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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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RSPO4
R-spondin 4
Chromosome 20 Β· 20p13
NCBI Gene: 343637Ensembl: ENSG00000101282.10HGNC: HGNC:16175UniProt: Q2I0M5
23PubMed Papers
21Diseases
0Drugs
12Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
positive regulation of Wnt signaling pathwayprotein bindingnail developmentGO:0005615nonsyndromic congenital nail disorder 4Anonychia congenita totalisCongenital anonychiagenetic disorder
✦AI Summary

RSPO4 is a secreted ligand that activates canonical Wnt signaling by binding to LGR4-6 receptors and antagonizing the E3 ubiquitin ligases ZNRF3 and RNF43 1. Upon LGR4-6 binding, RSPO4 promotes ternary complex formation with phosphorylated LRP6 and frizzled receptors, enabling Ξ²-catenin nuclear translocation and TCF/LEF-dependent gene transactivation 2. However, RSPO4 has the lowest binding affinity for ZNRF3/RNF43 and weakest efficacy among R-spondins, making it functionally distinct from RSPO1-3 3. In nail development, RSPO4 is expressed in onychofibroblasts proximal to LGR6+ nail matrix cells, activating Wnt/Ξ²-catenin signaling essential for nail specification 4. Biallelic RSPO4 mutations cause congenital anonychia/hyponychia, with mutations clustering in the highly conserved furin-like cysteine-rich domains 56. Beyond nail development, RSPO4 variants associate with severe periodontitis through effects on innate immune response and barrier integrity 7. Notably, RSPO4 exhibits tumor suppressor activity through antagonizing both canonical and non-canonical Wnt signaling, with frequent epigenetic silencing in multiple cancer types 8.

Sources cited
1
RSPO4 acts as a ligand for LGR4-6 receptors and directly antagonizes RNF43/ZNRF3 to amplify Wnt signaling
PMID: 29769720
2
RSPO ligands drive Lgr5+ intestinal stem cell self-renewal through cooperation with Wnt proteins in establishing stem cell niche biology
PMID: 28467820
3
RSPO4 is expressed in nail onychofibroblasts and is the major gene in congenital anonychia, with spatial proximity to LGR6+ nail matrix
PMID: 34099859
4
RSPO4 has the lowest LGR4 binding affinity and efficacy among R-spondins, with signaling potency determined by ternary complex formation
PMID: 25504990
5
RSPO4 mutations cluster in furin-like cysteine-rich domains and are the major cause of autosomal-recessive congenital anonychia
PMID: 17914448
6
Novel and recurrent RSPO4 mutations identified in congenital hyponychia families, expanding the mutational spectrum
PMID: 23234511
7
RSPO4 is associated with severe periodontitis and modifies innate immune response and oral barrier integrity
PMID: 36507580
8
RSPO4 acts as a tumor suppressor through antagonizing canonical and non-canonical Wnt signaling, frequently epigenetically silenced in cancers
PMID: 41522353
Disease Associationsβ“˜21
nonsyndromic congenital nail disorder 4Open Targets
0.76Strong
Anonychia congenita totalisOpen Targets
0.71Strong
Congenital anonychiaOpen Targets
0.68Moderate
genetic disorderOpen Targets
0.41Moderate
Genu valgumOpen Targets
0.32Weak
Genu varumOpen Targets
0.32Weak
open-angle glaucomaOpen Targets
0.30Weak
glaucomaOpen Targets
0.30Weak
neoplasmOpen Targets
0.30Weak
cancerOpen Targets
0.08Suggestive
MODYOpen Targets
0.07Suggestive
maturity-onset diabetes of the young type 3Open Targets
0.06Suggestive
hyperproinsulinemiaOpen Targets
0.05Suggestive
maturity-onset diabetes of the young type 10Open Targets
0.05Suggestive
Glycogen storage disease due to hepatic glycogen synthase deficiencyOpen Targets
0.04Suggestive
glycogen storage disorder due to hepatic glycogen synthase deficiencyOpen Targets
0.04Suggestive
ovarian dysfunctionOpen Targets
0.04Suggestive
male reproductive organ cancerOpen Targets
0.04Suggestive
diabetes mellitus, permanent neonatal 4Open Targets
0.03Suggestive
papillary thyroid carcinomaOpen Targets
0.03Suggestive
Nail disorder, non-syndromic congenital, 4UniProt
Pathogenic Variants12
NM_001029871.4(RSPO4):c.79+1G>APathogenic
Inborn genetic diseases|not provided|Nonsyndromic congenital nail disorder 4
β˜…β˜…β˜†β˜†2024
NM_001029871.4(RSPO4):c.64C>T (p.Arg22Ter)Likely pathogenic
Nonsyndromic congenital nail disorder 4
β˜…β˜†β˜†β˜†2024β†’ Residue 22
NM_001029871.4(RSPO4):c.76_79del (p.Gln26fs)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜…β˜†β˜†β˜†2024β†’ Residue 26
NM_001029871.4(RSPO4):c.335_338del (p.Tyr112fs)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜…β˜†β˜†β˜†2024β†’ Residue 112
NM_001029871.4(RSPO4):c.145_166dup (p.Leu56fs)Pathogenic
not provided
β˜…β˜†β˜†β˜†2022β†’ Residue 56
NM_001029871.4(RSPO4):c.190C>T (p.Arg64Cys)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2008β†’ Residue 64
NM_001029871.4(RSPO4):c.301C>T (p.Gln101Ter)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2008β†’ Residue 101
NM_001029871.4(RSPO4):c.199G>C (p.Gly67Arg)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2008β†’ Residue 67
NM_001029871.4(RSPO4):c.218G>A (p.Cys73Tyr)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2006β†’ Residue 73
NM_001029871.4(RSPO4):c.353G>A (p.Cys118Tyr)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2006β†’ Residue 118
NM_001029871.4(RSPO4):c.319T>C (p.Cys107Arg)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2006β†’ Residue 107
NM_001029871.4(RSPO4):c.194A>G (p.Gln65Arg)Pathogenic
Nonsyndromic congenital nail disorder 4
β˜†β˜†β˜†β˜†2006β†’ Residue 65
View on ClinVar β†—
Related Genes
RSPO2Shared pathway100%RNF43Protein interaction97%LGR5Protein interaction86%FURINProtein interaction80%ZNRF3Protein interaction75%LGR4Protein interaction68%
Tissue Expression6 tissues
Lung
100%
Ovary
5%
Brain
4%
Liver
4%
Bone Marrow
1%
Heart
0%
Gene Interaction Network
Click a node to explore
RSPO4RSPO2RNF43LGR5FURINZNRF3LGR4
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q2I0M5
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
1.33LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.94 [0.68–1.33]
RankingsWhere RSPO4 stands among ~20K protein-coding genes
  • #13,510of 20,598
    Most Researched23
  • #2,713of 5,498
    Most Pathogenic Variants12
  • #13,926of 17,882
    Most Constrained (LOEUF)1.33
Genes detectedRSPO4
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Non-equivalence of Wnt and R-spondin ligands during Lgr5
PMID: 28467820
Nature Β· 2017
1.00
2
RSPO4 is a potential risk gene of stages III-IV, grade C periodontitis through effects on innate immune response and oral barrier integrity.
PMID: 36507580
J Clin Periodontol Β· 2023
0.90
3
Single-cell RNA sequencing of human nail unit defines RSPO4 onychofibroblasts and SPINK6 nail epithelium.
PMID: 34099859
Commun Biol Β· 2021
0.80
4
RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6.
PMID: 29769720
Nature Β· 2018
0.70
5
Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I).
PMID: 23234511
BMC Med Genet Β· 2012
0.60