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RSPO1 (R-spondin homolog (Xenopus laevis))

Written2008-06Diana Blaydon
Centre for Cutaneous Research, Institute of Cell, Molecular Sciences, Barts, The London School of Medicine, Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel, London E1 2AT, United Kingdom

(Note : for Links provided by Atlas : click)

Identity

Alias_namesR-spondin homolog (Xenopus laevis)
Alias_symbol (synonym)FLJ40906
RSPONDIN
Other aliasR-spondin1
RP11-566C13
hRspo1
HGNC (Hugo) RSPO1
LocusID (NCBI) 284654
Atlas_Id 44137
Location 1p34.3  [Link to chromosome band 1p34]
Location_base_pair Starts at 37611350 and ends at 37634923 bp from pter ( according to hg19-Feb_2009)  [Mapping RSPO1.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CMTM7 (3p22.3) / RSPO1 (1p34.3)

DNA/RNA

Description 8 exons, 5 coding exons, 24 kb of genomic DNA.
Transcription mRNA about 2.5 kb, 263 residues in full-length translated protein, which contains an N-terminal signal peptide, followed by two cysteine-rich furin-like domains, one thrombospondin type 1 domain (TSP1 domain ) and a putative C-terminal nuclear localization signal domain.
Three alternatively spliced isoforms have been identified: one lacking the signal peptide encoded by exon 4, one lacking the thrombospondin domain encoded exon 7 and the third has an alternative 5'UTR.
Pseudogene None known

Protein

Description Secreted ligand with an N-terminal signal peptide, two cysteine-rich furin-like domains, one thrombospondin type 1 domain (TSP1) and a putative C-terminal nuclear localization signal domain.
Expression R-spondin1 expression is seen in a number of organs and appears to coincide with expression of genes that form part of the Wnt signaling pathway.
In the developing mouse Rspo1 transcripts are undetectable at E7, dramatically increased by E11 and significantly reduced again by E17. Rspo1 expression is predominantly found in mesenchymal cells in a number of developing organs, including the forebrain, dorsal neural tube (roof plate), whisker follicles, kidney, mammary gland, small intestine, the long bones and vertebrae (Nam et al., 2007).
Rspo1 expression is also detected in the mesenchyme underlying the developing dermis, while in adult skin, expression is restricted to the dermal papilla of the hair (Parma et al., 2006).
Similarly, in humans, RSPO1 expression is detected in the small intestine, kidney, prostate, adrenal gland and pancreas (Kim et al., 2005).
Expression of RSPO1 is detected in cultured primary human fibroblasts but not in cultured keratinocytes, indicating that R-spondin1 may be acting as a paracrine signaling molecule.
Localisation Secreted
Function R-spondin1 is implicated in the Wnt signaling pathway where it seems to act as an enhancer of Wnt signaling. R-spondin1 appears to antagonize Dickkopf1 action, an inhibitor of the Wnt signaling pathway, by binding to the receptor Kremen1 and inhibiting the internalization of LRP6, a Wnt signaling co-receptor (Binnerts et al., 2007).
Homology There are 3 paralogs of human RSPO1: RSPO2, RSPO3 and RSPO4. Orthologs have been identified in: mouse, chicken, dog, cow and chimpanzee.

Mutations

Germinal To date, three homozygous RSPO1 mutations have been identified: a single base pair insertion, 896insG, a 2752 bp deletion that includes exon 4 (the first coding exon) and 286+1G>A, a splice site mutation.
896insG and the 2752 bp deletion were identified in two families exhibiting palmoplantar hyperkeratosis with a predisposition to squamous cell carcinoma of the skin and XX sex reversal. 896insG leads to a frameshift and stop codon after 10 amino acids resulting in the abolition of all normal isoforms of RSPO1. While the 2752 bp deletion allows production of a shorter form of RSPO1 mRNA, that may translate to a shorter protein lacking the signal peptide and first furin-like domain (Parma et al., 2006).
The splice site mutation 286+1G>A was identified in a 46,XX female with true hermaphroditism, palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy and hearing impairment. 286+1G>A leads to aberrant splicing of the mRNA and skipping of the second coding exon in all RSPO1 isoforms and a predicted shortened R-spondin1 protein that lacks the entire first furin-like domain and the first two residues of the second furin-like repeat (Tomaselli et al., 2007).

Implicated in

Note
  
Entity Palmoplantar hyperkeratosis with a predisposition to squamous cell carcinoma of the skin and XX sex reversal.
Note Two families.
Disease Mutations in the RSPO1 gene have been implicated in an autosomal recessive syndrome identified in an Italian family spanning three generations (Micali et al., 2005). The syndrome is characterized by: sclerodactyly, non-epidermolytic palmar plantar keratoderma (PPK) associated with multiple cutaneous squamous cell carcinomas, dental anomlies and early tooth loss due to chronic periodontal disease (in three out of five brothers), hypogenitalism with hypospadias, gynecomastia (in one brother), altered plasma sex hormone levels in the two brothers with abnormal genitalia and hypertriglyceridemia. Four out of the five affected brothers had an abnormal XX karyotype that was associated with the genital abnormalities. None of the five sisters, or their offspring, were affected.
The squamous cell carcinoma lesions found in these patients first developed in the hyperkeratotic skin of the hands and feet (PPK) and then metastasized to other parts of the body, indicating that a single gene is responsible for both the PPK and predisposition to SCC (Radi et al., 2005). However, the sex reversal can be considered to be non-penetrant in affected XY individuals. In this extended Italian family there are eleven 46,XX individuals in two sibships, all of the affected individuals have a male phenotype (two 46,XY and four 46,XX), while none of the seven genetic females with a female phenotype show any sign of the PPK/SCC phenotype or sexual ambiguity. This indicates that a single gene defect underlies both the PPK/SCC and sex reversal, rather than two independent mutations. The family is informative for linkage analysis for the PPK trait and allows linkage exclusion for the sex reversal trait.
Linkage analysis performed on this family detected positive LOD scores for two markers at 1p34-p35. Furthermore, an additional affected individual, also from Southern Italy, who presented with XX sex reversal, PPK and SCC, also showed linkage to 1p34, but with a different haplotype (Parma et al., 2006). Sequencing identified two homozygous RSPO1 mutations in the two families. A single nucleotide insertion in codon 36 results in a frame-shift and stop codon after ten amino acid residues, predicted to lead to abolition of all RSPO1 isoforms. However, the second mutation, a 2752 bp deletion including exon 4, leads to a shorter mRNA that may translate to a putative, shorter protein lacking the signal peptide and first furin domain.
In situ hybridization analysis has identified expression of mRspo1 in the urogenital ridge at E10.5, with sex-specific differences appearing at E12.5 inline with an increase in the somatic cells of the XX gonad. Furthermore, qPCR detected no differences in mRspo1 levels between XX and XY gonads at E10.5 and E11.5, by E12.5, however, there is a clear increase of expression in XX gonads which is five-fold higher than XY gonads by E14.5. Therefore, there is a sex-specific regulation of R spondin1 at a crucial time in sex determination (Parma et al., 2006). What is more, in the XX sex reversal patients, functional testes are present, but the individuals are sterile, indicating that R-spondin1 is not required for testis differentiation and function (Parma et al., 2006).
RT-PCR has shown that RSPO1 is not expressed in cultured keratinocytes, but it is expressed in fibroblasts. Furthermore, plantar keratinocytes from an affected individual did not differentiate in organotypic culture. Together, this data suggests that R-spondin1 might act as a paracrine signal from fibroblasts to keratinocytes, regulating keratinocyte proliferation and differentiation (Parma et al., 2006).
  
  
Entity Syndromic true hermaphroditism with palmoplantar keratoderma, congenital bilateral corneal opacities, onychodystrophy and hearing impairment.
Note One patient
  

Bibliography

R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.
Binnerts ME, Kim KA, Bright JM, Patel SM, Tran K, Zhou M, Leung JM, Liu Y, Lomas WE 3rd, Dixon M, Hazell SA, Wagle M, Nie WS, Tomasevic N, Williams J, Zhan X, Levy MD, Funk WD, Abo A.
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14700-5.
PMID 17804805
 
Mitogenic influence of human R-spondin1 on the intestinal epithelium.
Kim KA, Kakitani M, Zhao J, Oshima T, Tang T, Binnerts M, Liu Y, Boyle B, Park E, Emtage P, Funk WD, Tomizuka K.
Science. 2005 Aug 19;309(5738):1256-9.
PMID 16109882
 
Association of palmoplantar keratoderma, cutaneous squamous cell carcinoma, dental anomalies, and hypogenitalism in four siblings with 46,XX karyotype: a new syndrome.
Micali G, Nasca MR, Innocenzi D, Frasin LA, Radi O, Parma P, Camerino G, Schwartz RA.
J Am Acad Dermatol. 2005 Nov;53(5 Suppl 1):S234-9.
PMID 16227098
 
Dynamic expression of R-spondin family genes in mouse development.
Nam JS, Turcotte TJ, Yoon JK.
Gene Expr Patterns. 2007 Jan;7(3):306-12.
PMID 17035101
 
R-spondin1 is essential in sex determination, skin differentiation and malignancy.
Parma P, Radi O, Vidal V, Chaboissier MC, Dellambra E, Valentini S, Guerra L, Schedl A, Camerino G.
Nat Genet. 2006 Nov;38(11):1304-9.
PMID 17041600
 
XX sex reversal, palmoplantar keratoderma, and predisposition to squamous cell carcinoma: genetic analysis in one family.
Radi O, Parma P, Imbeaud S, Nasca MR, Uccellatore F, Maraschio P, Tiepolo L, Micali G, Camerino G.
Am J Med Genet A. 2005 Oct 15;138A(3):241-6.
PMID 16158431
 
Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation.
Tomaselli S, Megiorni F, De Bernardo C, Felici A, Marrocco G, Maggiulli G, Grammatico B, Remotti D, Saccucci P, Valentini F, Mazzilli MC, Majore S, Grammatico P.
Hum Mutat. 2008 Feb;29(2):220-6.
PMID 18085567
 
R-spondin1 is a high affinity ligand for LRP6 and induces LRP6 phosphorylation and beta-catenin signaling.
Wei Q, Yokota C, Semenov MV, Doble B, Woodgett J, He X.
J Biol Chem. 2007 May 25;282(21):15903-11.
PMID 17400545
 
R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice.
Zhao J, de Vera J, Narushima S, Beck EX, Palencia S, Shinkawa P, Kim KA, Liu Y, Levy MD, Berg DJ, Abo A, Funk WD.
Gastroenterology. 2007 Apr;132(4):1331-43.
PMID 17408649
 

Citation

This paper should be referenced as such :
Blaydon, D
RSPO1 (R-spondin homolog (Xenopus laevis))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(5):364-366.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RSPO1ID44137ch1p34.html


External links

Nomenclature
HGNC (Hugo)RSPO1   21679
Cards
AtlasRSPO1ID44137ch1p34
Entrez_Gene (NCBI)RSPO1  284654  R-spondin 1
AliasesCRISTIN3; RSPO
GeneCards (Weizmann)RSPO1
Ensembl hg19 (Hinxton)ENSG00000169218 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000169218 [Gene_View]  chr1:37611350-37634923 [Contig_View]  RSPO1 [Vega]
ICGC DataPortalENSG00000169218
TCGA cBioPortalRSPO1
AceView (NCBI)RSPO1
Genatlas (Paris)RSPO1
WikiGenes284654
SOURCE (Princeton)RSPO1
Genetics Home Reference (NIH)RSPO1
Genomic and cartography
GoldenPath hg38 (UCSC)RSPO1  -     chr1:37611350-37634923 -  1p34.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)RSPO1  -     1p34.3   [Description]    (hg19-Feb_2009)
EnsemblRSPO1 - 1p34.3 [CytoView hg19]  RSPO1 - 1p34.3 [CytoView hg38]
Mapping of homologs : NCBIRSPO1 [Mapview hg19]  RSPO1 [Mapview hg38]
OMIM609595   610644   
Gene and transcription
Genbank (Entrez)AK098225 BC114966 CA438631 DB273983 DQ165084
RefSeq transcript (Entrez)NM_001038633 NM_001242908 NM_001242909 NM_001242910 NM_173640
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)RSPO1
Cluster EST : UnigeneHs.135015 [ NCBI ]
CGAP (NCI)Hs.135015
Alternative Splicing GalleryENSG00000169218
Gene ExpressionRSPO1 [ NCBI-GEO ]   RSPO1 [ EBI - ARRAY_EXPRESS ]   RSPO1 [ SEEK ]   RSPO1 [ MEM ]
Gene Expression Viewer (FireBrowse)RSPO1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)284654
GTEX Portal (Tissue expression)RSPO1
Human Protein AtlasENSG00000169218-RSPO1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ2MKA7   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ2MKA7  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ2MKA7
Splice isoforms : SwissVarQ2MKA7
PhosPhoSitePlusQ2MKA7
Domaine pattern : Prosite (Expaxy)TSP1 (PS50092)   
Domains : Interpro (EBI)Furin_repeat    Growth_fac_rcpt_    TSP1_rpt   
Domain families : Pfam (Sanger)Furin-like_2 (PF15913)   
Domain families : Pfam (NCBI)pfam15913   
Domain families : Smart (EMBL)FU (SM00261)  TSP1 (SM00209)  
Conserved Domain (NCBI)RSPO1
DMDM Disease mutations284654
Blocks (Seattle)RSPO1
PDB (SRS)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
PDB (PDBSum)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
PDB (IMB)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
PDB (RSDB)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
Structural Biology KnowledgeBase4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
SCOP (Structural Classification of Proteins)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
CATH (Classification of proteins structures)4BSO    4BSP    4BSR    4BSS    4BST    4BSU    4CDK    4KNG    4KT1    4LI2    4QXF   
SuperfamilyQ2MKA7
Human Protein Atlas [tissue]ENSG00000169218-RSPO1 [tissue]
Peptide AtlasQ2MKA7
HPRD08288
IPIIPI00719160   IPI00748481   IPI00787966   
Protein Interaction databases
DIP (DOE-UCLA)Q2MKA7
IntAct (EBI)Q2MKA7
FunCoupENSG00000169218
BioGRIDRSPO1
STRING (EMBL)RSPO1
ZODIACRSPO1
Ontologies - Pathways
QuickGOQ2MKA7
Ontology : AmiGOG-protein coupled receptor binding  positive regulation of protein phosphorylation  regulation of receptor internalization  receptor binding  protein binding  extracellular region  extracellular region  nucleus  heparin binding  Wnt signaling pathway  positive regulation of Wnt signaling pathway  positive regulation of Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  
Ontology : EGO-EBIG-protein coupled receptor binding  positive regulation of protein phosphorylation  regulation of receptor internalization  receptor binding  protein binding  extracellular region  extracellular region  nucleus  heparin binding  Wnt signaling pathway  positive regulation of Wnt signaling pathway  positive regulation of Wnt signaling pathway  positive regulation of canonical Wnt signaling pathway  
REACTOMEQ2MKA7 [protein]
REACTOME PathwaysR-HSA-4641263 [pathway]   
NDEx NetworkRSPO1
Atlas of Cancer Signalling NetworkRSPO1
Wikipedia pathwaysRSPO1
Orthology - Evolution
OrthoDB284654
GeneTree (enSembl)ENSG00000169218
Phylogenetic Trees/Animal Genes : TreeFamRSPO1
HOVERGENQ2MKA7
HOGENOMQ2MKA7
Homologs : HomoloGeneRSPO1
Homology/Alignments : Family Browser (UCSC)RSPO1
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRSPO1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RSPO1
dbVarRSPO1
ClinVarRSPO1
1000_GenomesRSPO1 
Exome Variant ServerRSPO1
ExAC (Exome Aggregation Consortium)ENSG00000169218
GNOMAD BrowserENSG00000169218
Genetic variants : HAPMAP284654
Genomic Variants (DGV)RSPO1 [DGVbeta]
DECIPHERRSPO1 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisRSPO1 
Mutations
ICGC Data PortalRSPO1 
TCGA Data PortalRSPO1 
Broad Tumor PortalRSPO1
OASIS PortalRSPO1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRSPO1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRSPO1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RSPO1
DgiDB (Drug Gene Interaction Database)RSPO1
DoCM (Curated mutations)RSPO1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RSPO1 (select a term)
intoGenRSPO1
NCG5 (London)RSPO1
Cancer3DRSPO1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609595    610644   
Orphanet11623   
MedgenRSPO1
Genetic Testing Registry RSPO1
NextProtQ2MKA7 [Medical]
TSGene284654
GENETestsRSPO1
Target ValidationRSPO1
Huge Navigator RSPO1 [HugePedia]
snp3D : Map Gene to Disease284654
BioCentury BCIQRSPO1
ClinGenRSPO1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD284654
Chemical/Pharm GKB GenePA142670967
Clinical trialRSPO1
Miscellaneous
canSAR (ICR)RSPO1 (select the gene name)
Probes
Litterature
PubMed55 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRSPO1
EVEXRSPO1
GoPubMedRSPO1
iHOPRSPO1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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