RSPO1

Summary

RSPO1 (R-spondin 1, HGNC:21679) is a protein-coding gene on chromosome 1p34.3, encoding R-spondin-1 (Q2MKA7). Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors.

This gene encodes a secreted activator protein with two cysteine-rich, furin-like domains and one thrombospondin type 1 domain. The encoded protein is a ligand for leucine-rich repeat-containing G-protein coupled receptors (LGR proteins) and positively regulates the Wnt signaling pathway. In mice, the protein induces the rapid onset of crypt cell proliferation and increases intestinal epithelial healing, providing a protective effect against chemotherapy-induced adverse effects. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 284654 — RefSeq curated summary.

At a glance

• Gene–disease (curated): palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 93 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 21
• MANE Select transcript: NM_001242908

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21679
Approved symbol	RSPO1
Name	R-spondin 1
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ40906, RSPONDIN
Ensembl gene	ENSG00000169218
Ensembl biotype	protein_coding
OMIM	609595
Entrez	284654

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000356545, ENST00000401068, ENST00000612451, ENST00000615459, ENST00000866279, ENST00000866280, ENST00000866281, ENST00000866282, ENST00000866283, ENST00000866284, ENST00000967724

RefSeq mRNA: 4 — MANE Select: NM_001242908 NM_001038633, NM_001242908, NM_001242909, NM_001242910

CCDS: CCDS41304, CCDS55590, CCDS55591

Canonical transcript exons

ENST00000356545 — 7 exons

Exon	Start	End
ENSE00001156091	37613704	37613892
ENSE00001156098	37614184	37614333
ENSE00001200038	37616484	37616675
ENSE00001401861	37611350	37612921
ENSE00001414687	37632287	37632353
ENSE00001459433	37629568	37629949
ENSE00001546214	37634566	37634892

Expression profiles

Bgee: expression breadth ubiquitous, 129 present calls, max score 89.10.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8870 / max 85.4535, expressed in 155 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11790	0.7469	142
11788	0.0781	38
11789	0.0619	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endocervix	UBERON:0000458	89.10	gold quality
body of uterus	UBERON:0009853	88.97	gold quality
germinal epithelium of ovary	UBERON:0001304	88.85	gold quality
ectocervix	UBERON:0012249	86.57	gold quality
right uterine tube	UBERON:0001302	85.97	gold quality
left uterine tube	UBERON:0001303	84.88	gold quality
uterine cervix	UBERON:0000002	83.44	gold quality
myometrium	UBERON:0001296	83.20	gold quality
smooth muscle tissue	UBERON:0001135	79.97	gold quality
fallopian tube	UBERON:0003889	79.64	gold quality
vagina	UBERON:0000996	77.95	gold quality
mucosa of stomach	UBERON:0001199	77.63	gold quality
parietal pleura	UBERON:0002400	77.11	gold quality
buccal mucosa cell	CL:0002336	75.32	gold quality
tibial artery	UBERON:0007610	75.27	gold quality
popliteal artery	UBERON:0002250	75.25	gold quality
skin of leg	UBERON:0001511	74.88	gold quality
peritoneum	UBERON:0002358	74.62	gold quality
omental fat pad	UBERON:0010414	74.60	gold quality
skin of abdomen	UBERON:0001416	73.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	73.49	gold quality
zone of skin	UBERON:0000014	73.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	73.25	gold quality
uterus	UBERON:0000995	70.08	gold quality
upper lobe of left lung	UBERON:0008952	69.97	gold quality
gall bladder	UBERON:0002110	69.47	gold quality
female reproductive system	UBERON:0000474	68.50	gold quality
oviduct epithelium	UBERON:0004804	68.29	gold quality
prostate gland	UBERON:0002367	68.22	gold quality
right lung	UBERON:0002167	68.19	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25
E-GEOD-99795	no	0.66

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• identified a gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells (PMID:16109882)
• Mice treated with R-spondin1 showed increased intestinal epithelial healing, providing a protective effect against chemotherapy-induced intestinal mucositis. (PMID:16306530)
• Human R-spondin1 (RSPO1) is the gene disrupted in a recessive syndrome characterized by XX sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. (PMID:17041600)
• RSPO1 regulates Wnt signaling by inhibiting internalization of LRP6. (PMID:17804805)
• Mutational analysis of the RSPO1 gene in a 46,XX woman with true hermaphroditism, palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy, and hearing impairment, is reported. (PMID:18085567)
• R-sponin1 (Rspo1) acted synergistically with Wnt3A to activate Wnt/beta-catenin signaling in the uncommitted mesenchymal C2C12 cells. (PMID:18242177)
• SRY represses the transcriptional of the Rspo1/Wnt target genes involved in ovarian determination. (PMID:19376480)
• R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of beta-catenin signaling to oppose testis determination. (PMID:21297984)
• study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration (PMID:22575959)
• R-Spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5 (PMID:22815884)
• Recent developments have demonstrated that ovarian development is an active process (rather than a default process); ovarian development/function requires expression of RSPO1, WNT4, and FOXL2. [REVIEW] (PMID:23044875)
• In conclusion, present study highlights the role of Rspo 1 in bone remodeling where it activates Wnt signaling to induce differentiation, as shown in human as well murine in vitro osteoblast cell models. (PMID:23617070)
• Crystal structures of the Lgr4 ectodomain alone and bound to Rspo1. (PMID:23891289)
• ZNRF3 and LGR4-binding sites in RSPO1 are required for Wnt signaling. (PMID:24165923)
• ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via RSPO1 furin-like 1 (Fu1) domain. (PMID:24349440)
• Loss of RSPO1 expression is associated with invasive ductal carcinoma of the breast. (PMID:24373193)
• RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex. (PMID:24639526)
• overexpressed in fibrotic liver tissue (PMID:25218283)
• the LGR4-Rspo1 complex crystal structure shows divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (PMID:25480784)
• R-Spondin1 has an effect on radiosensitivity of glioma cells (PMID:25865226)
• Changes in the expression levels of IRS1, IRS2, RIPK2, RSPO1, and DNA JC15 genes might contribute to the development of insulin resistance and glucose intolerance in the obese boys. (PMID:26040030)
• Genetic variants in ZC3H11B, RSPO1, and GJD2 are associated with susceptibility to the development of high myopia in a Han Chinese population. (PMID:26485405)
• DPY19L3-mediated C-mannosylation of Rspo1 at tryptophan(156) is required for Rspo1 secretion. (PMID:26764097)
• Results showed that Rspo1 expression is downregulated in adult follicles but its activation is sufficient in promoting ovarian tumors supporting its direct involvement in the initiation of ovarian cancers. (PMID:27270435)
• Rspo1 glycosylation at Asn137 is essential for secretion and stability but not for heparin binding. (PMID:27314333)
• RSPOs facilitate HSC activation and promote liver fibrogenesis by enhancing the Wnt pathway (PMID:27572318)
• We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity. (PMID:27604691)
• Role of RSPO1 in gastric cancer (PMID:28219935)
• Rspo1 increases the number of Lgr5(+) liver stem cells in human liver fibrosis tissues, and once they are isolated, these cells are able to form organoids, and treatment with HGF/Rspo1 promotes their expansion (PMID:29079780)
• first report of a RSPO1 missense mutation in association with human disease (familial 46,XX disorder of sexual development) . (PMID:29262419)
• In this study, we aimed at the Wnt signaling characteristic of Cancer stem cells (CSC) and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway coreceptor LGR5. (PMID:29695632)
• R-spondin1/Wnt activated Ascl2 expression dose-dependently in the CD133(+)CD44(+) colorectal cancer population. (PMID:29886802)
• High RSPO1 expression is associated with Gastric Carcinogenesis. (PMID:30096312)
• This study demonstrated the association between serum levels of RSPO1 and a range of metabolic parameters in humans. (PMID:30398036)
• R-spondin 1 regulates ovarian cancer biological activities via activating Wnt/beta-catenin. This highlights the critical roles of R-spondin 1 in ovarian cancer progression and chemoresistance. (PMID:30572097)
• Association of WNT7B and RSPO1 with Axial Length in School Children. (PMID:32761137)
• WNT Signaling Driven by R-spondin 1 and LGR6 in High-grade Serous Ovarian Cancer. (PMID:33109540)
• RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell-cell adhesion, EMT-like phenotype and invasiveness properties: implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development. (PMID:35854363)
• Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity. (PMID:36755192)
• R-spondin-1 induces Axin degradation via the LRP6-CK1epsilon axis. (PMID:38183076)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rspo1	ENSDARG00000104340
mus_musculus	Rspo1	ENSMUSG00000028871
rattus_norvegicus	Rspo1	ENSRNOG00000009656

Paralogs (3): RSPO4 (ENSG00000101282), RSPO3 (ENSG00000146374), RSPO2 (ENSG00000147655)

Protein

Protein identifiers

R-spondin-1 — Q2MKA7 (reviewed: Q2MKA7)

Alternative names: Roof plate-specific spondin-1

All UniProt accessions (1): Q2MKA7

UniProt curated annotations — full annotation on UniProt →

Function. Activator of the canonical Wnt signaling pathway by acting as a ligand for LGR4-6 receptors. Upon binding to LGR4-6 (LGR4, LGR5 or LGR6), LGR4-6 associate with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Acts as a ligand for frizzled FZD8 and LRP6. May negatively regulate the TGF-beta pathway. Has a essential roles in ovary determination. Regulates Wnt signaling by antagonizing DKK1/KREM1-mediated internalization of LRP6 through an interaction with KREM1.

Subunit / interactions. Interacts with the extracellular domain of FZD8 and LRP6. It however does not form a ternary complex with FZD8 and LRP6. Interacts with WNT1. Binds heparin. Interacts with ZNRF3; promoting indirect interaction between ZNRF3 and LGR4 and membrane clearance of ZNRF3. Interacts with LGR4, LGR5 and LGR6. Identified in a complex composed of RNF43, LGR5 and RSPO1. Interacts (via FU repeats) with KREM1.

Subcellular location. Secreted. Nucleus.

Tissue specificity. Abundantly expressed in adrenal glands, ovary, testis, thyroid and trachea but not in bone marrow, spinal cord, stomach, leukocytes colon, small intestine, prostate, thymus and spleen.

Post-translational modifications. C-, and N-glycosylated. N-glycosylation at Asn-137, negatively influences its secretion and enhancing effect on Wnt/beta-catenin signaling. C-mannosylation at Trp-156 by DPY19L3 is required for its secretion and regulates the enhancing activity of Wnt signaling.

Disease relevance. Keratoderma, palmoplantar, with squamous cell carcinoma of skin and sex reversal (PKKSCC) [MIM:610644] A recessive syndrome characterized by XX (female to male) SRY-independent sex reversal, palmoplantar hyperkeratosis and predisposition to squamous cell carcinoma of the skin. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FU repeats are required for activation and stabilization of beta-catenin.

Miscellaneous. Upon injection into mice, it induces rapid onset of crypt cell proliferation involving beta-catenin stabilization. It also displays efficacy in a model of chemotherapy-induced intestinal mucositis suggesting possible therapeutic application in gastrointestinal diseases.

Similarity. Belongs to the R-spondin family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q2MKA7-1	1	yes
Q2MKA7-2	2
Q2MKA7-3	3

RefSeq proteins (4): NP_001033722, NP_001229837, NP_001229838, NP_001229839 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR006212	Furin_repeat	Repeat
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR043601	Rspo_Fu-CRD_dom	Domain
IPR051514	R-spondin	Family

Pfam: PF15913

UniProt features (53 total): mutagenesis site 16, disulfide bond 11, strand 11, glycosylation site 3, repeat 2, splice variant 2, turn 2, signal peptide 1, chain 1, sequence conflict 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
4BSP	X-RAY DIFFRACTION	2
4BSO	X-RAY DIFFRACTION	2.2
4QXF	X-RAY DIFFRACTION	2.25
4KT1	X-RAY DIFFRACTION	2.5
4KNG	X-RAY DIFFRACTION	2.5
4CDK	X-RAY DIFFRACTION	2.8
4LI2	X-RAY DIFFRACTION	3.19
4BSR	X-RAY DIFFRACTION	3.2
4BSS	X-RAY DIFFRACTION	3.2
4BSU	X-RAY DIFFRACTION	3.2
8WVU	ELECTRON MICROSCOPY	3.61
4BST	X-RAY DIFFRACTION	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2MKA7-F1	75.16	0.41

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 (11): 40–47, 44–53, 56–75, 79–94, 97–105, 102–111, 114–125, 129–142, 148–190, 159–166, 199–206

Glycosylation sites (3): 137, 153, 156

Mutagenesis-validated functional residues (16):

Position	Phenotype
66	strongly reduces activation of wnt signaling.
66	reduces activation of wnt signaling.
70	strongly reduces activation of wnt signaling.
71	no effect on activation of wnt signaling.
71	strongly reduces activation of wnt signaling.
73	strongly reduces activation of wnt signaling.
87	nearly abolishes activation of wnt signaling.
106	abolishes activation of wnt signaling. abolishes lgr4 binding.
106	abolishes activation of wnt signaling.
110	nearly abolishes activation of wnt signaling.
110	abolishes activation of wnt signaling.
122	strongly reduces affinity for lgr4.
124	strongly reduces affinity for lgr4.
137	secretion of rspo1 is decreased. increased wnt/beta-catenin signaling-enhancing effects.
153	secretion of rspo1 is decreased; when associated with a-156. decreases activation of wnt signaling; when associated with
156	secretion of rspo1 is decreased; when associated with a-153. decreases activation of wnt signaling; when associated with

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 177 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_PHOSPHORYLATION, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_DN, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_RECEPTOR_INTERNALIZATION, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_RECEPTOR_MEDIATED_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, chr1p34

GO Biological Process (6): positive regulation of protein phosphorylation (GO:0001934), regulation of receptor internalization (GO:0002090), Wnt signaling pathway (GO:0016055), positive regulation of Wnt signaling pathway (GO:0030177), positive regulation of canonical Wnt signaling pathway (GO:0090263), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (4): G protein-coupled receptor binding (GO:0001664), signaling receptor binding (GO:0005102), heparin binding (GO:0008201), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
receptor internalization	1
regulation of receptor-mediated endocytosis	1
cell surface receptor signaling pathway	1
positive regulation of signal transduction	1
Wnt signaling pathway	1
regulation of Wnt signaling pathway	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
regulation of metabolic process	1
macromolecule metabolic process	1
signaling receptor binding	1
protein binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2093 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RSPO1	LGR5	O75473	998
RSPO1	LGR4	Q9BXB1	997
RSPO1	ZNRF3	Q9ULT6	988
RSPO1	LGR6	Q9HBX8	987
RSPO1	RNF43	Q68DV7	981
RSPO1	LRP5	O75197	962
RSPO1	LRP6	O75581	960
RSPO1	NOG	Q13253	925
RSPO1	WNT4	P56705	920
RSPO1	WNT3A	P56704	901
RSPO1	EGF	P01133	862
RSPO1	CTNNB1	P35222	832
RSPO1	SRY	Q05066	821
RSPO1	FGF10	O15520	796
RSPO1	FZD8	Q9H461	779

IntAct

29 interactions, top by confidence:

A	B	Type	Score
LGR5	RSPO1	psi-mi:“MI:0915”(physical association)	0.740
LGR5	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.740
RSPO1	ZNRF3	psi-mi:“MI:0407”(direct interaction)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0914”(association)	0.700
ZNRF3	RSPO1	psi-mi:“MI:0915”(physical association)	0.700
Znrf3	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.610
lgr4	RSPO1	psi-mi:“MI:0407”(direct interaction)	0.560
COMT	RSPO1	psi-mi:“MI:0915”(physical association)	0.560
RSPO1	C1QBP	psi-mi:“MI:0914”(association)	0.530
LGR4	RSPO1	psi-mi:“MI:0915”(physical association)	0.400
RSPO1	LGR4	psi-mi:“MI:0915”(physical association)	0.400
LGR6	RSPO1	psi-mi:“MI:0915”(physical association)	0.400
RSPO1	H1-5	psi-mi:“MI:0915”(physical association)	0.400
RSPO1	HIST2H2BF	psi-mi:“MI:0915”(physical association)	0.400
Znrf3	LGR5	psi-mi:“MI:0915”(physical association)	0.400
RSPO1	ZZEF1	psi-mi:“MI:0914”(association)	0.350
RSPO1	MYH7B	psi-mi:“MI:0914”(association)	0.350

BioGRID (38): C1QBP (Affinity Capture-MS), ZZEF1 (Affinity Capture-MS), SORL1 (Affinity Capture-MS), HECTD3 (Affinity Capture-MS), CHTOP (Affinity Capture-MS), LACRT (Affinity Capture-MS), LRP1B (Affinity Capture-MS), ZNF579 (Affinity Capture-MS), CEP76 (Affinity Capture-MS), ZNRF3 (FRET), RSPO1 (Reconstituted Complex), RSPO1 (Reconstituted Complex), RNF43 (Affinity Capture-Western), LACRT (Affinity Capture-MS), CHTOP (Affinity Capture-MS)

ESM2 similar proteins: A7MBS7, D3YXF5, F1LW30, O89103, P10643, P11680, P27918, P35446, P82987, P90884, Q29RQ1, Q2I0M5, Q2MKA7, Q3UPR9, Q3UTY6, Q4R7Z5, Q5M7L6, Q5RAD0, Q5RBP1, Q5RBP8, Q5UE90, Q64181, Q66PY1, Q69ZU6, Q6NZL8, Q6P4U0, Q6UXX9, Q6ZMP0, Q7T3Q2, Q7TSK7, Q80YN4, Q86TH1, Q8BFU0, Q8BJ73, Q8BLI0, Q8IUX8, Q8IWY4, Q8IX30, Q8N6G6, Q8VCC9

Diamond homologs: A7MBS7, B3EWY9, B3EWZ8, Q1RMU1, Q2MKA7, Q3UPR9, Q5R328, Q5R7Y0, Q69Z28, Q69ZU6, Q6P4U0, Q8BMS2, Q8IVN8, Q8TE57, Q9BUD6, Q9C0I4, Q9UPZ6, Q9WV75, Q9Z132, A0A044RE18, A0A6I8RMG7, G5ECN9, O13359, O17798, P04072, P09231, P09958, P0CY46, P13134, P13387, P16519, P21661, P21860, P23188, P23377, P26016, P28840, P28841, P29119, P29120

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RSPO1	down-regulates	ZNRF3	relocalization
RSPO1	“down-regulates quantity”	ZNRF3	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	49
Likely benign	20
Benign	14

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1603	NM_001242908.2(RSPO1):c.108dup (p.Ser37Glufs*9)	Pathogenic
1604	NM_001242908.2(RSPO1):c.-288-413_94+1957del	Pathogenic
1605	NM_001242908.2(RSPO1):c.286+1G>A	Pathogenic
4281654	NM_001242908.2(RSPO1):c.477C>A (p.Cys159Ter)	Pathogenic
4745559	NM_001242908.2(RSPO1):c.745C>T (p.Gln249Ter)	Pathogenic
2585482	NM_001242908.2(RSPO1):c.254del (p.Asp85fs)	Likely pathogenic

SpliceAI

1451 predictions. Top by Δscore:

Variant	Effect	Δscore
1:37613722:T:A	donor_gain	1.0000
1:37616482:A:AC	donor_gain	1.0000
1:37616483:C:CC	donor_gain	1.0000
1:37616672:CTGA:C	acceptor_gain	1.0000
1:37616676:C:CC	acceptor_gain	1.0000
1:37613727:A:AC	donor_gain	0.9900
1:37613728:C:CC	donor_gain	0.9900
1:37613737:T:TA	donor_gain	0.9900
1:37613888:TTGCG:T	acceptor_gain	0.9900
1:37613889:TGCG:T	acceptor_gain	0.9900
1:37613891:CG:C	acceptor_gain	0.9900
1:37613898:A:T	acceptor_gain	0.9900
1:37614178:GCTT:G	donor_loss	0.9900
1:37614179:CTTA:C	donor_loss	0.9900
1:37614180:TTA:T	donor_loss	0.9900
1:37614181:T:TA	donor_loss	0.9900
1:37614182:ACCAG:A	donor_loss	0.9900
1:37614330:CATT:C	acceptor_gain	0.9900
1:37614331:ATTC:A	acceptor_loss	0.9900
1:37614332:TT:T	acceptor_gain	0.9900
1:37614333:TCTGA:T	acceptor_loss	0.9900
1:37614334:C:CA	acceptor_loss	0.9900
1:37614334:C:CC	acceptor_gain	0.9900
1:37616484:TGATG:T	donor_gain	0.9900
1:37616673:TGA:T	acceptor_gain	0.9900
1:37619430:C:A	donor_gain	0.9900
1:37629876:T:TA	donor_gain	0.9900
1:37634561:CTCA:C	donor_loss	0.9900
1:37634562:TCA:T	donor_loss	0.9900
1:37634563:CA:C	donor_loss	0.9900

AlphaMissense

1722 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:37613870:C:A	W153C	1.000
1:37613870:C:G	W153C	1.000
1:37613861:C:A	W156C	0.999
1:37613861:C:G	W156C	0.999
1:37614291:A:C	F110C	0.999
1:37614303:A:C	F106C	0.999
1:37616489:C:G	C94S	0.999
1:37616490:A:T	C94S	0.999
1:37616545:G:C	C75W	0.999
1:37616546:C:G	C75S	0.999
1:37616547:A:G	C75R	0.999
1:37616547:A:T	C75S	0.999
1:37616603:C:G	C56S	0.999
1:37616604:A:T	C56S	0.999
1:37616612:C:G	C53S	0.999
1:37616613:A:T	C53S	0.999
1:37616616:C:A	G52C	0.999
1:37614253:C:A	G123C	0.998
1:37614287:G:C	C111W	0.998
1:37614288:C:G	C111S	0.998
1:37614288:C:T	C111Y	0.998
1:37614289:A:T	C111S	0.998
1:37614290:G:C	F110L	0.998
1:37614290:G:T	F110L	0.998
1:37614292:A:G	F110L	0.998
1:37614302:G:C	F106L	0.998
1:37614302:G:T	F106L	0.998
1:37614304:A:G	F106L	0.998
1:37616488:G:C	C94W	0.998
1:37616490:A:G	C94R	0.998

dbSNP variants (sampled 300 via entrez): RS1000089907 (1:37614359 T>C), RS1000137396 (1:37617586 T>C), RS1000210093 (1:37617930 A>T), RS1000241112 (1:37618200 A>C,G), RS1000393502 (1:37612086 G>A,T), RS1000410051 (1:37615626 C>A), RS1000508883 (1:37633285 C>G), RS1000607574 (1:37629199 C>G), RS1000638588 (1:37629468 A>C), RS1000764466 (1:37611834 C>T), RS1001103625 (1:37634515 C>T), RS1001115136 (1:37626130 C>T), RS1001150317 (1:37623599 T>C), RS1001195846 (1:37611432 C>T), RS1001228256 (1:37611749 A>T)

Disease associations

OMIM: gene MIM:609595 | disease phenotypes: MIM:610644

GenCC curated gene-disease

Disease	Classification	Inheritance
palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome	Strong	Autosomal recessive

Mondo (1): palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (MONDO:0012530)

Orphanet (1): Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome (Orphanet:85112)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000062	Ambiguous genitalia
HP:0000771	Gynecomastia
HP:0000982	Palmoplantar keratoderma
HP:0001792	Small nail
HP:0002155	Hypertriglyceridemia
HP:0003124	Hypercholesterolemia
HP:0003241	External genital hypoplasia
HP:0006357	Premature loss of permanent teeth
HP:0006739	Squamous cell carcinoma of the skin
HP:0007410	Palmoplantar hyperhidrosis
HP:0008404	Nail dystrophy
HP:0008665	Clitoral hypertrophy
HP:0008734	Decreased testicular size
HP:0011838	Sclerodactyly
HP:0012118	Laryngeal carcinoma
HP:0012245	Sex reversal
HP:0012861	Ovotestis
HP:0025080	Orthokeratotic hyperkeratosis
HP:0030731	Carcinoma

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002115_4	Axial length	4.000000e-13
GCST002748_13	Epithelial ovarian cancer	1.000000e-08
GCST002748_18	Epithelial ovarian cancer	1.000000e-11
GCST003476_2	Eyebrow thickness	7.000000e-06
GCST006394_27	Intraocular pressure	1.000000e-09
GCST006412_10	Intraocular pressure	4.000000e-12
GCST009725_55	Intraocular pressure	1.000000e-09
GCST90011770_53	Glaucoma (primary open-angle)	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005318	axial length measurement
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567165	Palmoplantar Hyperkeratosis And True Hermaphroditism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sotorasib	affects cotreatment, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Diazinon	increases methylation	1
Estradiol	increases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Phenobarbital	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 3 embryonic stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5X9	SEES3-1V human RSPO1, clone1	Embryonic stem cell	Male
CVCL_A5Y0	SEES3-1V human RSPO1, clone2	Embryonic stem cell	Male
CVCL_A5Y1	SEES3-1V human RSPO1, clone3	Embryonic stem cell	Male
CVCL_E6RN	Genomeditech CHO-K1 H_RSPO1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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