheral cystoid retinal degeneration
HP:0007722	Retinal pigment epithelial atrophy
HP:0007902	Vitreous hemorrhage
HP:0007984	ERG: Reduced dark-adapted b-wave amplitude
HP:0025158	Hyperautofluorescent retinal lesion
HP:0030502	Retinoschisis
HP:0030824	Mizuo phenomenon
HP:0030825	Absent foveal reflex
HP:0000556	Retinal dystrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D041441	Retinoschisis	C11.768.585.865
C564064	CDKL5 deficiency disorder (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
jasplakinolide	decreases secretion	1
CGP 52608	affects binding, increases reaction	1
Y 27632	increases secretion	1
Benzo(a)pyrene	affects methylation	1
Dibutyryl Cyclic GMP	increases secretion	1
Malathion	increases expression	1
Cytochalasin D	decreases secretion	1
Paclitaxel	decreases secretion	1

Cellosaurus cell lines

10 cell lines: 10 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B5GM	ZOCi002-A	Induced pluripotent stem cell	Male
CVCL_B5GN	ZOCi004-A	Induced pluripotent stem cell	Male
CVCL_D6KP	CSUASOi001-A-1	Induced pluripotent stem cell	Male
CVCL_E3CK	CSUi007-A	Induced pluripotent stem cell	Male
CVCL_E5KY	KRIBBi010-A	Induced pluripotent stem cell	Male
CVCL_E5KZ	KRIBBi011-A	Induced pluripotent stem cell	Male
CVCL_E5L0	KRIBBi012-A	Induced pluripotent stem cell	Male
CVCL_QY15	TVGH-iPSC-013-05	Induced pluripotent stem cell	Male
CVCL_WU16	CSUASOi001-A	Induced pluripotent stem cell	Male
CVCL_YU19	CSUASOi005-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01995045	PHASE4	COMPLETED	Postoperative Pain Control Following Vitreoretinal Surgery
NCT05878860	PHASE3	RECRUITING	ATSN-201 Gene Therapy in RS1-Associated X-linked Retinoschisis
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT06114537	PHASE2	COMPLETED	The AXIS Study: the Efficacy of Acetazolamide for the Treatment of Cystoid Fluid Collections in Retinoschisis
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT02416622	PHASE1/PHASE2	COMPLETED	Safety and Efficacy of rAAV-hRS1 in Patients With X-linked Retinoschisis (XLRS)
NCT06066008	EARLY_PHASE1	COMPLETED	Safety and Efficacy Study of Novel Gene Therapy ZM-01 for X-linked Retinoschisis Patients
NCT06345898	EARLY_PHASE1	RECRUITING	Safety and Efficacy of a Single Subretinal Injection of JWK002 Gene Therapy in Subjects With X-linked Retinoschisis(XLRS)
NCT02331173	Not specified	COMPLETED	Clinical Evaluation of Patients With X-linked Retinoschisis
NCT05814952	Not specified	RECRUITING	Safety and Efficacy Study of LX103 Treatment of X-Linked Retinoschisis (XLRS)
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)
NCT02317887	PHASE1/PHASE2	COMPLETED	Study of RS1 Ocular Gene Transfer for X-linked Retinoschisis
NCT06289452	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Safety and Efficacy Study of IVB102 Injection in Subjects With X-linked Retinoschisis
NCT00055029	Not specified	ACTIVE_NOT_RECRUITING	Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis
NCT02317354	Not specified	COMPLETED	People s Expectations When Enrolling in a Phase I/II RS1 Ocular Gene Transfer Clinical Trial
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02682797	Not specified	COMPLETED	Optical Coherence Tomography Evaluation of Retinoschisis and Retinal Detachment
NCT03023800	Not specified	COMPLETED	Effects of Macular Buckle Versus Vitrectomy on Macular Schisis and Macular Detachment in Highly Myopic Eyes
NCT03354403	Not specified	COMPLETED	Mothers Experiences With X-linked Retinoschisis Compared to Fathers Experiences
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD