NDP
protein-codingnorrin cystine knot growth factor NDP, the group of Receptor ligands
Gene summary
This gene encodes a secreted protein with a cystein-knot motif that activates the Wnt/beta-catenin pathway. The protein forms disulfide-linked oligomers in the extracellular matrix. Mutations in this gene result in Norrie disease and X-linked exudative vitreoretinopathy. [provided by RefSeq, Feb 2009]
- EVR2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~24.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010588
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010588
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019516
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019631
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010691
Submitter: ClinGen
The association between the NDP gene and Norrie disease (ND) is well-characterized, with over 100 unique variants described in HGMD, including nonsense, missense, splice, and deletion variants reported in dozens of publications. Familial segregation data is readily available; only a subset are included in this curation. Experimental evidence includes several mouse models of disease and protein interaction studies highlighting NDP's role in FZD4 interaction and Wnt signaling. NOTE: In terms of X-linked intellectual disability, ND is incompletely penetrant. The main phenotype associated with ND is abnormal vascular development within the eye, and only ~50% of patients with ND exhibit intellectual disability.
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NDP variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000266.4. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 27 | 28 | |||
| missense | 21 | 33 | 60 | 7 | 121 | |
| nonsense | 10 | 6 | 1 | 17 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 9 | 9 | 18 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 1 | 4 | ||
| Total | 43 | 50 | 63 | 34 | 0 | 190 |
Highest pathogenic variant AF is 9.332032e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000257.1 | 2 | MANE Select | |
| Ensembl | ENSP00000495972.1 | 2 | MANE Select | |
| Ensembl | ENSP00000495811.1 | 2 | Standard | |
| Ensembl | ENSP00000495811.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ndp | Danio rerio | Structure: ocular blood vessel Quality: decreased area abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- GPCR signaling-G alpha q
- GPCR signaling-cholera toxin
- GPCR signaling-pertussis toxin
- GPCR signaling-G alpha s Epac and ERK
- GPCR signaling-G alpha s PKA and ERK
Biological Process
- placenta development
- vacuole organization
- signal transduction
- cell-cell signaling
- nervous system development
Molecular Function
- frizzled binding
- cytokine activity
- protein binding
- growth factor activity
- protein homodimerization activity
Cellular Component
- extracellular space
- cell surface
- collagen-containing extracellular matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000378062
- Coding exons
- 2
- Length
- 24729
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.969 | 31 | 50.4 | 0.616 | 0.00000330 | 855 |
| Missense (PolyPhen) | 5 | 22.881 | 0.21853 | 392 | ||
| Synonymous | -0.757 | 26 | 21.5 | 1.21 | 0.00000144 | 272 |
| Loss of Function | 1.71 | 0 | 3.39 | 0.00 | 2.12e-7 | 55 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor. Plays a central role in retinal vascularization by acting as a ligand for FZD4 that signals via stabilizing beta-catenin (CTNNB1) and activating LEF/TCF-mediated transcriptional programs. Acts in concert with TSPAN12 to activate FZD4 independently of the Wnt-dependent activation of FZD4, suggesting the existence of a Wnt-independent signaling that also promote accumulation the beta-catenin (CTNNB1). May be involved in a pathway that regulates neural cell differentiation and proliferation. Possible role in neuroectodermal cell-cell interaction.;
- Disease
- DISEASE: Vitreoretinopathy, exudative 2 (EVR2) [MIM:305390]: A disorder of the retinal vasculature characterized by an abrupt cessation of growth of peripheral capillaries, leading to an avascular peripheral retina. This may lead to compensatory retinal neovascularization, which is thought to be induced by hypoxia from the initial avascular insult. New vessels are prone to leakage and rupture causing exudates and bleeding, followed by scarring, retinal detachment and blindness. Clinical features can be highly variable, even within the same family. Patients with mild forms of the disease are asymptomatic, and their only disease related abnormality is an arc of avascular retina in the extreme temporal periphery. {ECO:0000269|PubMed:16163268, ECO:0000269|PubMed:16970763, ECO:0000269|PubMed:17296899, ECO:0000269|PubMed:17325173, ECO:0000269|PubMed:8252044, ECO:0000269|PubMed:8946107, ECO:0000269|PubMed:9143917}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.479
Intolerance Scores
- RVIS EVS
- 0.28
- RVIS percentile EVS
- 70.87
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.234
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |