Protan Color Vision Deficiency

Mendelian MONDO:0010565 Pathograph 12 Show in embeddings browser Color vision disorder Congenital stationary cone dysfunction

X-linked red-green color vision deficiency of the protan type, in which the long-wavelength-sensitive (L) cone contribution to vision is absent. It covers the dichromatic form, protanopia, and the anomalous trichromatic form, protanomaly. The X-chromosome opsin gene array at Xq28 normally carries one OPN1LW (L-opsin) gene followed by one or more OPN1MW (M-opsin) genes, and only the first two genes are expressed. Unequal homologous recombination between the highly similar genes in female meiosis produces arrays that lack OPN1LW or replace it with a 5'L-3'M hybrid gene whose product absorbs in the M range, so every expressed gene encodes an M-class pigment. Cones that would have been L cones contain M-class pigment instead. When the expressed pigments are spectrally identical the result is protanopia; when they differ by a few nanometres the result is protanomaly, whose severity scales with that spectral separation. Affected males have reduced red-green discrimination and reduced sensitivity to long-wavelength (red) light. No disease-modifying treatment exists; gene addition of L opsin restored trichromatic behaviour in adult dichromatic squirrel monkeys but has not been tested in humans.

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1
Inheritance
5
Pathophys.
3
Phenotypes
12
Pathograph
1
Genes
4
Medical Actions
2
Subtypes
3
Differentials
1
Models
1
Deep Research
👪

Inheritance

1
X-linked recessive HP:0001419
The L and M opsin genes lie on the X chromosome at Xq28, so the defect is expressed in hemizygous males. Heterozygous protan carriers tend to carry fewer L-opsin genes than non-carriers and can be identified molecularly.
X-linked recessive inheritance
Show evidence (3 references)
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"As predicted by inheritance patterns of red-green (Waaler, 1968) and blue-yellow (Kalmus, 1955) color vision deficiencies, the genes for human long-wavelength (L) and middle-wavelength (M) cone opsins were localized to the X-chromosome at Xq28"
Places the L and M opsin genes on the X chromosome, the basis of X-linked transmission of protan defects.
PMID:22472762 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Large random population surveys show that the prevalence of deficiency in European Caucasians is about 8% in men and about 0.4% in women"
The roughly twentyfold male excess of red-green deficiency is the pattern expected of an X-linked recessive trait.
PMID:9893850 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"We describe a molecular genetic method to identify protan carriers that involves characterizing the genes that occur in the most upstream position in each of the X-chromosome photopigment gene arrays."
Heterozygous females carrying a protan array are a recognised carrier state, as expected for an X-linked recessive trait.
◆

Subtypes

2
Protanopia (protan dichromacy)
OPN1LW hgnc:9936 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in OPN1LW (hgnc:9936). hgnc:9936 is a gene from the HUGO Gene Nomenclature Committee.
Dichromatic form. The X-chromosome array has a single gene encoding an M-class pigment (OPN1LW deleted, or replaced by a 5'L-3'M hybrid encoding an M-class pigment), or several genes whose first two encode M-class pigments with identical spectra. No functional L-cone signal is present.
Show evidence (2 references)
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"X-chromosome opsin gene arrays underlying the dichromatic form, protanopia, either have a single opsin gene that encodes an M pigment, or have multiple genes in which the first two encode opsins that produce M pigments that are identical in spectra"
Defines the genotypes underlying protanopia.
PMID:33544131 SUPPORT PRIMARY RESULT Human Clinical
"Both protanopes (subjects S9 and S10) carried a single M gene and no L gene."
Genotyped protanopes in a cone-resolved imaging study had a single M gene and no L gene.
Protanomaly (protanomalous trichromacy)
OPN1LW hgnc:9936 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in OPN1LW (hgnc:9936). hgnc:9936 is a gene from the HUGO Gene Nomenclature Committee.
Anomalous trichromatic form. The array lacks a normal L gene and its first two genes encode two M-class pigments that differ slightly in spectral peak, for example a 5'L-3'M hybrid together with a normal M gene. The two M-class cone populations support a weak red-green signal. Because M-class pigments can be separated by only a few nanometres, protanomalous observers as a group discriminate colours somewhat worse than deuteranomalous observers.
Show evidence (2 references)
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"The anomalous trichromatic form, protanomaly, is associated with opsin gene arrays in which the first two genes encode opsins that produce M pigments that differ in spectra."
Defines the genotypes underlying protanomaly.
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"This can explain why, as a group, protanomalous observers have somewhat poorer color discrimination than deuteranomalous observers."
Relates the narrow spectral separation available within the M class to the severity of protanomaly.
⚙

Pathophysiology

5
Unequal Recombination in the Xq28 L/M Opsin Gene Array
The L and M pigments share 96% amino acid identity and their genes sit in a head-to-tail tandem array. Misalignment of the arrays in female meiosis followed by an intergenic or intragenic crossover (unequal homologous recombination, with gene conversion as a further route) yields arrays that have lost OPN1LW or carry a 5'L-3'M hybrid gene in its place. This germline rearrangement is the initiating lesion for most protan defects; rarer routes include inactivating OPN1LW exon 3 haplotypes and truncating variants.
OPN1LW hgnc:9936 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves OPN1LW (hgnc:9936). hgnc:9936 is a gene from the HUGO Gene Nomenclature Committee. OPN1MW hgnc:4206 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves OPN1MW (hgnc:4206). hgnc:4206 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Absence of an Expressed L-Class Opsin Gene The rearranged array no longer has a gene encoding an L-class pigment in either of the two expressed positions.
Show evidence (6 references)
PMID:3485310 SUPPORT PRIMARY RESULT Human Clinical
"The hypothesis that red-green "color blindness" is caused by alterations in the genes encoding red and green visual pigments has been tested and shown to be correct."
Founding genotype study of red-green colour vision deficiency.
PMID:3485310 SUPPORT PRIMARY RESULT Human Clinical
"The observed genotypes appear to result from unequal recombination or gene conversion (or both)."
Identifies unequal recombination and gene conversion as the mutational mechanism in affected males.
PMID:2937147 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"The red and green pigments show 96 percent mutual identity but only 43 percent identity with the blue pigment."
The near-identity of L and M opsin sequences is what predisposes the array to misalignment.
+ 3 more references
Absence of an Expressed L-Class Opsin Gene
Only the first two genes of the X-linked array are expressed in the retina. In protans neither expressed gene encodes an L-class pigment: the expressed genes are normal OPN1MW copies or 5'L-3'M hybrids. Spectral tuning is dominated by exon 5, which accounts for a shift of roughly 15 to 25 nm, so a hybrid carrying M-type exon 5 encodes an M-class pigment whatever its 5' exons.
OPN1LW hgnc:9936 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves OPN1LW (hgnc:9936). hgnc:9936 is a gene from the HUGO Gene Nomenclature Committee.
long-wavelength G protein-coupled photoreceptor activity GO:0008020 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal long-wavelength G protein-coupled photoreceptor activity, annotated with G protein-coupled photoreceptor activity (GO:0008020). GO:0008020 is a molecular function from the Gene Ontology.
Animal models
Dichromatic male squirrel monkey lacking L opsin Squirrel monkey (Saimiri sciureus) recapitulates Naturally L-opsin-deficient dichromatic primate with S and M-class cones only.
Downstream
L Cones Filled with M-Class Photopigment Cones that would express L opsin instead express the M-class pigment encoded by the remaining genes.
Show evidence (5 references)
PMID:15518188 SUPPORT REVIEW SYNTHESIS Other
"Analysis of the gene order in arrays of normal and deutan subjects indicates that only the two most proximal genes of the array contribute to the color-vision phenotype."
Only the two most upstream genes determine the phenotype.
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"Protan defects are characterized by the absence of an L cone contribution to vision."
Defines the protan defect as absence of L-cone contribution.
PMID:1411542 SUPPORT PRIMARY RESULT In Vitro
"Amino acids encoded by exons 2, 3, 4, and 5 produce spectral shifts at the wavelength of maximal absorbance of 0 to 4, 0 to 4, 3 to 4, and 15 to 21 nanometers, respectively"
Expressed hybrid pigments show that exon 5 carries most of the L versus M spectral difference, explaining why 5'L-3'M hybrids encode M-class pigments.
+ 2 more references
L Cones Filled with M-Class Photopigment
Protan retinas contain M-class and S cones but no functional L cones. Fundus reflectometry and electroretinography in X-linked dichromats fit a replacement model, in which the total number of cones is unchanged and the missing cone class is replaced by the remaining one. Cone-resolved optoretinography shows that the remaining M and S cones respond normally.
L cone cell CL:0003048 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves L cone cell (CL:0003048). CL:0003048 is a cell type from the Cell Ontology. M cone cell CL:0003049 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves M cone cell (CL:0003049). CL:0003049 is a cell type from the Cell Ontology.
detection of long-wavelength light in visual perception GO:0050908 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased detection of long-wavelength light in visual perception, annotated with detection of light stimulus involved in visual perception (GO:0050908). GO:0050908 is a biological process from the Gene Ontology.
Downstream
Loss of L-versus-M Cone Opponent Signal Without a long-wavelength cone class there is no, or only a weak, difference signal for red-green opponent processing.
Reduced Long-Wavelength Luminous Sensitivity M-class pigment absorbs poorly at long wavelengths, so sensitivity to red light falls.
Show evidence (3 references)
PMID:33544131 SUPPORT PRIMARY RESULT Human Clinical
"(3) protanopes are missing L cones but are normal otherwise"
Adaptive-optics optoretinography finds no functional L cones in protanopes and normal M and S cone responses.
PMID:8730604 SUPPORT PRIMARY RESULT Human Clinical
"A replacement model, i.e. one where the total number of cones remains unchanged and all cones are filled with a single type of pigment, was found to fit our data best."
Foveal reflectometry in protanopes and deuteranopes supports pigment replacement rather than cone loss.
PMID:10102289 SUPPORT PRIMARY RESULT Human Clinical
"The data strongly suggest that the missing cone type in dichromats is replaced by the remaining cone type."
Cone-isolating ERG in X-linked dichromats supports replacement of the missing cone class.
Loss of L-versus-M Cone Opponent Signal
Red-green colour discrimination depends on comparing signals from two cone classes in the middle-to-long wavelength range. When both expressed pigments are spectrally identical (protanopia) the comparison is impossible and vision is dichromatic; when they differ by a few nanometres (protanomaly) a weak signal remains. Severity is inversely related to the spectral separation between the two expressed pigments. Left unbound to GO: the nearest process term, GO:0007601 visual perception, is broader than red-green opponent comparison and an OLS label/synonym search of GO for "color vision", "colour vision", "color discrimination" and "color perception" returned no terms.
Animal models
Dichromatic male squirrel monkey lacking L opsin Squirrel monkey (Saimiri sciureus) rescues L-opsin gene addition in adult animals produced trichromatic behaviour on a colour discrimination task.
Downstream
Protanopia Spectrally identical expressed pigments leave no red-green opponent signal.
Protanomaly Slightly different M-class pigments leave a reduced red-green signal.
Red-Green Dyschromatopsia Both forms share impaired discrimination of hues along the red-green axis.
Show evidence (3 references)
PMID:15811001 SUPPORT REVIEW SYNTHESIS Other
"The severity of red-green color vision defects is inversely proportional to the difference between the wavelengths of maximal absorption of the photopigments encoded by the first two genes of the array."
Links severity to the spectral separation of the two expressed pigments.
PMID:34440353 SUPPORT REVIEW SYNTHESIS Other
"Males have protanopia if the first and second genes specify M cone photopigments that are identical in their wavelengths of peak sensitivity or if they have a single gene array that encodes an M pigment"
Identical M-class pigments give dichromacy.
PMID:34440353 SUPPORT REVIEW SYNTHESIS Other
"Males have protanomaly if the first and second genes encode M cone photopigments that differ in their wavelengths of peak sensitivity"
Two spectrally different M-class pigments give anomalous trichromacy.
Reduced Long-Wavelength Luminous Sensitivity
Because the remaining cones carry M-class pigment, protans are relatively insensitive to long-wavelength light; red lights look dim and are seen at a shorter range. In laboratory spectral sensitivity data every protan had lower red-light sensitivity than the least sensitive colour-normal observer, which bears on recognition of red signal lights and on occupational and driving standards.
Show evidence (3 references)
PMID:12135418 SUPPORT PRIMARY RESULT Human Clinical
"A laboratory study of the spectral sensitivity of protan and colour normal subjects that largely removes these sources' variability shows that all protans have a sensitivity to red light that is less than that of the least sensitive colour normal."
Re-analysis of spectral sensitivity data shows uniformly reduced red-light sensitivity in protans.
PMID:12135418 SUPPORT PRIMARY RESULT Human Clinical
"Field trial data show that protans have a very reduced visual range for red signals compared to colour normal observers"
Field trials show a reduced range at which red signals are seen.
PMID:14702998 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"response times of deuteranopes and protanopes were 53% and 35% longer than those of color normals"
Protanopes identified simulated red traffic lights more slowly than colour normals. The same study found deuteranopes slower still, so slowed signal recognition is not specific to the protan red-light deficit.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Protan Color Vision Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

3
Protanopia Ophthalmologic HP:0011522 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protanopia (HP:0011522). HP:0011522 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33544131 SUPPORT PRIMARY RESULT Human Clinical
"(3) protanopes are missing L cones but are normal otherwise"
Protanopia corresponds to absence of functional L cones.
PMID:27622081 SUPPORT PRIMARY RESULT Human Clinical
"Five of them had arrays comprised solely of multiple identical M genes, making them obligate protanopes."
Genotype-defined protanopes in a large screened cohort.
Protanomaly Ophthalmologic HP:0200018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protanomaly (HP:0200018). HP:0200018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27622081 SUPPORT PRIMARY RESULT Human Clinical
"another 5 had M opsins with differences in both spectral tuning sites and in exon 2, making them, at best, protanomalous."
Males lacking L genes but with spectrally different M-class genes have protanomaly.
Red-Green Dyschromatopsia Ophthalmologic HP:0000642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Red-green dyschromatopsia (HP:0000642). HP:0000642 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:19759534 SUPPORT BACKGROUND Human Clinical
"individuals with L but no M cones (termed deuteranopes) have a relatively enhanced sensitivity to red light but they are still as dichromatic as individuals with M but no L cones (protanopes), in that they are unable to distinguish particular “colours” from grey."
Describes the colour-confusion deficit of human protanopes; the statement is background in a primate gene-therapy study.
PMID:35113505 SUPPORT BACKGROUND Human Clinical
"Congenital colour vision deficiencies are caused by inherited photopigment abnormalities (Nathans et al. 1986; Nathans et al. 1986) and impair the affected individual’s ability to discriminate colours."
States the discrimination deficit caused by inherited photopigment abnormalities.
🧬

Genetic Associations

1
OPN1LW (Genetic Mutation)
Gene: OPN1LW hgnc:9936 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is OPN1LW (hgnc:9936). hgnc:9936 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
X-linked recessive
Show evidence (3 references)
PMID:21167193 SUPPORT REVIEW SYNTHESIS Other
"A male with a normal S-pigment and one X-chomosome pigment gene encoding an M pigment is an obligate protanope."
Loss of all L-class genes from the X-linked array is sufficient for protanopia.
PMID:27622081 SUPPORT PRIMARY RESULT Human Clinical
"Protan and deutan deficiencies were classified correctly in all subjects identified by MassArray as having red-green defects."
Opsin-array genotype predicts protan type in a large cohort.
PMID:37097228 SUPPORT PRIMARY RESULT Human Clinical
"Of the 68 families, 42 affected male patients (31 families) with the first class of variants (LVAVA or LIVVA in OPN1LW) had eoHM alone, whereas 37 male patients with the latter 3 classes had eoHM with protanopia."
Complete loss of L pigment from exon 3 haplotypes or truncations also produces protanopia, but together with early-onset high myopia; this allelic route is outside the scope of the uncomplicated protan defect.
💊

Medical Actions

4
Colour-enhancing filter glasses
Action: colour-enhancing spectaclesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is colour-enhancing spectacles, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Device
Commercial notch-filter (EnChroma) and other colour-enhancing (VINO) spectacles alter the relative stimulation of the remaining cones. They do not restore the missing L cone class. A controlled study found no overall improvement on clinical colour tests with EnChroma lenses; another found a functionally meaningful change on the CAD test only with VINO glasses. Tinted ChromaGen lenses reduced plate-test errors without reducing severity, and no protanope passed any test with them.
Target Phenotypes: Red-green dyschromatopsia HP:0000642 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Red-green dyschromatopsia (HP:0000642). HP:0000642 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:36242261 REFUTE PRIMARY RESULT Human Clinical
"Comparing the performance of 86 well-categorized CVD observers and 24 controls on two clinical tests we report no overall improvement when EnChroma lenses were worn."
Controlled study finding no overall benefit of EnChroma lenses on clinical colour tests in red-green deficient observers.
PMID:36242206 SUPPORT PRIMARY RESULT Human Clinical
"Although there was a statistically significant effect of both glasses, only that of VINO could be considered functionally meaningful."
In red-green deficient individuals with characterised opsin arrays, only VINO glasses gave a functionally meaningful change in CAD thresholds.
PMID:36189411 REFUTE REVIEW SYNTHESIS Other
"This review concludes that commercially available color vision devices, such as EnChroma Glasses, Chromagen filters, and EnChroma Cx-14 do not provide clinically significant evidence that subjective color perception has improved."
Systematic review finding no clinically significant benefit of colour vision devices.
+ 1 more reference
Occupational and driving counselling
Action: occupational counsellingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is occupational counselling, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Early identification lets affected children and their teachers plan for colour-critical tasks and careers. Because protans see red signal lights poorly, some jurisdictions and occupations restrict protans from colour-critical roles.
Show evidence (3 references)
PMID:32285548 SUPPORT BACKGROUND Human Clinical
"Early screening is essential to counsel schoolchildren with congenital colour vision deficiency (CVD) in determining their future career path and to advise teachers of the impact of CVD on classroom difficulties."
Recommends screening and counselling for career planning.
PMID:12135418 SUPPORT BACKGROUND Human Clinical
"Protans are precluded from holding a commercial driver's licence in Australia because they have a substantially reduced ability to see red lights and have more road accidents involving signal lights."
Documents a licensing standard based on the protan red-light deficit.
PMID:30443703 SUPPORT REVIEW SYNTHESIS Other
"people with some degree of color vision loss face challenges in different aspects of their daily life, especially in their work activities."
Integrative review identifying work activities as the most affected domain, the rationale for occupational counselling. Not protan-specific.
Genetic counselling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counselling explains X-linked recessive transmission; carrier status in female relatives can be determined from the opsin array.
Show evidence (1 reference)
PMID:27622081 SUPPORT PRIMARY RESULT Human Clinical
"it provides information to patients about the underlying pathobiology of their disease."
Opsin genotyping supplies information for counselling.
L-opsin gene addition (preclinical)
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
Subretinal AAV delivery of a human L-opsin gene to adult dichromatic male squirrel monkeys, which lack an L opsin gene, produced a third cone submosaic and trichromatic colour vision behaviour. No human trial for protan defects exists.
Mechanism Target:
RESTORES Absence of an Expressed L-Class Opsin Gene — Supplies an L-class opsin to a subset of cones in an animal model; human efficacy is untested.
Show evidence (1 reference)
PMID:19759534 SUPPORT PRIMARY RESULT Model Organism
"here we show that the addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour."
Gene addition of L opsin restored trichromatic behaviour in adult primates.
Show evidence (1 reference)
PMID:19759534 SUPPORT PRIMARY RESULT Model Organism
"Gene therapy was performed on adult squirrel monkeys (Saimiri sciureus) that were missing the L opsin gene."
The treated animals lacked L opsin, the protan genotype.
🔬

Diagnosis

3
Pseudoisochromatic plate screening
Ishihara and Hardy-Rand-Rittler plates are the usual screening tests; HRR diagnostic plates classify protan versus deutan type and grade severity. Plates miss a substantial fraction of genetically defined colour-deficient males.
colour vision testing NCIT:C156778 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35113505 SUPPORT PRIMARY RESULT Human Clinical
"MassArray identified twice as many colour-deficient males as identified from PIC tests alone."
Plate tests alone under-detect colour deficiency compared with genotyping.
Anomaloscopy (Rayleigh match)
The Nagel anomaloscope classifies X-linked red-green defects by the red-green mixture matched to a yellow primary, separating protanopia from protanomaly and protan from deutan defects.
anomaloscopy NCIT:C156778 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:15290149 SUPPORT BACKGROUND Human Clinical
"The Nagel anomaloscope Model I is the definitive clinical instrument for classifying phenotypic variations in X-linked color-vision disorders."
Anomaloscopy is the reference test for classifying protan type and form.
Opsin gene array analysis
Analysis of the OPN1LW/OPN1MW array (gene copy number, gene order and spectral-tuning sites) identifies the protan genotype, estimates severity and detects carrier females.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:27622081 SUPPORT PRIMARY RESULT Human Clinical
"The MassArray assay provides genetic information that can be useful in the diagnosis of inherited color vision deficiency including presence versus absence, type, and severity"
Genotyping gives type and severity of the defect.
PMID:9893850 SUPPORT PRIMARY RESULT Human Clinical
"We describe a molecular genetic method to identify protan carriers that involves characterizing the genes that occur in the most upstream position in each of the X-chromosome photopigment gene arrays."
Molecular analysis of the first array gene detects protan carriers.
📊

Prevalence

4
Children and adolescents worldwide, males (pooled meta-analysis of 56 studies, 1932-2022)
Point Prevalence 1540.0 per 100,000 (1300.0–1820.0) >1 in 1,000
Pooled protan prevalence in males 1.54% (95% CI 1.30-1.82%), from screening studies that classified the defect type; includes protanopia and protanomaly.
Show evidence (1 reference)
PMID:40769301 SUPPORT PRIMARY RESULT Human Clinical
"followed by protan (male, 1.54% [95% CI, 1.30%-1.82%]; female, 0.30% [95% CI, 0.21%-0.43%])"
Meta-analysis estimate of protan prevalence in males.
Children and adolescents worldwide, females (pooled meta-analysis of 56 studies, 1932-2022)
Point Prevalence 300.0 per 100,000 (210.0–430.0) >1 in 1,000
Pooled protan prevalence in females 0.30% (95% CI 0.21-0.43%). This is a screening-test classification, not a genotype count, and is higher than the square of the male frequency would predict for an X-linked recessive trait.
Show evidence (1 reference)
PMID:40769301 SUPPORT PRIMARY RESULT Human Clinical
"followed by protan (male, 1.54% [95% CI, 1.30%-1.82%]; female, 0.30% [95% CI, 0.21%-0.43%])"
Meta-analysis estimate of protan prevalence in females.
Schoolchildren, Republic of Ireland, boys
Point Prevalence 1700.0 per 100,000 >1 in 1,000
Protan defects in 1.7% of 882 boys tested with HRR plates; deutan 4.8%.
Show evidence (1 reference)
PMID:32285548 SUPPORT PRIMARY RESULT Human Clinical
"As expected, deutan (boys 4.8 per cent, girls 0.8 per cent) was the most common type of CVD, followed by protan (boys 1.7 per cent, girls 0.1 per cent)"
Population school survey giving the protan frequency in boys.
Adults aged 19-49 years, South Korea (KNHANES 2013), both sexes
Point Prevalence 400.0 per 100,000 >1 in 1,000
Weighted protan prevalence 0.4% across both sexes on HRR screening; deutan 2.5%.
Show evidence (1 reference)
PMID:31688694 SUPPORT PRIMARY RESULT Human Clinical
"Among all participants, deutan deficiency (2.5%) had a higher prevalence than did protan deficiency (0.4%)."
Nationally representative survey estimate of protan deficiency.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Protan Color Vision Deficiency:

Deutan color vision deficiency Not Yet Curated MONDO:0010564
Overlapping Features X-linked red-green defect in which the M-cone contribution is absent and the expressed genes all encode L-class pigments.
Distinguishing Features
  • Anomaloscope match and HRR diagnostic plates classify deutan rather than protan type.
  • Genotype retains an L-class gene in the expressed array positions.
Show evidence (1 reference)
PMID:33544131 SUPPORT PRIMARY RESULT Human Clinical
"(2) deuteranopes are missing M cones but are normal otherwise"
The missing cone class distinguishes deutan from protan dichromacy.
Blue cone monochromacy MONDO:0010563
Overlapping Features Loss of both L- and M-cone function from locus control region deletion or inactivation of all expressed opsin genes, with reduced acuity, nystagmus and photophobia.
Distinguishing Features
  • Both L- and M-cone function are lost, rather than L alone.
  • Some patients given a clinical diagnosis of blue cone monochromacy have protanopia genotypes.
Show evidence (2 references)
PMID:15518188 SUPPORT REVIEW SYNTHESIS Other
"Blue-cone monochromacy is a rare disorder that involves absence of L- and M-cone function."
Distinguishes the two-cone-class loss of BCM from the single-class loss in protans.
PMID:34440353 SUPPORT PRIMARY RESULT Other
"Three other subjects received a clinical diagnosis of blue cone monochromacy (BCM160-23130, ZD314-18057, BCM51-12359), but all three have genotypes consistent with protanopia, not blue cone monochromacy, and color vision tests performed were not adequate to reliably detect BCM."
Genotyping reclassified clinically diagnosed BCM cases as protanopia.
X-linked cone dysfunction syndrome with myopia Not Yet Curated MONDO:0010446
Overlapping Features Allelic OPN1LW disorders (Bornholm eye disease and related exon 3 haplotype disease) combine protanopia or deuteranopia with high myopia and reduced cone function.
Distinguishing Features
  • Early-onset high myopia and reduced cone density or function.
  • OPN1LW exon 3 haplotypes (LIAVA, LVAVA, LIVVA) or truncating variants rather than a hybrid-gene array.
Show evidence (3 references)
PMID:34440353 SUPPORT REVIEW SYNTHESIS Other
"Males with an OPN1LWLIAVA gene and an OPN1MW gene that is transcribed and translated into functional photopigment will have protanopia because all L cones will be devoid of photopigment."
The LIAVA route empties L cones of pigment rather than refilling them with M-class pigment.
PMID:37097228 SUPPORT PRIMARY RESULT Human Clinical
"This is different from the replacement of red with green owing to unequal re-arrangement causing red-green colorblindness alone."
Separates the high-myopia OPN1LW disorders from ordinary protan defects.
PMID:23322568 SUPPORT PRIMARY RESULT Human Clinical
"All except one of the BED families possessed L opsin genes that contained a rare exon 3 haplotype. The exception was a family with the deleterious Cys203Arg substitution."
Bornholm eye disease families carry rare exon 3 haplotypes or Cys203Arg in the L opsin gene rather than the hybrid-gene arrays of ordinary protan defects.
🐁

Animal Models

1
Dichromatic male squirrel monkey lacking L opsin
In squirrel monkeys a single polymorphic X-linked opsin locus makes all males dichromatic. Males lacking an L-opsin allele behave as protanopes; they were used to test L-opsin gene addition.
Species
Squirrel monkey (Saimiri sciureus)
Genotype
Hemizygous males carrying an M-class allele at the single X-linked opsin locus
Publication
PMID:19759534
Pathograph links
Absence of an Expressed L-Class Opsin Gene recapitulates fidelity: moderate observes: organism Naturally L-opsin-deficient dichromatic primate with S and M-class cones only.
Limitations: Dichromacy arises from allelic variation at a single X-linked locus, not from unequal recombination in a tandem L/M array, so the model does not reproduce the human mutational mechanism or hybrid-gene genotypes.
Show evidence (2 references)
PMID:10413401 SUPPORT BACKGROUND Model Organism
"most New World primates have only a single polymorphic X-linked opsin gene; all males are dichromats and trichromacy is achieved only in those females that possess a different form of this gene on each X chromosome."
Explains why male New World monkeys such as the squirrel monkey are natural X-linked dichromats.
+ 1 more reference
Loss of L-versus-M Cone Opponent Signal rescues fidelity: moderate observes: organism L-opsin gene addition in adult animals produced trichromatic behaviour on a colour discrimination task.
Limitations: Only a fraction of M cones co-expressed the transgene; long-term safety and human translation are untested.
Show evidence (1 reference)
PMID:19759534 SUPPORT PRIMARY RESULT Model Organism
"here we show that the addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour."
Adding L opsin restored red-green discrimination capacity in the model.
{ }

Source YAML

click to show 
name: Protan Color Vision Deficiency
creation_date: '2026-10-14T12:36:44Z'
category: Mendelian
parents:
- Color vision disorder
- Congenital stationary cone dysfunction
description: >-
  X-linked red-green color vision deficiency of the protan type, in which the
  long-wavelength-sensitive (L) cone contribution to vision is absent. It covers
  the dichromatic form, protanopia, and the anomalous trichromatic form,
  protanomaly. The X-chromosome opsin gene array at Xq28 normally carries one
  OPN1LW (L-opsin) gene followed by one or more OPN1MW (M-opsin) genes, and only
  the first two genes are expressed. Unequal homologous recombination between the
  highly similar genes in female meiosis produces arrays that lack OPN1LW or
  replace it with a 5'L-3'M hybrid gene whose product absorbs in the M range, so
  every expressed gene encodes an M-class pigment. Cones that would have been L
  cones contain M-class pigment instead. When the expressed pigments are
  spectrally identical the result is protanopia; when they differ by a few
  nanometres the result is protanomaly, whose severity scales with that spectral
  separation. Affected males have reduced red-green discrimination and reduced
  sensitivity to long-wavelength (red) light. No disease-modifying treatment
  exists; gene addition of L opsin restored trichromatic behaviour in adult
  dichromatic squirrel monkeys but has not been tested in humans.
disease_term:
  preferred_term: red color blindness
  term:
    id: MONDO:0010565
    label: red color blindness
synonyms:
- red color blindness
- protan defect
- protanopia
- colorblindness, protan
- colorblindness, partial, protan series
- partial achromatopsia, protan type
notes: >-
  Scope. The MONDO term (OMIM:303900, Orphanet:319691) is labelled red color
  blindness and its definition describes protanopia, but its OMIM source is the
  whole protan series, so this entry covers protanopia and protanomaly as
  subtypes. OLS searches of MONDO and ORDO for "protanopia" and "protanomaly"
  return no term for either form beyond MONDO:0010565 itself; HPO
  has phenotype terms for both (HP:0011522 Protanopia, HP:0200018 Protanomaly),
  which are bound on the phenotypes. Lump/split: protan and deutan defects share
  the array-rearrangement mechanism, but MONDO, OMIM and Orphanet keep them as
  separate diseases, the expressed pigment class differs (only M-class pigments
  in protans, only L-class in deutans), protans alone have reduced sensitivity to
  red light, and deutan defects are more than twice as common in the prevalence surveys cited below. The deutan defect
  (MONDO:0010564, OPN1MW side of the array) and the tritan defect (MONDO:0008610,
  OPN1SW) therefore have their own stubs and are not subtypes here. Blue cone
  monochromacy (loss of both L and M cone function) has its own entry. OPN1LW
  exon 3 haplotypes that cause exon skipping (LIAVA) and OPN1LW truncations remove
  L pigment completely and give protanopia, but together with early-onset high
  myopia and reduced cone density; these allelic disorders (X-linked cone
  dysfunction syndrome with myopia, MONDO:0010446, including Bornholm eye
  disease) are listed under differential diagnosis rather than curated here. No
  GeneReviews chapter exists for red-green colour vision defects (Bookshelf index
  and a live PubMed genereviews[book] search).
inheritance:
- name: X-linked recessive
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    The L and M opsin genes lie on the X chromosome at Xq28, so the defect is
    expressed in hemizygous males. Heterozygous protan carriers tend to carry
    fewer L-opsin genes than non-carriers and can be identified molecularly.
  evidence:
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As predicted by inheritance patterns of red-green (Waaler, 1968) and
      blue-yellow (Kalmus, 1955) color vision deficiencies, the genes for human
      long-wavelength (L) and middle-wavelength (M) cone opsins were localized to
      the X-chromosome at Xq28
    explanation: >-
      Places the L and M opsin genes on the X chromosome, the basis of X-linked
      transmission of protan defects.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:22472762
    reference_title: "Worldwide prevalence of red-green color deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Large random population surveys show that the prevalence of deficiency in
      European Caucasians is about 8% in men and about 0.4% in women
    explanation: >-
      The roughly twentyfold male excess of red-green deficiency is the pattern
      expected of an X-linked recessive trait.
    quote_role: REVIEW_SYNTHESIS
    directness: INDIRECT
  - reference: PMID:9893850
    reference_title: "Molecular genetic detection of female carriers of protan defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a molecular genetic method to identify protan carriers that
      involves characterizing the genes that occur in the most upstream position in
      each of the X-chromosome photopigment gene arrays.
    explanation: >-
      Heterozygous females carrying a protan array are a recognised carrier state,
      as expected for an X-linked recessive trait.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
has_subtypes:
- name: Protanopia
  display_name: Protanopia (protan dichromacy)
  description: >-
    Dichromatic form. The X-chromosome array has a single gene encoding an M-class
    pigment (OPN1LW deleted, or replaced by a 5'L-3'M hybrid encoding an M-class
    pigment), or several genes whose first two encode M-class pigments with
    identical spectra. No functional L-cone signal is present.
  genes:
  - preferred_term: OPN1LW
    term:
      id: hgnc:9936
      label: OPN1LW
  evidence:
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      X-chromosome opsin gene arrays underlying the dichromatic form, protanopia,
      either have a single opsin gene that encodes an M pigment, or have multiple
      genes in which the first two encode opsins that produce M pigments that are
      identical in spectra
    explanation: >-
      Defines the genotypes underlying protanopia.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:33544131
    reference_title: "Revealing How Color Vision Phenotype and Genotype Manifest in Individual Cone Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both protanopes (subjects S9 and S10) carried a single M gene and no L gene.
    explanation: >-
      Genotyped protanopes in a cone-resolved imaging study had a single M gene and
      no L gene.
    quote_role: PRIMARY_RESULT
- name: Protanomaly
  display_name: Protanomaly (protanomalous trichromacy)
  description: >-
    Anomalous trichromatic form. The array lacks a normal L gene and its first two
    genes encode two M-class pigments that differ slightly in spectral peak, for
    example a 5'L-3'M hybrid together with a normal M gene. The two M-class cone
    populations support a weak red-green signal. Because M-class pigments can be
    separated by only a few nanometres, protanomalous observers as a group
    discriminate colours somewhat worse than deuteranomalous observers.
  genes:
  - preferred_term: OPN1LW
    term:
      id: hgnc:9936
      label: OPN1LW
  evidence:
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The anomalous trichromatic form, protanomaly, is associated with opsin gene
      arrays in which the first two genes encode opsins that produce M pigments that
      differ in spectra.
    explanation: >-
      Defines the genotypes underlying protanomaly.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This can explain why, as a group, protanomalous observers have somewhat poorer
      color discrimination than deuteranomalous observers.
    explanation: >-
      Relates the narrow spectral separation available within the M class to the
      severity of protanomaly.
    quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Children and adolescents worldwide, males (pooled meta-analysis of 56 studies, 1932-2022)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1540.0
  rate_low: 1300.0
  rate_high: 1820.0
  notes: >-
    Pooled protan prevalence in males 1.54% (95% CI 1.30-1.82%), from screening
    studies that classified the defect type; includes protanopia and protanomaly.
  evidence:
  - reference: PMID:40769301
    reference_title: "Global Prevalence of Congenital Color Vision Deficiency among Children and Adolescents, 1932-2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by protan (male, 1.54% [95% CI, 1.30%-1.82%]; female, 0.30% [95% CI,
      0.21%-0.43%])
    explanation: >-
      Meta-analysis estimate of protan prevalence in males.
    quote_role: PRIMARY_RESULT
- population: Children and adolescents worldwide, females (pooled meta-analysis of 56 studies, 1932-2022)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 300.0
  rate_low: 210.0
  rate_high: 430.0
  notes: >-
    Pooled protan prevalence in females 0.30% (95% CI 0.21-0.43%). This is a
    screening-test classification, not a genotype count, and is higher than the
    square of the male frequency would predict for an X-linked recessive trait.
  evidence:
  - reference: PMID:40769301
    reference_title: "Global Prevalence of Congenital Color Vision Deficiency among Children and Adolescents, 1932-2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by protan (male, 1.54% [95% CI, 1.30%-1.82%]; female, 0.30% [95% CI,
      0.21%-0.43%])
    explanation: >-
      Meta-analysis estimate of protan prevalence in females.
    quote_role: PRIMARY_RESULT
- population: Schoolchildren, Republic of Ireland, boys
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1700.0
  notes: >-
    Protan defects in 1.7% of 882 boys tested with HRR plates; deutan 4.8%.
  evidence:
  - reference: PMID:32285548
    reference_title: "Prevalence of colour vision deficiency in the Republic of Ireland schoolchildren and associated socio-demographic factors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As expected, deutan (boys 4.8 per cent, girls 0.8 per cent) was the most
      common type of CVD, followed by protan (boys 1.7 per cent, girls 0.1 per cent)
    explanation: >-
      Population school survey giving the protan frequency in boys.
    quote_role: PRIMARY_RESULT
- population: Adults aged 19-49 years, South Korea (KNHANES 2013), both sexes
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 400.0
  notes: >-
    Weighted protan prevalence 0.4% across both sexes on HRR screening; deutan
    2.5%.
  evidence:
  - reference: PMID:31688694
    reference_title: "Prevalence of Color Vision Deficiency in an Adult Population in South Korea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among all participants, deutan deficiency (2.5%) had a higher prevalence than
      did protan deficiency (0.4%).
    explanation: >-
      Nationally representative survey estimate of protan deficiency.
    quote_role: PRIMARY_RESULT
pathophysiology:
- name: Unequal Recombination in the Xq28 L/M Opsin Gene Array
  description: >-
    The L and M pigments share 96% amino acid identity and their genes sit in a
    head-to-tail tandem array. Misalignment of the arrays in female meiosis followed
    by an intergenic or intragenic crossover (unequal homologous recombination, with
    gene conversion as a further route) yields arrays that have lost OPN1LW or carry
    a 5'L-3'M hybrid gene in its place. This germline rearrangement is the
    initiating lesion for most protan defects; rarer routes include inactivating
    OPN1LW exon 3 haplotypes and truncating variants.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: OPN1LW
    term:
      id: hgnc:9936
      label: OPN1LW
  - preferred_term: OPN1MW
    term:
      id: hgnc:4206
      label: OPN1MW
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:3485310
    reference_title: "Molecular genetics of inherited variation in human color vision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The hypothesis that red-green "color blindness" is caused by alterations in
      the genes encoding red and green visual pigments has been tested and shown to
      be correct.
    explanation: >-
      Founding genotype study of red-green colour vision deficiency.
    quote_role: PRIMARY_RESULT
  - reference: PMID:3485310
    reference_title: "Molecular genetics of inherited variation in human color vision."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed genotypes appear to result from unequal recombination or gene
      conversion (or both).
    explanation: >-
      Identifies unequal recombination and gene conversion as the mutational
      mechanism in affected males.
    quote_role: PRIMARY_RESULT
  - reference: PMID:2937147
    reference_title: "Molecular genetics of human color vision: the genes encoding blue, green, and red pigments."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The red and green pigments show 96 percent mutual identity but only 43
      percent identity with the blue pigment.
    explanation: >-
      The near-identity of L and M opsin sequences is what predisposes the array to
      misalignment.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  - reference: PMID:15811001
    reference_title: "The molecular basis of variation in human color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The high homology between these genes has predisposed the locus to relatively
      common unequal recombination events that give rise to red/green hybrid genes
      and to deletion of the green-pigment genes. Such events constitute the most
      common cause of red-green color vision defects.
    explanation: >-
      Review synthesis that unequal recombination producing hybrid genes is the
      common cause of red-green defects.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inherited color vision deficiencies can be explained by gene rearrangements
      that arose through unequal homologous recombination in females during meiosis
    explanation: >-
      Places the recombination events in female meiosis.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the protan-causing array the one remaining opsin gene is a hybrid between
      the parental L and M genes.
    explanation: >-
      Describes the protan product of an intragenic crossover.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Absence of an Expressed L-Class Opsin Gene
    causal_link_type: DIRECT
    description: >-
      The rearranged array no longer has a gene encoding an L-class pigment in
      either of the two expressed positions.
    evidence:
    - reference: PMID:1411542
      reference_title: "Absorption spectra of the hybrid pigments responsible for anomalous color vision."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Unequal homologous recombination events between green and red cone pigment
        genes produce the red-green or green-red hybrid pigment genes found in many
        individuals with variant color vision.
      explanation: >-
        The recombination products are the hybrid pigment genes found in
        individuals with variant colour vision.
      quote_role: BACKGROUND
- name: Absence of an Expressed L-Class Opsin Gene
  description: >-
    Only the first two genes of the X-linked array are expressed in the retina. In
    protans neither expressed gene encodes an L-class pigment: the expressed genes
    are normal OPN1MW copies or 5'L-3'M hybrids. Spectral tuning is dominated by
    exon 5, which accounts for a shift of roughly 15 to 25 nm, so a hybrid carrying
    M-type exon 5 encodes an M-class pigment whatever its 5' exons.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: OPN1LW
    term:
      id: hgnc:9936
      label: OPN1LW
  molecular_functions:
  - preferred_term: long-wavelength G protein-coupled photoreceptor activity
    term:
      id: GO:0008020
      label: G protein-coupled photoreceptor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:15518188
    reference_title: "Molecular genetics of color-vision deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Analysis of the gene order in arrays of normal and deutan subjects indicates
      that only the two most proximal genes of the array contribute to the
      color-vision phenotype.
    explanation: >-
      Only the two most upstream genes determine the phenotype.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Protan defects are characterized by the absence of an L cone contribution to
      vision.
    explanation: >-
      Defines the protan defect as absence of L-cone contribution.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:1411542
    reference_title: "Absorption spectra of the hybrid pigments responsible for anomalous color vision."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Amino acids encoded by exons 2, 3, 4, and 5 produce spectral shifts at the
      wavelength of maximal absorbance of 0 to 4, 0 to 4, 3 to 4, and 15 to 21
      nanometers, respectively
    explanation: >-
      Expressed hybrid pigments show that exon 5 carries most of the L versus M
      spectral difference, explaining why 5'L-3'M hybrids encode M-class pigments.
    quote_role: PRIMARY_RESULT
  - reference: PMID:9822760
    reference_title: "Red, green, and red-green hybrid pigments in the human retina: correlations between deduced protein sequences and psychophysically measured spectral sensitivities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      approximately 54% of the single-gene protanopes (and approximately 19% of all
      protanopes) possess any one of several 5'red-3'green hybrid genes that encode
      anomalous pigments
    explanation: >-
      Genotyped protanopes frequently carry 5'L-3'M hybrid genes rather than a
      plain loss of OPN1LW.
    quote_role: PRIMARY_RESULT
  - reference: PMID:11772996
    reference_title: "The molecular basis of dichromatic color vision in males with multiple red and green visual pigment genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most genotypes (92%) included hybrid genes whose sequence and position and
      whose encoded pigment correlated exactly with the phenotype.
    explanation: >-
      In multigene dichromats (including 23 protanopes) the position and sequence of
      hybrid genes predicted the phenotype.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: L Cones Filled with M-Class Photopigment
    causal_link_type: DIRECT
    description: >-
      Cones that would express L opsin instead express the M-class pigment encoded
      by the remaining genes.
- name: L Cones Filled with M-Class Photopigment
  description: >-
    Protan retinas contain M-class and S cones but no functional L cones. Fundus
    reflectometry and electroretinography in X-linked dichromats fit a replacement
    model, in which the total number of cones is unchanged and the missing cone
    class is replaced by the remaining one. Cone-resolved optoretinography shows
    that the remaining M and S cones respond normally.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: L cone cell
    term:
      id: CL:0003048
      label: L cone cell
  - preferred_term: M cone cell
    term:
      id: CL:0003049
      label: M cone cell
  biological_processes:
  - preferred_term: detection of long-wavelength light in visual perception
    term:
      id: GO:0050908
      label: detection of light stimulus involved in visual perception
    modifier: DECREASED
  evidence:
  - reference: PMID:33544131
    reference_title: "Revealing How Color Vision Phenotype and Genotype Manifest in Individual Cone Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (3) protanopes are missing L cones but are normal otherwise
    explanation: >-
      Adaptive-optics optoretinography finds no functional L cones in protanopes and
      normal M and S cone responses.
    quote_role: PRIMARY_RESULT
  - reference: PMID:8730604
    reference_title: "Foveal cone mosaic and visual pigment density in dichromats."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A replacement model, i.e. one where the total number of cones remains unchanged
      and all cones are filled with a single type of pigment, was found to fit our
      data best.
    explanation: >-
      Foveal reflectometry in protanopes and deuteranopes supports pigment
      replacement rather than cone loss.
    quote_role: PRIMARY_RESULT
  - reference: PMID:10102289
    reference_title: "Cone signal contributions to electroretinograms [correction of electrograms] in dichromats and trichromats."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data strongly suggest that the missing cone type in dichromats is replaced
      by the remaining cone type.
    explanation: >-
      Cone-isolating ERG in X-linked dichromats supports replacement of the missing
      cone class.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Loss of L-versus-M Cone Opponent Signal
    causal_link_type: DIRECT
    description: >-
      Without a long-wavelength cone class there is no, or only a weak, difference
      signal for red-green opponent processing.
  - target: Reduced Long-Wavelength Luminous Sensitivity
    causal_link_type: DIRECT
    description: >-
      M-class pigment absorbs poorly at long wavelengths, so sensitivity to red
      light falls.
- name: Loss of L-versus-M Cone Opponent Signal
  description: >-
    Red-green colour discrimination depends on comparing signals from two cone
    classes in the middle-to-long wavelength range. When both expressed pigments are
    spectrally identical (protanopia) the comparison is impossible and vision is
    dichromatic; when they differ by a few nanometres (protanomaly) a weak signal
    remains. Severity is inversely related to the spectral separation between the
    two expressed pigments. Left unbound to GO: the nearest process term,
    GO:0007601 visual perception, is broader than red-green opponent comparison
    and an OLS label/synonym search of GO for "color vision", "colour vision",
    "color discrimination" and "color perception" returned no terms.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:15811001
    reference_title: "The molecular basis of variation in human color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The severity of red-green color vision defects is inversely proportional to
      the difference between the wavelengths of maximal absorption of the
      photopigments encoded by the first two genes of the array.
    explanation: >-
      Links severity to the spectral separation of the two expressed pigments.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34440353
    reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Males have protanopia if the first and second genes specify M cone
      photopigments that are identical in their wavelengths of peak sensitivity or
      if they have a single gene array that encodes an M pigment
    explanation: >-
      Identical M-class pigments give dichromacy.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34440353
    reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Males have protanomaly if the first and second genes encode M cone
      photopigments that differ in their wavelengths of peak sensitivity
    explanation: >-
      Two spectrally different M-class pigments give anomalous trichromacy.
    quote_role: REVIEW_SYNTHESIS
  downstream:
  - target: Protanopia
    causal_link_type: DIRECT
    description: >-
      Spectrally identical expressed pigments leave no red-green opponent signal.
    evidence:
    - reference: PMID:34440353
      reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Males have protanopia if the first and second genes specify M cone
        photopigments that are identical in their wavelengths of peak sensitivity or
        if they have a single gene array that encodes an M pigment
      explanation: >-
        Genotype-to-phenotype rule for protanopia.
      quote_role: REVIEW_SYNTHESIS
  - target: Protanomaly
    causal_link_type: DIRECT
    description: >-
      Slightly different M-class pigments leave a reduced red-green signal.
    evidence:
    - reference: PMID:34440353
      reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Males have protanomaly if the first and second genes encode M cone
        photopigments that differ in their wavelengths of peak sensitivity
      explanation: >-
        Genotype-to-phenotype rule for protanomaly.
      quote_role: REVIEW_SYNTHESIS
  - target: Red-Green Dyschromatopsia
    causal_link_type: DIRECT
    description: >-
      Both forms share impaired discrimination of hues along the red-green axis.
- name: Reduced Long-Wavelength Luminous Sensitivity
  description: >-
    Because the remaining cones carry M-class pigment, protans are relatively
    insensitive to long-wavelength light; red lights look dim and are seen at a
    shorter range. In laboratory spectral sensitivity data every protan had lower
    red-light sensitivity than the least sensitive colour-normal observer, which
    bears on recognition of red signal lights and on occupational and driving
    standards.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:12135418
    reference_title: "Protan colour vision deficiency and road accidents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A laboratory study of the spectral sensitivity of protan and colour normal
      subjects that largely removes these sources' variability shows that all protans
      have a sensitivity to red light that is less than that of the least sensitive
      colour normal.
    explanation: >-
      Re-analysis of spectral sensitivity data shows uniformly reduced red-light
      sensitivity in protans.
    quote_role: PRIMARY_RESULT
  - reference: PMID:12135418
    reference_title: "Protan colour vision deficiency and road accidents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Field trial data show that protans have a very reduced visual range for red
      signals compared to colour normal observers
    explanation: >-
      Field trials show a reduced range at which red signals are seen.
    quote_role: PRIMARY_RESULT
  - reference: PMID:14702998
    reference_title: "Traffic signal color recognition is a problem for both protan and deutan color-vision deficients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      response times of deuteranopes and protanopes were 53% and 35% longer than
      those of color normals
    explanation: >-
      Protanopes identified simulated red traffic lights more slowly than colour
      normals. The same study found deuteranopes slower still, so slowed signal
      recognition is not specific to the protan red-light deficit.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
phenotypes:
- name: Protanopia
  category: Ophthalmologic
  subtype: Protanopia
  description: >-
    Dichromatic colour vision with no functional L cones.
  phenotype_term:
    preferred_term: Protanopia
    term:
      id: HP:0011522
      label: Protanopia
  evidence:
  - reference: PMID:33544131
    reference_title: "Revealing How Color Vision Phenotype and Genotype Manifest in Individual Cone Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (3) protanopes are missing L cones but are normal otherwise
    explanation: >-
      Protanopia corresponds to absence of functional L cones.
    quote_role: PRIMARY_RESULT
  - reference: PMID:27622081
    reference_title: "Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five of them had arrays comprised solely of multiple identical M genes, making
      them obligate protanopes.
    explanation: >-
      Genotype-defined protanopes in a large screened cohort.
    quote_role: PRIMARY_RESULT
- name: Protanomaly
  category: Ophthalmologic
  subtype: Protanomaly
  description: >-
    Anomalous trichromacy of the protan type; colour matches and discrimination are
    abnormal along the red-green axis but some red-green discrimination remains.
  phenotype_term:
    preferred_term: Protanomaly
    term:
      id: HP:0200018
      label: Protanomaly
  evidence:
  - reference: PMID:27622081
    reference_title: "Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      another 5 had M opsins with differences in both spectral tuning sites and in
      exon 2, making them, at best, protanomalous.
    explanation: >-
      Males lacking L genes but with spectrally different M-class genes have
      protanomaly.
    quote_role: PRIMARY_RESULT
- name: Red-Green Dyschromatopsia
  category: Ophthalmologic
  description: >-
    Reduced discrimination of hues along the red-green axis, common to protanopia and
    protanomaly. Detected on pseudoisochromatic plates and characterised by
    anomaloscopy.
  phenotype_term:
    preferred_term: Red-green dyschromatopsia
    term:
      id: HP:0000642
      label: Red-green dyschromatopsia
  evidence:
  - reference: PMID:19759534
    reference_title: "Gene therapy for red-green colour blindness in adult primates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with L but no M cones (termed deuteranopes) have a relatively
      enhanced sensitivity to red light but they are still as dichromatic as
      individuals with M but no L cones (protanopes), in that they are unable to
      distinguish particular “colours” from grey.
    explanation: >-
      Describes the colour-confusion deficit of human protanopes; the statement is
      background in a primate gene-therapy study.
    quote_role: BACKGROUND
  - reference: PMID:35113505
    reference_title: "Limitation of standard pseudoisochromatic plates in identifying colour vision deficiencies when compared with genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital colour vision deficiencies are caused by inherited photopigment
      abnormalities (Nathans et al. 1986; Nathans et al. 1986) and impair the
      affected individual’s ability to discriminate colours.
    explanation: >-
      States the discrimination deficit caused by inherited photopigment
      abnormalities.
    quote_role: BACKGROUND
genetic:
- name: OPN1LW
  association: Genetic Mutation
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: OPN1LW
    term:
      id: hgnc:9936
      label: OPN1LW
  inheritance:
  - name: X-linked recessive
  notes: >-
    The causal lesion is usually not a point mutation but an array rearrangement:
    loss of OPN1LW or its replacement by a 5'L-3'M hybrid gene, leaving only M-class
    genes in the expressed positions. Rare protan alleles include OPN1LW exon 3
    haplotypes that cause exon skipping (LIAVA) and truncating variants, which remove
    L pigment completely; these are usually accompanied by early-onset high myopia
    and are treated as allelic disorders. OPN1MW is retained and functional in
    protans.
  evidence:
  - reference: PMID:21167193
    reference_title: "The genetics of normal and defective color vision."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A male with a normal S-pigment and one X-chomosome pigment gene encoding an M
      pigment is an obligate protanope.
    explanation: >-
      Loss of all L-class genes from the X-linked array is sufficient for
      protanopia.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:27622081
    reference_title: "Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Protan and deutan deficiencies were classified correctly in all subjects
      identified by MassArray as having red-green defects.
    explanation: >-
      Opsin-array genotype predicts protan type in a large cohort.
    quote_role: PRIMARY_RESULT
  - reference: PMID:37097228
    reference_title: "Unique Haplotypes in OPN1LW as a Common Cause of High Myopia With or Without Protanopia: A Potential Window Into Myopic Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 68 families, 42 affected male patients (31 families) with the first
      class of variants (LVAVA or LIVVA in OPN1LW) had eoHM alone, whereas 37 male
      patients with the latter 3 classes had eoHM with protanopia.
    explanation: >-
      Complete loss of L pigment from exon 3 haplotypes or truncations also
      produces protanopia, but together with early-onset high myopia; this allelic
      route is outside the scope of the uncomplicated protan defect.
    quote_role: PRIMARY_RESULT
diagnosis:
- name: Pseudoisochromatic plate screening
  description: >-
    Ishihara and Hardy-Rand-Rittler plates are the usual screening tests; HRR
    diagnostic plates classify protan versus deutan type and grade severity. Plates
    miss a substantial fraction of genetically defined colour-deficient males.
  diagnosis_term:
    preferred_term: colour vision testing
    term:
      id: NCIT:C156778
      label: Vision Assessment
  evidence:
  - reference: PMID:35113505
    reference_title: "Limitation of standard pseudoisochromatic plates in identifying colour vision deficiencies when compared with genetic testing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MassArray identified twice as many colour-deficient males as identified from
      PIC tests alone.
    explanation: >-
      Plate tests alone under-detect colour deficiency compared with genotyping.
    quote_role: PRIMARY_RESULT
- name: Anomaloscopy (Rayleigh match)
  description: >-
    The Nagel anomaloscope classifies X-linked red-green defects by the red-green
    mixture matched to a yellow primary, separating protanopia from protanomaly and
    protan from deutan defects.
  diagnosis_term:
    preferred_term: anomaloscopy
    term:
      id: NCIT:C156778
      label: Vision Assessment
  evidence:
  - reference: PMID:15290149
    reference_title: "The Nagel anomaloscope: its calibration and recommendations for diagnosis and research."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Nagel anomaloscope Model I is the definitive clinical instrument for
      classifying phenotypic variations in X-linked color-vision disorders.
    explanation: >-
      Anomaloscopy is the reference test for classifying protan type and form.
    quote_role: BACKGROUND
- name: Opsin gene array analysis
  description: >-
    Analysis of the OPN1LW/OPN1MW array (gene copy number, gene order and
    spectral-tuning sites) identifies the protan genotype, estimates severity and
    detects carrier females.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:27622081
    reference_title: "Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The MassArray assay provides genetic information that can be useful in the
      diagnosis of inherited color vision deficiency including presence versus
      absence, type, and severity
    explanation: >-
      Genotyping gives type and severity of the defect.
    quote_role: PRIMARY_RESULT
  - reference: PMID:9893850
    reference_title: "Molecular genetic detection of female carriers of protan defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a molecular genetic method to identify protan carriers that
      involves characterizing the genes that occur in the most upstream position in
      each of the X-chromosome photopigment gene arrays.
    explanation: >-
      Molecular analysis of the first array gene detects protan carriers.
    quote_role: PRIMARY_RESULT
differential_diagnoses:
- name: Deutan color vision deficiency
  description: >-
    X-linked red-green defect in which the M-cone contribution is absent and the
    expressed genes all encode L-class pigments.
  disease_term:
    preferred_term: deutan defect
    term:
      id: MONDO:0010564
      label: red-green color blindness
  distinguishing_features:
  - Anomaloscope match and HRR diagnostic plates classify deutan rather than protan type.
  - Genotype retains an L-class gene in the expressed array positions.
  evidence:
  - reference: PMID:33544131
    reference_title: "Revealing How Color Vision Phenotype and Genotype Manifest in Individual Cone Cells."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      (2) deuteranopes are missing M cones but are normal otherwise
    explanation: >-
      The missing cone class distinguishes deutan from protan dichromacy.
    quote_role: PRIMARY_RESULT
- name: Blue cone monochromacy
  description: >-
    Loss of both L- and M-cone function from locus control region deletion or
    inactivation of all expressed opsin genes, with reduced acuity, nystagmus and
    photophobia.
  disease_term:
    preferred_term: blue cone monochromacy
    term:
      id: MONDO:0010563
      label: blue cone monochromacy
  distinguishing_features:
  - Both L- and M-cone function are lost, rather than L alone.
  - Some patients given a clinical diagnosis of blue cone monochromacy have protanopia genotypes.
  evidence:
  - reference: PMID:15518188
    reference_title: "Molecular genetics of color-vision deficiencies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Blue-cone monochromacy is a rare disorder that involves absence of L- and
      M-cone function.
    explanation: >-
      Distinguishes the two-cone-class loss of BCM from the single-class loss in
      protans.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34440353
    reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Three other subjects received a clinical diagnosis of blue cone monochromacy
      (BCM160-23130, ZD314-18057, BCM51-12359), but all three have genotypes
      consistent with protanopia, not blue cone monochromacy, and color vision tests
      performed were not adequate to reliably detect BCM.
    explanation: >-
      Genotyping reclassified clinically diagnosed BCM cases as protanopia.
    quote_role: PRIMARY_RESULT
- name: X-linked cone dysfunction syndrome with myopia
  description: >-
    Allelic OPN1LW disorders (Bornholm eye disease and related exon 3 haplotype
    disease) combine protanopia or deuteranopia with high myopia and reduced cone
    function.
  disease_term:
    preferred_term: X-linked cone dysfunction syndrome with myopia
    term:
      id: MONDO:0010446
      label: X-linked cone dysfunction syndrome with myopia
  distinguishing_features:
  - Early-onset high myopia and reduced cone density or function.
  - OPN1LW exon 3 haplotypes (LIAVA, LVAVA, LIVVA) or truncating variants rather than a hybrid-gene array.
  evidence:
  - reference: PMID:34440353
    reference_title: "Intermixing the OPN1LW and OPN1MW Genes Disrupts the Exonic Splicing Code Causing an Array of Vision Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Males with an OPN1LWLIAVA gene and an OPN1MW gene that is transcribed and
      translated into functional photopigment will have protanopia because all L
      cones will be devoid of photopigment.
    explanation: >-
      The LIAVA route empties L cones of pigment rather than refilling them with
      M-class pigment.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:37097228
    reference_title: "Unique Haplotypes in OPN1LW as a Common Cause of High Myopia With or Without Protanopia: A Potential Window Into Myopic Mechanism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is different from the replacement of red with green owing to unequal
      re-arrangement causing red-green colorblindness alone.
    explanation: >-
      Separates the high-myopia OPN1LW disorders from ordinary protan defects.
    quote_role: PRIMARY_RESULT
  - reference: PMID:23322568
    reference_title: "Variations in opsin coding sequences cause x-linked cone dysfunction syndrome with myopia and dichromacy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All except one of the BED families possessed L opsin genes that contained a
      rare exon 3 haplotype. The exception was a family with the deleterious
      Cys203Arg substitution.
    explanation: >-
      Bornholm eye disease families carry rare exon 3 haplotypes or Cys203Arg in the
      L opsin gene rather than the hybrid-gene arrays of ordinary protan defects.
    quote_role: PRIMARY_RESULT
treatments:
- name: Colour-enhancing filter glasses
  description: >-
    Commercial notch-filter (EnChroma) and other colour-enhancing (VINO) spectacles
    alter the relative stimulation of the remaining cones. They do not restore the
    missing L cone class. A controlled study found no overall improvement on clinical
    colour tests with EnChroma lenses; another found a functionally meaningful change
    on the CAD test only with VINO glasses. Tinted ChromaGen lenses reduced plate-test
    errors without reducing severity, and no protanope passed any test with them.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: colour-enhancing spectacles
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Red-green dyschromatopsia
    term:
      id: HP:0000642
      label: Red-green dyschromatopsia
  evidence:
  - reference: PMID:36242261
    reference_title: "Do EnChroma glasses improve performance on clinical tests for red-green color deficiencies?"
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Comparing the performance of 86 well-categorized CVD observers and 24 controls
      on two clinical tests we report no overall improvement when EnChroma lenses were
      worn.
    explanation: >-
      Controlled study finding no overall benefit of EnChroma lenses on clinical
      colour tests in red-green deficient observers.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36242206
    reference_title: "Effects of color-enhancing glasses on color vision in congenital red-green color deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although there was a statistically significant effect of both glasses, only
      that of VINO could be considered functionally meaningful.
    explanation: >-
      In red-green deficient individuals with characterised opsin arrays, only VINO
      glasses gave a functionally meaningful change in CAD thresholds.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36189411
    reference_title: "Color vision devices for color vision deficiency patients: A systematic review and meta-analysis."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      This review concludes that commercially available color vision devices, such as
      EnChroma Glasses, Chromagen filters, and EnChroma Cx-14 do not provide
      clinically significant evidence that subjective color perception has improved.
    explanation: >-
      Systematic review finding no clinically significant benefit of colour vision
      devices.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:41806157
    reference_title: "Impact of ChromaGen lenses on colour vision test performance of individuals with congenital colour vision deficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The dichromatic individuals showed minimal improvement, with none of the
      participants with protanopia passing any of the tests using any ChromaGen lens.
    explanation: >-
      In a study including 5 protanopes and 18 protanomalous males, tinted ChromaGen
      lenses lowered plate-test error counts but no protanope passed any test.
    quote_role: PRIMARY_RESULT
- name: Occupational and driving counselling
  description: >-
    Early identification lets affected children and their teachers plan for
    colour-critical tasks and careers. Because protans see red signal lights poorly,
    some jurisdictions and occupations restrict protans from colour-critical roles.
  treatment_term:
    preferred_term: occupational counselling
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:32285548
    reference_title: "Prevalence of colour vision deficiency in the Republic of Ireland schoolchildren and associated socio-demographic factors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early screening is essential to counsel schoolchildren with congenital colour
      vision deficiency (CVD) in determining their future career path and to advise
      teachers of the impact of CVD on classroom difficulties.
    explanation: >-
      Recommends screening and counselling for career planning.
    quote_role: BACKGROUND
  - reference: PMID:12135418
    reference_title: "Protan colour vision deficiency and road accidents."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Protans are precluded from holding a commercial driver's licence in Australia
      because they have a substantially reduced ability to see red lights and have
      more road accidents involving signal lights.
    explanation: >-
      Documents a licensing standard based on the protan red-light deficit.
    quote_role: BACKGROUND
  - reference: PMID:30443703
    reference_title: "The impacts of abnormal color vision on people's life: an integrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      people with some degree of color vision loss face challenges in different
      aspects of their daily life, especially in their work activities.
    explanation: >-
      Integrative review identifying work activities as the most affected domain,
      the rationale for occupational counselling. Not protan-specific.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic counselling
  description: >-
    Counselling explains X-linked recessive transmission; carrier status in female
    relatives can be determined from the opsin array.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27622081
    reference_title: "Genetic Testing as a New Standard for Clinical Diagnosis of Color Vision Deficiencies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it provides information to patients about the underlying pathobiology of their
      disease.
    explanation: >-
      Opsin genotyping supplies information for counselling.
    quote_role: PRIMARY_RESULT
- name: L-opsin gene addition (preclinical)
  description: >-
    Subretinal AAV delivery of a human L-opsin gene to adult dichromatic male
    squirrel monkeys, which lack an L opsin gene, produced a third cone submosaic
    and trichromatic colour vision behaviour. No human trial for protan defects
    exists.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Absence of an Expressed L-Class Opsin Gene
    treatment_effect: RESTORES
    description: >-
      Supplies an L-class opsin to a subset of cones in an animal model; human
      efficacy is untested.
    evidence:
    - reference: PMID:19759534
      reference_title: "Gene therapy for red-green colour blindness in adult primates."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        here we show that the addition of a third opsin in adult red-green
        colour-deficient primates was sufficient to produce trichromatic colour vision
        behaviour.
      explanation: >-
        Gene addition of L opsin restored trichromatic behaviour in adult primates.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:19759534
    reference_title: "Gene therapy for red-green colour blindness in adult primates."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gene therapy was performed on adult squirrel monkeys (Saimiri sciureus) that
      were missing the L opsin gene.
    explanation: >-
      The treated animals lacked L opsin, the protan genotype.
    quote_role: PRIMARY_RESULT
animal_models:
- name: Dichromatic male squirrel monkey lacking L opsin
  species: Squirrel monkey (Saimiri sciureus)
  genotype: Hemizygous males carrying an M-class allele at the single X-linked opsin locus
  publication: PMID:19759534
  description: >-
    In squirrel monkeys a single polymorphic X-linked opsin locus makes all males
    dichromatic. Males lacking an L-opsin allele behave as protanopes; they were
    used to test L-opsin gene addition.
  modeled_mechanisms:
  - target: Absence of an Expressed L-Class Opsin Gene
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Naturally L-opsin-deficient dichromatic primate with S and M-class cones only.
    limitations: >-
      Dichromacy arises from allelic variation at a single X-linked locus, not from
      unequal recombination in a tandem L/M array, so the model does not reproduce
      the human mutational mechanism or hybrid-gene genotypes.
    evidence:
    - reference: PMID:10413401
      reference_title: "The evolution of trichromatic color vision by opsin gene duplication in New World and Old World primates."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        most New World primates have only a single polymorphic X-linked opsin gene;
        all males are dichromats and trichromacy is achieved only in those females
        that possess a different form of this gene on each X chromosome.
      explanation: >-
        Explains why male New World monkeys such as the squirrel monkey are natural
        X-linked dichromats.
      quote_role: BACKGROUND
    - reference: PMID:21167193
      reference_title: "The genetics of normal and defective color vision."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The treated monkeys were protanopes and after treatment, a subset of the cones
        co-expressed L-pigment with the native M pigment.
      explanation: >-
        The model animals were protanopes.
      quote_role: REVIEW_SYNTHESIS
  - target: Loss of L-versus-M Cone Opponent Signal
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      L-opsin gene addition in adult animals produced trichromatic behaviour on a
      colour discrimination task.
    limitations: >-
      Only a fraction of M cones co-expressed the transgene; long-term safety and
      human translation are untested.
    evidence:
    - reference: PMID:19759534
      reference_title: "Gene therapy for red-green colour blindness in adult primates."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        here we show that the addition of a third opsin in adult red-green
        colour-deficient primates was sufficient to produce trichromatic colour vision
        behaviour.
      explanation: >-
        Adding L opsin restored red-green discrimination capacity in the model.
      quote_role: PRIMARY_RESULT
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Protan Color Vision Deficiency · 2026-10-14T13:30:07Z · View source

New entry for MONDO:0010565 (red color blindness; OMIM:303900 protan series) with OPN1LW as the causal gene, X-linked recessive (HP:0001419). Lump/split: protanopia and protanomaly are has_subtypes rows (OLS searches of MONDO and ORDO found no separate disease terms; HPO phenotype terms HP:0011522 and HP:0200018 are bound on the phenotypes). Deutan (MONDO:0010564) and tritan (MONDO:0008610) defects keep their own stubs; blue cone monochromacy has its own entry; OPN1LW exon 3 haplotype disease with high myopia (MONDO:0010446, Bornholm eye disease) is a differential diagnosis. Pathograph: unequal recombination in the Xq28 L/M array, absence of an expressed L-class opsin gene, L cones filled with M-class pigment, then loss of the L-versus-M opponent signal (to Protanopia, Protanomaly, Red-green dyschromatopsia) and reduced long-wavelength luminous sensitivity; all three phenotypes are causally connected. Prevalence from a 2025 meta-analysis, an Irish school survey and the Korean KNHANES survey. Treatments: colour-enhancing filter glasses (EnChroma and ChromaGen studies recorded as REFUTE, the VINO CAD result as SUPPORT), occupational and genetic counselling, and preclinical L-opsin gene addition in squirrel monkeys (also recorded as an animal model). Deep research: one OpenScientist report (19/19 references resolved; 1 quote flagged, a truncated prevalence quote from PMID:40769301 whose own text matches the abstract; term validation flagged CL:0000573 used for L cones). just preflight-dr returned WARN only because OPN1MW, the array partner gene, is mentioned; the report is about the protan defect. The report misstates the OPN1LW HGNC id as HGNC:4206 (that is OPN1MW; the entry binds hgnc:9936 from the HGNC REST lookup) and maps HP:0011519 (Anomalous trichromacy) to protanomaly; neither was used. Report citations used: 27622081, 9822760, 22472762, 40769301, 23322568, 41806157, 30443703, 10413401. Not used: 22349213 (vertebrate LWS spectral tuning, not human disease), 35103751 (protan share of cases only, no protan prevalence figure), 24702753, 33955536, 38396435 (not protan-specific), 29386880, 26603570 (mouse and promoter gene-therapy work not specific to protan defects), 12678637 (normal L:M ratio). Additional primary sources found by PubMed search include Nathans 1986 (3485310, 2937147), Merbs and Nathans 1992, Sharpe 1998, Deeb reviews, Neitz reviews (21167193, 34440353), cone-resolved optoretinography (33544131), reflectometry and ERG replacement studies, red-signal sensitivity and traffic-light studies, and the Mancuso 2009 squirrel monkey gene therapy. PMID:39354153 (EnChroma prospective study) was not used because its cache has no quotable text. No GeneReviews chapter exists. Validation: just validate, validate-terms, count-verified-snippets (65/65), check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-block-scalar-comments, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles and validate-disorders all pass.

OpenScientist ▸
Key Findings
openscientist-autonomous 16 citations 2026-10-14T13:21:06.849877

Key Findings

1. Molecular etiology: altered copy number or sequence of X-linked cone opsin genes [human clinical/molecular]

The core etiology of protan CVD is firmly established. Causative mutations change the copy number or sequence of the L, M, or S cone opsin genes; for protan defects, the lesion specifically affects the L-cone opsin gene (OPN1LW). Davidoff, Neitz & Neitz (2016) performed direct sequencing and MassArray SNP genotyping of 1,872 subjects (1,074 with psychophysical testing) and correctly classified all protan/deutan red-green defects, with SNPs controlling spectral tuning correlating with Nagel anomaloscopy severity.

"The genetics underlying inherited color vision deficiencies is well understood: causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes." — PMID: 27622081

"Estimates of defect severity based on SNPs that control photopigment spectral tuning correlated with estimates derived from Nagel anomaloscopy." — PMID: 27622081

This finding (F001) anchors the entire disease model: protan CVD is a Mendelian photopigment disorder, not a neural or acquired condition, and its severity tracks directly with the molecular spectral-tuning state of the surviving opsin gene(s).

2. Mechanism — deletions and L/M hybrid genes from unequal recombination at Xq28 [human clinical/molecular]

Protan deficiency maps to the OPN1LW gene (HGNC:4206; OMIM gene 300822) at the proximal (5′) end of the OPN1LW/OPN1MW tandem array on Xq28; the phenotype "Colorblindness, partial, protan series" is OMIM 303900. The lesions are produced by intergenic and intragenic unequal homologous recombination between the highly similar L and M genes, yielding 5′L–3′M hybrid genes (encoding M-like pigments, causing protanomaly or protanopia depending on the crossover point) and gene deletions (removing the L gene entirely). Single-gene dichromats carry only a single X-linked pigment gene, the structural signature of recombination-mediated loss of the L gene (Sharpe et al. 1998).

"causative mutations change the copy number or sequence of the long (L), middle (M), or short (S) wavelength sensitive cone opsin genes" — PMID: 27622081

Molecular analysis of Japanese men by Deeb et al. (1995) identified exon 3 as a recombination/gene-conversion hotspot and found abnormal array patterns (deletions, hybrids) in ~5% of men, matching the phenotypic frequency of CVD (F009, F011).

3. Phenotype determination by spectral-tuning residues (sites 180, 277, 285) [human psychophysics / in vitro]

The protan phenotype and its severity are set by the amino-acid identity at key spectral-tuning sites of the surviving opsin. Sharpe et al. (1998) studied 41 single-gene male dichromats and showed the deduced opsin amino-acid sequence correlated directly with psychophysically measured cone spectral sensitivity and Rayleigh matches.

"allows for a straightforward correlation between each observer's spectral sensitivity measured at the cornea and the amino acid sequence of his visual pigment" — PMID: 9822760

The LWS pigment λmax (~525–560 nm) is tuned by substitutions at a small set of sites — notably 180, 197, 277, 285, and 308 (the "five-site rule") (Davies et al. 2012). The L and M opsins differ by ~15–19 residues, with sites 277 and 285 producing the largest (red↔green) spectral shifts and site 180 (Ser↔Ala) causing a ~2–5 nm polymorphism that modulates the exact λmax and thus the severity of anomalous trichromacy.

"amino acid substitutions at five sites (180, 197, 277, 285 and 308) are useful in predicting the λ(max) values of the LWS pigment class" — PMID: 22349213

Importantly, the normal L:M cone ratio varies widely (28–93% L; mean ~65% L) among color-normal males (Carroll et al. 2002, PMID: 12678637), so the separation between the two surviving pigments' λmax — not the cone ratio per se — determines whether color discrimination is normal, anomalous, or absent (F008).

4. Severe allelic branch — Bornholm Eye Disease (dichromacy + cone dystrophy + myopia) [human families / in vitro]

A rare but clinically important branch arises when specific L-opsin exon-3 haplotypes destabilize the opsin protein. McClements et al. (2013) studied 7 Bornholm Eye Disease (BED) families and found affected L opsin genes carried a rare exon-3 haplotype (e.g., LIAVA / LVAVA) in the first array position. In vitro, the variant opsins trafficked to membranes but were less stable and produced in reduced amounts, with defective exon-3 splicing implicated. One family instead carried the deleterious Cys203Arg substitution.

"The variant opsins were, however, less stable than wild type." — PMID: 23322568

"Both mechanisms explain the presence of dichromacy and cone dystrophy." — PMID: 23322568

This establishes a mechanistic bridge from simple color deficiency (benign) to a progressive, sight-threatening cone dystrophy with high myopia (F010, F012). It is the single exception to the otherwise benign prognosis of protan CVD.

5. Epidemiology — ~2.6% global prevalence with strong male predominance [meta-analysis / cross-sectional]

A meta-analysis of 1,703,619 participants across 56 studies in 21 countries estimated global congenital CVD prevalence at 2.59% (95% CI 2.20–3.03%) (Jeong et al. 2025).

"The global prevalence of CVD was estimated at 2.59% (95% confidence interval [CI], 2.20-3.03" — PMID: 40769301

Male predominance is consistent across cohorts. In a Chinese children's study, prevalence was 2.81% in boys vs 0.16% in girls, with deutan comprising 91.6% and protan only 8.3% of color-deficient cases.

"The prevalence of color vision deficiency was 1.68%, with 2.81% in boys and 0.16% in girls. Color-deficient cases consisted of 91.6% deutan and 8.3% protan." — PMID: 35103751

6. Ancestry variation driven by founder effects/genetic drift [review / cross-sectional]

Red-green CVD prevalence varies substantially by ancestry. Birch's review reported ~8% of European Caucasian men and ~0.4% of women affected, and 4–6.5% of Chinese and Japanese men, attributing differences to founder events and genetic drift rather than natural selection.

"the prevalence of deficiency in European Caucasians is about 8% in men and about 0.4% in women and between 4% and 6.5% in men of Chinese and Japanese ethnicity" — PMID: 22472762

"founder events and genetic drift, rather than natural selection, are the cause of these differences" — PMID: 22472762

The Multi-Ethnic Pediatric Eye Disease Study (4,177 children) confirmed ancestry- and sex-specific patterns:

"The prevalence of CVD among boys was 1.4% for black, 3.1% for Asian, 2.6% for Hispanic, and 5.6% for non-Hispanic white children; the prevalence in girls was 0.0% to 0.5%" — PMID: 24702753

(F002, F011)

7. Diagnosis — pseudoisochromatic plates with anomaloscopy as gold standard [diagnostic validation]

Protan CVD is diagnosed clinically by Ishihara pseudoisochromatic plates (screening), with the Nagel anomaloscope (Rayleigh red-green match) as the gold standard for distinguishing dichromacy from anomalous trichromacy and protan from deutan. Digital tests (e.g., DIVE) show excellent agreement with Ishihara and quantify severity along the protan axis.

"The DIVE and Ishihara tests exhibited excellent agreement in identifying participants with color deficiency (Cohen's kappa = 1.00)" — PMID: 38396435

Molecular opsin-gene analysis (MassArray/sequencing) provides definitive confirmation of type and severity (Davidoff-Neitz 2016, PMID: 27622081) (F005).

8. Quality-of-life impact — functional, not medical [review / cross-sectional]

An integrative review (PRISMA, 20 studies) categorized CVD impacts into daily routine, occupational, product choice, emotional, education, and self-care domains, with work activities most affected.

"people with some degree of color vision loss face challenges in different aspects of their daily life, especially in their work activities" — PMID: 30443703

In 1,426 Egyptian students, those with CVD had significantly higher odds of difficulties in daily and study/work color tasks.

"Students with colour vision defects had significantly higher odds ratios for difficulties in daily activities and study/work tasks related to colour perception." — PMID: 33955536

Protan individuals additionally have reduced luminous sensitivity to long-wavelength light, a distinguishing feature with safety implications (F004).

9. No curative treatment; filters do not reduce severity [interventional]

In 80 CVD males (5 protanopes, 18 protanomalous), ChromaGen filters altered the nature of the deficiency without correcting it; no protanope passed any test with any lens.

"ChromaGen filters may influence the nature of CVD without reducing its severity" — PMID: 41806157

"none of the participants with protanopia passing any of the tests using any ChromaGen lens" — PMID: 41806157

(F006)

10. Gene therapy — proof-of-concept in preclinical models [model organism]

AAV-mediated opsin gene augmentation has restored L/M-cone function in animal models, establishing proof-of-concept relevant to protan correction. AAV5 vectors expressing human OPN1LW/OPN1MW regenerated cone outer segments and rescued M-cone function in M-opsin knockout mice (Deng et al. 2018); AAV8-Y733F expressing human L-opsin rescued cone function for ≥5 months in a C198R all-cone mouse model (Cahill et al. 2026). Optimized primate L-opsin promoters (PR1.7) drive strong cone-specific expression in nonhuman primates.

"Exogenously expressed human opsins can regenerate cone outer segments and rescue M-cone function in" — PMID: 29386880

"subretinal injection of an AAV-GFP vector containing a 1.7-kb L-opsin promoter (PR1.7) achieved strong and specific GFP expression in all cone photoreceptors" — PMID: 26603570

(F003)

11. Comparative/evolutionary context [computational/comparative]

The human L/M opsin tandem array arose by gene duplication. Old World primates (including humans) have separate X-linked MW/LW genes in a head-to-tail array flanked by an LCR; most New World monkeys have a single polymorphic X-linked opsin gene, so all males are dichromats and trichromacy occurs only in heterozygous females — a natural model of X-linked polymorphic color vision. Howler monkeys independently evolved routine trichromacy via opsin duplication.

"most New World primates have only a single polymorphic X-linked opsin gene; all males are dichromats and trichromacy is achieved only in those females that possess a different form of this gene on each X chromosome" — PMID: 10413401

"organized into a head-to-tail tandem array flanked on the upstream side by a locus control region (LCR)" — PMID: 10413401

(F007)

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Unequal homologous recombination (or gene conversion) occurs within the highly homologous OPN1LW/OPN1MW tandem array at Xq28, favored by the >96% sequence identity between the L and M genes and the exon-3 recombination hotspot. (demonstrated — Deeb 1995, Sharpe 1998) → leads to one of two structural outcomes (the mechanism branches here):

Branch A — Deletion of the L gene → only M-type gene(s) remain expressed in the "L" position → no functional L photopigment → protanopia (dichromacy).

Branch B — 5′L–3′M hybrid (chimeric) gene in the first array position → encodes a photopigment with an M-shifted λmax → the two expressed pigments (hybrid + M) have λmax separated by only a few nm → protanomaly (anomalous trichromacy); the smaller the λmax separation, the more severe the anomaly.

  1. The surviving opsin's amino-acid identity at spectral-tuning sites 180, 277, 285 (and 197, 308) sets the exact λmax of the L-position pigment. (demonstrated — Sharpe 1998, Davies 2012) → results in a shift or collapse of the long-wavelength spectral sensitivity function measured at the cornea.

  2. Loss/shift of L-cone spectral sensitivity → reduced or absent red-green chromatic signal at the L-vs-M cone-opponent pathway, plus reduced luminous sensitivity to long-wavelength (red) light (L cones dominate the luminance channel). → results in the perceptual phenotype: confusion of reds/greens/browns and dimming of red stimuli. (demonstrated — psychophysics)

  3. Clinical manifestation: congenital, bilateral, non-progressive red-green color confusion with the protan signature (red appears dim), present from birth and stable for life. (demonstrated)

Severe sub-branch (Bornholm Eye Disease): If the first-array L gene carries a destabilizing exon-3 haplotype (LIAVA/LVAVA) or Cys203Arg, the opsin protein is less stable / produced in reduced amounts / mis-spliced → cone outer-segment dysfunction → cone dystrophy + high myopia superimposed on dichromacy. (demonstrated in vitro — McClements 2013; the splicing contribution is partly inferred)

Schematic

   Xq28 OPN1LW/OPN1MW tandem array (head-to-tail, LCR upstream)
   LCR --[ L gene (5') ]--[ M gene(s) (3') ]-->
 |
      unequal recombination / gene conversion (exon-3 hotspot)
 /                                    \
   DELETION of L                        5'L-3'M HYBRID gene
 |                                     |
   no L pigment                        M-shifted pigment (small Δλmax)
 |                                     |
   PROTANOPIA                           PROTANOMALY
  (dichromacy)                     (anomalous trichromacy)
 \                                    /
  --> loss/shift of L-cone spectral sensitivity
  --> reduced red-green opponency + dim red (luminance)
  --> congenital, bilateral, stable red-green CVD
               |
     (if destabilizing exon-3 haplotype / C203R)
               v
     Bornholm Eye Disease: + cone dystrophy + myopia

Ontology mapping

Entity Term
Disease MONDO:0010565 (protan defect)
Gene OPN1LW HGNC:4206, OMIM 300822
Phenotype HP:0000551 Abnormality of color vision; HP:0011519 Protanomaly / protan defect
Cell type CL:0000573 retinal cone cell (L cone)
Anatomy UBERON:0000966 retina; UBERON:0000970 eye
Biological process GO:0007601 visual perception; GO:0007602 phototransduction; GO:0050908 detection of light stimulus involved in visual perception
Cellular component GO:0001750 photoreceptor outer segment; GO:0016020 membrane (opsin)
Chemical CHEBI:17201 11-cis-retinal (chromophore)

Anatomical, Temporal, and Population Summary (consolidated)

  • Anatomy: Retina (UBERON:0000966), specifically L-cone photoreceptors (CL:0000573) of both eyes; the defect is bilateral and symmetric. The opsin is a membrane protein of the cone outer segment (GO:0001750). No other organ system is involved.
  • Onset/temporal course: Congenital (fixed at conception, germline X-linked); non-progressive and lifelong/stable. The only progressive presentation is the rare Bornholm Eye Disease branch.
  • Inheritance: X-linked recessive; males (hemizygous) affected, females affected only when homozygous/compound (rare) — explaining the strong male predominance. Carrier females may show subtle anomalies and, by Lyonization and heterozygosity for two pigment alleles, can occasionally be tetrachromatic.
  • Prognosis: Benign — no systemic morbidity or mortality; morbidity is functional/occupational (color-dependent tasks, certain career restrictions such as aviation, electrical work, some military/transport roles).
  • Prevention/counseling: No primary prevention exists for a germline X-linked trait; genetic counseling can inform carrier risk. There is no newborn screening mandate; school-age pseudoisochromatic screening enables early awareness and career guidance.

Evidence Base

PMID Title (abbrev.) Evidence type Supports
27622081 Genetic testing as new standard for CVD diagnosis Human clinical/molecular (n=1,872) F001, F005, F009 — copy-number/sequence etiology; molecular diagnosis
9822760 Red/green/hybrid pigments; sequence↔spectral sensitivity Human psychophysics/molecular (n=41) F008, F009 — sequence determines spectral sensitivity; single-gene dichromats
22349213 Spectral tuning of MWS/LWS pigments In vitro / comparative F008 — five-site tuning rule (180,197,277,285,308)
12678637 L:M cone ratio from ERG + genetics Human (n=62) F008 — wide normal L:M ratio (28–93% L)
23322568 Opsin coding variants → cone dysfunction + myopia Human families + in vitro (7 families) F010, F012 — Bornholm Eye Disease mechanism
7759069 Molecular patterns in Japanese men Human population molecular (n=203) F009, F011 — hybrids/deletions ~5%; exon-3 hotspot
40769301 Global prevalence of congenital CVD Meta-analysis (n=1.7M) F002 — 2.59% global prevalence
35103751 CVD & myopia in Chinese children Cross-sectional F002 — male predominance; deutan 91.6% vs protan 8.3%
22472762 Worldwide prevalence of red-green deficiency Review F011 — ancestry variation; founder/drift
24702753 Multi-ethnic pediatric eye disease study Cross-sectional (n=4,177) F011 — sex/ancestry-specific prevalence
38396435 Validation of digital color test (DIVE) Diagnostic validation F005 — plate/digital screening, kappa=1.00
30443703 Impacts of abnormal color vision (integrative review) Review (20 studies) F004, F012 — QoL/occupational impact
33955536 CVD prevalence/predictors, Egyptian students Cross-sectional (n=1,426) F004 — functional difficulty
41806157 ChromaGen lenses on CVD test performance Interventional (n=80) F006 — filters do not reduce severity
29386880 Human L/M opsins restore M-cone function (mouse) Model organism F003 — gene therapy proof-of-concept
26603570 Cone-specific promoters for gene therapy Model organism / NHP F003 — PR1.7 L-opsin promoter
42275379 Gene therapy in all-cone C203R mouse Model organism F003 — AAV L-opsin rescue ≥5 months
10413401 Evolution of trichromacy by opsin duplication Comparative genetics F007 — array origin; NW monkey model
14963105 Trichromacy + pheromones in howler monkeys Comparative genetics F007 — independent opsin duplication

Model-organism note: The mouse is the principal model. Wild-type mice lack an L-opsin (only S and M), so human protan biology is studied via humanized/knock-in opsin mice and all-cone (Nrl−/−) backgrounds. These recapitulate cone opsin loss and gene-therapy rescue (outer-segment regeneration, ERG restoration) but cannot fully model human trichromatic perception or the foveal cone architecture. New World monkeys serve as a natural genetic model of single-locus X-linked polymorphic dichromacy/trichromacy (OPN1LW/MW orthologs; NCBI Taxonomy under Platyrrhini).

Limitations and Knowledge Gaps

  1. Protan-specific vs red-green-combined data. Most epidemiologic and QoL studies report red-green CVD as a whole; protan-only figures are scarcer. Protan is consistently the minority (~8% of CVD cases), so protan-specific prevalence is roughly ~1% of European-ancestry men — but precise protanope-vs-protanomal breakdowns across ancestries are incompletely characterized.
  2. No human gene-therapy trials for isolated protan CVD. All restorative evidence is preclinical (mouse, NHP promoter work). The benign, non-degenerative nature of common protan CVD makes a surgical subretinal AAV intervention a difficult risk/benefit proposition; clinical translation is more plausible for the degenerative Bornholm/BCM branch.
  3. Genotype–phenotype fine mapping. While the five-site rule predicts λmax, individual-level prediction of anomaloscope matching range from genotype still carries uncertainty, particularly for intermediate hybrids and the effect of site-180 polymorphism.
  4. Carrier (heterozygous female) phenotypes — including possible tetrachromacy and subclinical anomalies — are under-quantified in the retrieved literature.
  5. Epigenetic/environmental modifiers. No strong evidence implicates epigenetic regulation or environmental exposure in congenital protan CVD; acquired red-green changes (e.g., in multiple sclerosis, optic neuropathy, diabetes) are a distinct differential, not the Mendelian entity.
  6. Splicing mechanism in BED is partly inferred; the relative contribution of reduced protein stability vs defective exon-3 splicing to the LIAVA/LVAVA phenotype is not fully resolved.

Proposed Follow-up Experiments / Actions

  1. Protan-stratified meta-analysis: Re-analyze existing large cohorts to extract protanopia vs protanomaly frequencies by ancestry and sex, improving knowledge-base epidemiology fields.
  2. Genotype→anomaloscope predictive model: Build and validate a quantitative model mapping opsin array structure + spectral-tuning SNPs to Nagel matching midpoint/range, extending Davidoff-Neitz 2016.
  3. Natural-history registry for exon-3 haplotype carriers (LIAVA/LVAVA/C203R): Prospectively track myopia and cone-dystrophy progression to define the benign-vs-BED boundary and intervention windows.
  4. Preclinical→clinical gene-therapy pathway for the degenerative branch: Prioritize AAV L-opsin augmentation (PR1.7/PR2.1 promoters, AAV8-Y733F capsids) for BED/BCM where there is a clear degenerative target, building on the C198R all-cone mouse rescue.
  5. Carrier-female phenotyping study: Quantify subtle discrimination deficits and potential tetrachromacy in obligate carriers using modern digital tests (DIVE) plus opsin genotyping.
  6. Assistive-technology benchmarking: Rigorously compare digital aids/apps against filters (which do not reduce severity) for task-specific performance (e.g., signal recognition), given the confirmed null result for ChromaGen.

Conclusion

Protan color vision deficiency is a paradigmatic, molecularly resolved Mendelian photopigment disorder: X-linked recessive loss or spectral alteration of the L-cone opsin (OPN1LW, Xq28), arising predominantly through unequal recombination–generated deletions and 5′L–3′M hybrid genes, with phenotype severity set by amino-acid spectral-tuning residues (180/277/285). It is common (~1% of European-ancestry men; ~2.6% CVD overall), benign and non-progressive, diagnosed by pseudoisochromatic plates and anomaloscopy/opsin genotyping, and currently untreatable (filters do not reduce severity; gene therapy is preclinical). A rare destabilizing exon-3 allelic branch (LIAVA/LVAVA; C203R) crosses into sight-threatening Bornholm Eye Disease, the one context where restorative gene therapy has a compelling rationale.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 21
Quoted claims found in source 20
Quoted claims not found in source 1
References weighed for topical relevance 19
On topic 12
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:40769301 (abstract only): "The global prevalence of CVD was estimated at 2.59% (95% confidence interval [CI], 2.20-3.03"
  • closest text in source: "The global prevalence of CVD was estimated at 2.59% (95% confidence interval [CI], 2.20-3.03"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 13
Resolved 12
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 3
Terms named correctly 1
Terms named as a different term 1
Terms whose name is worth a second look 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:0000573 (2 mentions) - the report calls it "L-cone photoreceptors"; CL calls it retinal cone cell

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0000966 (2 mentions) - the report calls it "Anatomy: Retina"; UBERON calls it retina**