GeneBe

TOPORS

protein-coding

TOP1 binding arginine/serine rich protein, E3 ubiquitin ligase, the group of Ring finger proteins

Gene summary

This gene encodes a nuclear protein which is serine and arginine rich, and contains a RING-type zinc finger domain. It is highly expressed in the testis, and functions as an ubiquitin-protein E3 ligase. Mutations in this gene are associated with retinitis pigmentosa type 31. Alternatively spliced transcript variants, encoding different isoforms, have been observed for this locus. [provided by RefSeq, Sep 2010]

Previous symbols:
  • RP31

MANE transcript

NM_005802.5

Inheritance

AR, AD

ClinVar variants

P:39U:468B:235

Top phenotype

Retitinis pigmentosa 31

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr9:32,540,544-32,552,586

External References & Databases

Ensembl (ENSG00000197579)NCBI Gene (10210)OMIM (609507)HGNC:21653GenCCUniProt (Q9NS56)AlphaFoldClinVar (TOPORS)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~12.0 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia

retinitis pigmentosa 31DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012367

Submitter: G2P

retinitis pigmentosa 31STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012367

Submitter: PanelApp Australia

TOPORS-related retinopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0700233

Submitter: ClinGen

*TOPORS* was first reported in relation to autosomal dominant retinitis pigmentosa (adRP) in 2005 (by Papaioannou et al., PMID: 16189705). Retinitis pigmentosa is a progressive disease, with common symptoms of night blindness, tunnel vision and reduced visual acuity. It is a clinically and genetically heterogenous, with more than 250 genes reported to be involved in different RP modes of inheritance. Variants in the *TOPORS* gene are thought to cause defects in the structure of photoreceptor connecting cilium, leading to photoreceptor degeneration and RP. Curiously, although *TOPORS* is ubiquitously expressed, variants in *TOPORS* are only known to cause adRP. Ten variants (three nonsense, five frameshift, and two missense) that have been reported in sixteen probands in eleven publications (PMIDs: 17924349, 28041643, 18509552, 24938718, 31736247, 28224992, 19183411, 19373681, 28453362, 33576794, 33691693) are included in this curation. Additionally, two families were scored in which *TOPORS* mutations were found to co-segregate with adRP for a combined LOD score of 8.81 (PMIDs: 18509552 and 19183411). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be haploinsufficiency. This gene-disease association is also supported by expression studies showing that *TOPORS* is expressed in retina tissue (PMIDs: 21159800, 28940711, 17924349). *TOPORS* also performs a similar biochemical function to the *RPGR* protein, which is definitively associated with X-linked retinitis pigmentosa. Finally, Chakarova et al. provide evidence for the pathogenicity of *TOPORS* mutations in a zebrafish model (PMID: 21159800). In summary, *TOPORS* is definitively associated with TOPORS-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on April 6, 2023 (SOP Version 9).

retinitis pigmentosa 31STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012367

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Clinical Genomic Database (CGD)

Retitinis pigmentosa 31AD

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16189705; 17924349; 18509552; 19183411Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TOPORS variants in ClinVar

21 Conditions Cataloged
not providedTotal: 643
Inborn genetic diseasesTotal: 126
not specifiedTotal: 117
TOPORS-related disorderTotal: 90
Retinitis pigmentosaTotal: 54
Retinal dystrophyTotal: 45
Retinitis pigmentosa 31Total: 29
Optic atrophyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005802.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
8
clinvar
171
clinvar
4
clinvar
 183
missense
2
clinvar
441
clinvar
59
clinvar
1
clinvar
 503
nonsense
4
clinvar
8
clinvar
3
clinvar
 15
start loss
2
clinvar
 2
frameshift
5
clinvar
20
clinvar
9
clinvar
 34
splice donor/acceptor (+/-2bp)
5
clinvar
 5
Total9304682305742

Highest pathogenic variant AF is 0.00001923053

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_005802.5RefSeqNP_005793.23MANE Select
ENST00000360538.7EnsemblENSP00000353735.23MANE Select
NM_001195622.2RefSeqNP_001182551.12Standard
ENST00000379858.1EnsemblENSP00000369187.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
toporsaDanio rerio

Structure: photoreceptor outer segment layer

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • protein polyubiquitination
  • transcription, DNA-templated
  • ubiquitin-dependent protein catabolic process
  • protein monoubiquitination
  • cellular response to DNA damage stimulus

Molecular Function

  • DNA binding
  • antigen binding
  • ubiquitin-protein transferase activity
  • protein binding
  • SUMO transferase activity

Cellular Component

  • ubiquitin ligase complex
  • spindle pole
  • gamma-tubulin complex
  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000360538
Coding exons
3
Length
12010
Individuals with no LoFs
125729
Homozygous LoFs
0
Heterozygous LoFs
19
Defined
125748
p
0.0000756
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.054865560.8750.00002986832
Missense (PolyPhen)101154.130.65531831
Synonymous-1.212232011.110.00001012047
Loss of Function5.09437.80.1060.00000264475

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish00.0absent
European (Non-Finnish)0.0000710.000070rare
South Asian0.000130.00013rare
Other0.000340.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase. Probable tumor suppressor involved in cell growth, cell proliferation and apoptosis that regulates p53/TP53 stability through ubiquitin-dependent degradation. May regulate chromatin modification through sumoylation of several chromatin modification-associated proteins. May be involved in DNA damage- induced cell death through IKBKE sumoylation. {ECO:0000269|PubMed:15247280, ECO:0000269|PubMed:15735665, ECO:0000269|PubMed:16122737, ECO:0000269|PubMed:17803295, ECO:0000269|PubMed:18077445, ECO:0000269|PubMed:19473992, ECO:0000269|PubMed:20188669}.;
Disease
DISEASE: Retinitis pigmentosa 31 (RP31) [MIM:609923]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:17924349}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.125

Intolerance Scores

LoFtool
0.173
RVIS EVS
0.03
RVIS percentile EVS
55.81

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.884

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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