CRX
protein-codingcone-rod homeobox, the group of PRD class homeoboxes and pseudogenes
Gene summary
The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]
- CORD2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013449
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018998
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015993
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0020242
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0007362
Submitter: ClinGen
General Description: The CRX gene was first reported in relation to retinal disease in 1994 (Evans et al., 1994 PMID 8162077). Missense variants in the CRX gene, which encodes a homeobox domain transcription factor critical for photoreceptor development (PMID 9390562), were then found in multiple families diagnosed with cone-rod dystrophy, characterized by abnormal color vision (Freund et al., 1997, PMID 9390563 and Swain et al., 1997, PMID 9427255). CRX-related retinal dystrophy is characterized by early adult onset of cone-rod dystrophy. Additionally, multiple cases of CRX-related early onset retinal dystrophy (Leber Congenital Amaurosis; PMIDs: 11748859, 20513135, 24265693 and 9931337) have been described. CRX-related disease is most commonly inherited in an autosomal dominant pattern; however, biallelic pathogenic CRX variants have also been described (PMIDs 20513135, 991337). Broader phenotypes including retinitis pigmentosa (PMID 11139241), rod-cone dystrophy (PMID 33910785), pigmented paravenous retinochoroidal atrophy (PMID 32927963) and adult onset macular dystrophy (PMID 25270190); age of onset and severity of disease appears to be variable. Because most cases with different diagnoses exhibit a dominant mode of inheritance and share overlapping phenotypes consistent with a single spectrum of disease, and consistent with criteria outlined by the ClinGen Lumping and Splitting Working Group, these cases have been lumped into a single disease entity, CRX-related retinopathy. Summary of Case Level Data (11.5 points): 8 variants suspected disease-causing variants (4 predicted null and 4 missense or other variants) that have been reported in 8 probands in 6 publications (PMIDs: 9792858, 9427255, 20513135, 11748859, 9931337, 9390563) were scored in this curation. De novo and inherited null variants in families from multiple countries were included in the curation (PMID 11748859 and 20513135). However, missense mutations have also been associated with CRX-related disease in multiple publications (PMIDs: 9390563, 9427255, 9931337, 20513135). More evidence is available in the literature. Mechanism for Disease: The mechanism of pathogenicity appears to be variable, as multiple nonsense and missense variants and full exon or whole gene deletions are reported to be disease causing (PMID: 33910785, 24888636). Missense variants in the homeodomain apparently impact DNA binding variably (PMID 36778408), while truncating variants and experimental data suggest that haploinsufficiency underlies some cases (PMIDs 38049871, 30557390, 27032803). A number of whole gene deletions have also been described to be correlated with a milder, later-onset retinopathy, mimicking age-related macular degeneration. Emerging research may elucidate a more well defined genotype-phenotype correlation, but to date, a genotype-phenotype correlation is under investigation. Experimental Evidence: 6 POINTS While the CRX gene product has been extensively studied in murine, cell-culture and human organoid models (PMID 38049871, 35484285, 34653402). Consistent with a critical role in photoreceptor health, CRX is expressed in photoreceptors (PMIDs 19686387, 12949469) and is essential for photoreceptor development (PMID 38049871). Summary Statement: In summary, CRX is definitively associated with retinal dystrophy; while pathogenic variants are largely associated with autosomal dominant cone-rod dystrophy, other CRX-related phenotypes have also been described, including recessive disease, early onset retinal dystrophy and later onset macular dystrophy. Though the disease mechanism is likely complex and determined by the properties of a specific variant, the association with retinal dystrophy has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0013449
Submitter: G2P
Inheritance Pattern: SD
Disease ID:MONDO:0013449
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0013449
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013449
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0019200
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007362
Submitter: Ambry Genetics
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 CRX variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000554.6. 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 | 5 | 85 | 1 | 91 | ||
| missense | 4 | 24 | 171 | 20 | 1 | 220 |
| nonsense | 10 | 15 | 2 | 27 | ||
| start loss | 1 | 1 | ||||
| frameshift | 63 | 39 | 12 | 114 | ||
| splice donor/acceptor (+/-2bp) | 3 | 3 | 3 | 9 | ||
| Total | 80 | 81 | 194 | 105 | 2 | 462 |
Highest pathogenic variant AF is 0.000016108308
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000545.1 | 3 | MANE Select | |
| Ensembl | ENSP00000221996.5 | 3 | MANE Select | |
| Ensembl | ENSP00000457808.2 | 2 | Standard | |
| Ensembl | ENSP00000478106.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| otx5 | Danio rerio | Structure: pineal complex Quality: process quality abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- regulation of transcription, DNA-templated
- visual perception
- circadian rhythm
- animal organ morphogenesis
- positive regulation of transcription by RNA polymerase II
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000221996
- Coding exons
- 3
- Length
- 23885
- Individuals with no LoFs
- 125741
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125746
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.329 | 171 | 184 | 0.932 | 0.0000112 | 1900 |
| Missense (PolyPhen) | 52 | 60.794 | 0.85534 | 693 | ||
| Synonymous | -0.690 | 92 | 84.0 | 1.10 | 0.00000557 | 662 |
| Loss of Function | 2.43 | 2 | 10.5 | 0.190 | 5.36e-7 | 115 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000064 | 0.000062 | rare |
| 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) | 0.000018 | 0.000018 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that binds and transactivates the sequence 5'-TAATC[CA]-3' which is found upstream of several photoreceptor-specific genes, including the opsin genes. Acts synergistically with other transcription factors, such as NRL, RORB and RAX, to regulate photoreceptor cell-specific gene transcription. Essential for the maintenance of mammalian photoreceptors. {ECO:0000269|PubMed:10625658}.;
- Disease
- DISEASE: Cone-rod dystrophy 2 (CORD2) [MIM:120970]: An inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. {ECO:0000269|PubMed:10887186, ECO:0000269|PubMed:9390563, ECO:0000269|PubMed:9427255, ECO:0000269|PubMed:9792858}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Retinitis pigmentosa (RP) [MIM:268000]: 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:11139241, ECO:0000269|PubMed:9427255, ECO:0000269|PubMed:9792858}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.338
Intolerance Scores
- LoFtool
- 0.114
- RVIS EVS
- 0.08
- RVIS percentile EVS
- 60.31
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.775
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |