Congenital Stationary Night Blindness

Mendelian MONDO:0016293 Pathograph 9 Show in embeddings browser Ophthalmological Disease Inherited retinal dystrophy

Congenital stationary night blindness (CSNB) is a genetically heterogeneous group of non-progressive inherited retinal disorders in which the retina is structurally normal on fundus examination but cannot signal in dim light. Its importance to disease modelling is that a single clinical label covers two mechanistically opposite lesions, and the electroretinogram tells them apart. In the Riggs form the defect is inside the rod photoreceptor, in the phototransduction cascade itself: the rod cannot generate a light response, the a-wave is lost, and the b-wave falls with it. In the far commoner Schubert-Bornschein form the photoreceptor works and the defect lies at the synapse onto the depolarizing (ON) bipolar cell: the a-wave is preserved while the b-wave is selectively lost, giving the electronegative waveform. The Schubert-Bornschein group divides again by electroretinogram into a complete form, in which only the ON pathway fails, and an incomplete form, in which both ON and OFF pathways are affected and daytime acuity suffers too. Beyond night blindness, patients commonly have high myopia, nystagmus, strabismus and reduced acuity. Because the disease is stationary and recessive, the retina remains available to treat throughout life, and gene augmentation restores function in mature animals rather than only in developing ones.

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1
Inheritance
6
Pathophys.
6
Phenotypes
1
Gaps
9
Pathograph
10
Genes
2
Medical Actions
3
Subtypes
2
Models
1
References
👪

Inheritance

1
Genetically heterogeneous
CSNB is inherited as an autosomal recessive trait (most complete and incomplete Schubert-Bornschein forms), X-linked recessive (NYX in cCSNB, CACNA1F in icCSNB), or autosomal dominant (several Riggs-form genes, including gain-of-function RHO and GNAT1 alleles). Mode of inheritance therefore does not identify the mechanistic arm and cannot substitute for electroretinography.
Show evidence (1 reference)
PMID:29390235 SUPPORT Other
"The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB)."
States the three inheritance modes across the CSNB group. Evidence source is OTHER because this is a review.
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Subtypes

3
Complete CSNB (Schubert-Bornschein, ON pathway) MONDO:0010690
The complete Schubert-Bornschein form, caused by loss of a component of the mGluR6 signalplex at the dendritic tips of depolarizing (ON) bipolar cells - NYX, GRM6, TRPM1, GPR179 or LRIT3. Rod signalling to the ON pathway is abolished, the ON-pathway b-wave is absent, and the OFF pathway is spared. Night blindness is profound; there is no retinal degeneration.
Show evidence (1 reference)
PMID:42471459 SUPPORT Model Organism
"These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration."
Names the five cCSNB signalplex genes and states the defining absence of retinal degeneration that separates this from the dystrophies.
Incomplete CSNB (Schubert-Bornschein, ON and OFF pathways) MONDO:0010241
The incomplete Schubert-Bornschein form, caused most often by CACNA1F variants affecting the Cav1.4 calcium channel at the photoreceptor ribbon synapse, or by CABP4. Because the lesion is presynaptic it impairs transmitter release to both ON and OFF bipolar pathways, so daytime acuity and cone function are affected as well as scotopic vision - the reason "incomplete" describes a broader, not a milder, deficit.
Show evidence (1 reference)
PMID:24466230 SUPPORT Model Organism
"Mutations in the human CACNA1F gene encoding the α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2)."
Assigns CACNA1F to the incomplete form and identifies the channel subunit involved.
Riggs CSNB (rod phototransduction cascade) MONDO:0012498
The rarer Riggs form, in which the lesion is inside the rod photoreceptor rather than at its synapse - RHO, GNAT1, PDE6B, GNB3 or SLC24A1 - and the rod phototransduction cascade cannot generate or cannot terminate a light response. The a-wave is lost with the b-wave, distinguishing it electrophysiologically from the Schubert-Bornschein forms, and the fundus and daytime vision are normal.
Show evidence (1 reference)
PMID:29390235 SUPPORT Other
"genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade"
Assigns the Riggs form specifically to the rod phototransduction cascade, which is what justifies conforming only this arm to the phototransduction module. Evidence source is OTHER because this is a review.
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Discussions and Knowledge Gaps

1
Is "stationary" a safe description of every CSNB genotype, given that some alleles in CSNB genes produce progressive photoreceptor degeneration?
KNOWLEDGE GAP csnb_stationary_label_versus_progressive_alleles
Attached to
pathophysiology#Presynaptic Calcium Channel Defect at the Photoreceptor Ribbon Synapse pathophysiology#Impaired Scotopic Vision with Normal Fundus
The absence of degeneration is treated as definitional for CSNB and is the basis for the claim that the retina remains treatable into adulthood. Yet both mouse models of CSNB2 - a loss-of-function Cacna1f line and a gain-of-function I756T line - showed progressive photoreceptor loss, worse in the gain-of-function line, and CACNA1F variants in humans present either as incomplete CSNB or as progressive cone-rod dystrophy. GNAT1 shows the same allelic split between stationary and degenerative outcomes. If stationarity is an allele-level rather than a gene-level property, then a CSNB diagnosis alone does not license indefinite deferral of intervention, and the therapeutic window argument needs qualifying per genotype.
Proposed experiments
Longitudinal outer-retinal imaging in CSNB stratified by allele class
csnb_longitudinal_oct_by_allele_class
Follow molecularly defined CSNB cohorts with serial optical coherence tomography of the outer nuclear layer and ellipsoid zone, stratified by whether the variant is predicted loss of function or gating-altering, to test whether measurable photoreceptor loss occurs in any subgroup over a decade.
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Pathophysiology

6
Rod Phototransduction Cascade Defect (Riggs Arm)
In the Riggs form the causative variant sits in the rod phototransduction cascade itself - the visual pigment (RHO), the transducin subunits (GNAT1, GNB3), the phosphodiesterase (PDE6B), or the sodium-calcium exchanger that sets the outer-segment ion balance (SLC24A1). Some are loss-of-function and the rod cannot mount a response; some, notably the RHO G90D and T94I substitutions, are gain-of-function changes that keep the pigment constitutively active in darkness so the rod behaves as though it were permanently light-adapted. Either way the rod's own light response is abolished or desensitized, and the electroretinographic a-wave goes with it.
rod photoreceptor cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves rod photoreceptor cell, annotated with retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Phototransduction GO:0007602 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Phototransduction (GO:0007602). GO:0007602 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Loss of Rod Light-Response Generation
Show evidence (2 references)
PMID:29390235 SUPPORT Other
"genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade"
Directly assigns the Riggs-form genes to the rod phototransduction cascade, which is the claim this node and its module conformance rest on. Evidence source is OTHER because this is a review.
PMID:27063057 SUPPORT Human Clinical
"Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade"
Independent confirmation, in a gene-discovery paper, that the Riggs form is a selective rod photoreceptor cascade defect.
Loss of Rod Light-Response Generation
The rod fails to convert absorbed photons into the graded hyperpolarization that drives the rest of the visual pathway. Because the defect is inside the photoreceptor, the summed rod response that generates the scotopic a-wave is lost, and the b-wave falls secondarily for want of an input - the pattern that distinguishes this arm from the Schubert-Bornschein forms, where the a-wave survives.
rod photoreceptor cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves rod photoreceptor cell, annotated with retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
Detection of light stimulus involved in visual perception GO:0050908 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Detection of light stimulus involved in visual perception (GO:0050908). GO:0050908 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Scotopic Vision with Normal Fundus
Show evidence (1 reference)
PMID:29850563 SUPPORT Human Clinical
"Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves."
Ties altered phototransduction to the a-wave-dominant electroretinographic signature this node asserts, in a molecularly confirmed adCSNB family.
mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
The complete Schubert-Bornschein arm, and mechanistically NOT a phototransduction defect. In darkness photoreceptors release glutamate tonically onto depolarizing (ON) bipolar cells, where the metabotropic receptor GRM6 keeps the TRPM1 cation channel closed; light, by reducing glutamate release, opens TRPM1 and depolarizes the bipolar cell - a sign-inverting synapse. NYX, GRM6, TRPM1, GPR179 and LRIT3 form a single interdependent signalplex at the ON-bipolar dendritic tip, so loss of any one of them disassembles the complex and abolishes the inversion. The photoreceptor upstream is entirely normal.
ON-bipolar cell CL:0000749 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ON-bipolar cell (CL:0000749). CL:0000749 is a cell type from the Cell Ontology.
G protein-coupled glutamate receptor signaling pathway GO:0007216 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased G protein-coupled glutamate receptor signaling pathway (GO:0007216). GO:0007216 is a biological process from the Gene Ontology. ↓ DECREASED Synapse organization GO:0050808 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Synapse organization (GO:0050808). GO:0050808 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Lrit3-null mouse model of complete CSNB Mouse rescues Subretinal AAV-LRIT3 in mature Lrit3-null retina restores the signalplex and rescues retinal function and cortical visual acuity, establishing that the defect is correctable after development is complete.
Canine LRIT3-CSNB model Dog rescues Subretinal ON-bipolar-targeted AAV-LRIT3 produced durable functional recovery and restored the signalplex member TRPM1 in the outer plexiform layer of the treated area.
Downstream
Failure of Photoreceptor-to-Bipolar Signal Transmission
Show evidence (2 references)
PMID:37220680 SUPPORT Model Organism
"One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
Localizes the five complete-CSNB genes to the mGluR6 cascade at the ON-bipolar dendritic tip, which is the anatomical claim separating this node from the Riggs arm.
PMID:42471459 SUPPORT Model Organism
"Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes that are part of a large, interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors."
Supports the specific claim that these genes act as one interdependent complex, which is why losing any single member produces the same phenotype.
Presynaptic Calcium Channel Defect at the Photoreceptor Ribbon Synapse
The incomplete Schubert-Bornschein arm. Cav1.4, encoded by CACNA1F, sits at the photoreceptor ribbon synapse and does two jobs: it gates the calcium influx that drives tonic glutamate release, and it organizes the synapse structurally. A loss-of-function variant therefore starves both the ON and the OFF bipolar pathways of input, which is why the incomplete form compromises daytime acuity and cone function as well as night vision. The lesion is presynaptic but still postphototransduction: the rod's light response itself is intact.
photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
Calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↓ DECREASED Neurotransmitter secretion GO:0007269 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Neurotransmitter secretion (GO:0007269). GO:0007269 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Failure of Photoreceptor-to-Bipolar Signal Transmission
Show evidence (2 references)
PMID:24466230 SUPPORT Model Organism
"Light-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses."
Establishes the presynaptic function whose loss defines this node, and locates it at the ribbon synapse rather than in the outer segment.
PMID:29390235 SUPPORT Other
"Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors."
Assigns the incomplete-form genes specifically to presynaptic glutamate release, distinguishing them from the postsynaptic signalplex genes of the complete form. Evidence source is OTHER because this is a review.
Failure of Photoreceptor-to-Bipolar Signal Transmission
Both Schubert-Bornschein arms converge here: the photoreceptor generates a normal light response that fails to reach the inner retina. Because the a-wave is generated by the photoreceptor and the b-wave by the bipolar cells downstream, the result is the electronegative electroretinogram - a b-wave that falls below the a-wave. This waveform localizes the lesion to the inner retina or the photoreceptor-bipolar synapse, and it is the single most informative bedside test in CSNB because it partitions the disease group by mechanism before any sequencing is done. It is not specific to CSNB: X-linked retinoschisis and KCNV2-associated disease produce it too, by their own routes.
ON-bipolar cell CL:0000749 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ON-bipolar cell (CL:0000749). CL:0000749 is a cell type from the Cell Ontology. photoreceptor cell CL:0000210 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves photoreceptor cell (CL:0000210). CL:0000210 is a cell type from the Cell Ontology.
Chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Scotopic Vision with Normal Fundus
Show evidence (4 references)
PMID:42106701 SUPPORT Other
"The electronegative electroretinogram (ERG)-in which the dark-adapted bright-flash b-wave amplitude falls below the a-wave (b: a ratio < 1.0)-localizes dysfunction to the inner retina or photoreceptor-bipolar synapse."
Defines the waveform quantitatively and states the anatomical localization this node asserts. Evidence source is OTHER because this is a systematic review.
PMID:42106701 SUPPORT Other
"The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2)."
Supports the discriminating value of the waveform while establishing the specificity caveat this node states. Marked PARTIAL because the same review rates the underlying evidence as high risk of bias.
PMID:29390235 SUPPORT Other
"While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form."
States the transmission-versus-photoreceptor contrast that this node's placement, and the entry's selective module conformance, depend on. Evidence source is OTHER because this is a review.
+ 1 more reference
Impaired Scotopic Vision with Normal Fundus
The shared clinical endpoint. Vision in dim light is impaired from birth and stays that way - the disease is stationary, and the fundus is essentially normal, which is why CSNB is missed or misattributed when electroretinography is not done. Accompanying signs are common and are what usually bring the child to attention: high myopia, nystagmus, strabismus and reduced acuity, the last most marked in the incomplete form where the cone pathway is involved too. There is no retinal degeneration, which both defines the group and, because the retina stays intact, keeps it treatable into adulthood. This node deliberately carries NO conforms_to. It is the shared endpoint of all three arms - the Riggs cascade lesion above it and both Schubert-Bornschein transmission lesions - so wiring it to phototransduction_cascade_dysfunction would silently readmit the very forms that module's scope note excludes, and would assert "photoreceptor dysfunction" of arms in which the photoreceptor is intact and the synapse is what fails. Module conformance for this entry is therefore confined to the two Riggs-arm nodes upstream, which is where the module's key conformance target sits.
Visual perception GO:0007601 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Visual perception (GO:0007601). GO:0007601 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (3 references)
PMID:29390235 SUPPORT Other
"Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
Enumerates the accompanying ocular signs this node lists. Evidence source is OTHER because this is a review.
PMID:20301423 SUPPORT Other
"X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia"
GeneReviews supplies the acuity range and confirms the non-progressive character and normal fundus that define this node, for the X-linked forms. Evidence source is OTHER because GeneReviews is an expert-curated clinical synthesis rather than a primary study.
PMID:42471459 SUPPORT Model Organism
"These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration."
Supports the combination of impaired low-light vision with myopia and nystagmus, and the explicit absence of degeneration that this node treats as defining.
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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 Congenital Stationary Night Blindness 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

6
Night Blindness VERY_FREQUENT Ocular HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"Congenital stationary night blindness (CSNB) is a group of inherited retinal diseases in which either rod-to-ON-bipolar cell (ON-BC) signaling, or rod function is affected leading to impaired vision under low light conditions."
States impaired low-light vision as the defining consequence common to both mechanistic arms. VERY_FREQUENT is a Pattern C mapping of that definitional framing (docs/frequency-evidence-guidelines.md); no proportion is reported, and the band is defensible because impaired low-light vision is what defines membership of the group.
Electronegative Electroretinogram Ocular HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42106701 SUPPORT Other
"Electronegative ERG patterns were commonly described across the CSNB and XLRS literature, with the greatest consistency for complete CSNB and KCNV2."
Supports both the association and the specific point that consistency is greatest for the complete form, which is why this phenotype is scoped to the cCSNB subtype.
Myopia Ocular HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27063057 SUPPORT Human Clinical
"Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus."
Establishes the association across both Schubert-Bornschein subtypes rather than in the complete form alone. No frequency band is asserted: the source reports "variable degrees" without a proportion, and this entry spans three mechanistically distinct subtypes whose refractive and ocular-motor profiles differ, so a single disease-level band would not be supportable.
PMID:42471459 SUPPORT Model Organism
"the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration"
Corroborates the association specifically in the complete form, whose description names myopia as a characteristic feature.
Nystagmus Ocular HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27063057 SUPPORT Human Clinical
"Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus."
Establishes the association across both Schubert-Bornschein subtypes rather than in the complete form alone. No frequency band is asserted: the source reports "variable degrees" without a proportion, and this entry spans three mechanistically distinct subtypes whose refractive and ocular-motor profiles differ, so a single disease-level band would not be supportable.
PMID:42471459 SUPPORT Model Organism
"the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration"
Corroborates the association specifically in the complete form, whose description names nystagmus among the characteristic features.
Strabismus Ocular HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29390235 SUPPORT Other
"Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
Lists strabismus among the additional ocular signs. Evidence source is OTHER because this is a review.
Reduced Visual Acuity Ocular HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced visual acuity (HP:0007663). HP:0007663 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29390235 SUPPORT Other
"While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well."
States that acuity is affected specifically in the incomplete form because both pathways are involved, which is why this phenotype is scoped to that subtype.
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Genetic Associations

10
NYX (Loss-of-function variants causing complete CSNB (X-linked))
Gene: NYX hgnc:8082 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NYX (hgnc:8082). hgnc:8082 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
Assigns NYX to the mGluR6 signalplex of the complete form.
GRM6 (Biallelic loss-of-function variants causing complete CSNB)
Gene: GRM6 hgnc:4598 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GRM6 (hgnc:4598). hgnc:4598 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
Assigns GRM6, the metabotropic glutamate receptor that names the cascade, to the complete form.
TRPM1 (Biallelic loss-of-function variants causing complete CSNB)
Gene: TRPM1 hgnc:7146 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TRPM1 (hgnc:7146). hgnc:7146 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
Assigns TRPM1, the effector cation channel of the cascade, to the complete form.
LRIT3 (Biallelic loss-of-function variants causing complete CSNB)
Gene: LRIT3 hgnc:24783 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LRIT3 (hgnc:24783). hgnc:24783 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:42471459 SUPPORT Model Organism
"We used a mouse model of cCSNB caused by LRIT3 loss to evaluate the efficacy of a single subretinal injection of an rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity."
Establishes LRIT3 loss as a cause of complete CSNB, and is the gene whose restoration rescued function in the model.
GPR179 (Biallelic loss-of-function variants causing complete CSNB)
Gene: GPR179 hgnc:31371 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GPR179 (hgnc:31371). hgnc:31371 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
Assigns GPR179 to the mGluR6 signalplex of the complete form.
CACNA1F (Hemizygous variants causing incomplete CSNB (X-linked))
Gene: CACNA1F hgnc:1393 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CACNA1F (hgnc:1393). hgnc:1393 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:24466230 SUPPORT Model Organism
"Mutations in the human CACNA1F gene encoding the α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2)."
Assigns CACNA1F to the incomplete form.
PMID:24466230 SUPPORT Model Organism
"Both mutants showed a progressive photoreceptor loss, but degeneration was more severe and significantly enhanced in the I756T mutants compared to the ΔEx14-17 mutants."
Supports the notes' caution that some CACNA1F alleles produce progressive degeneration, with the gain-of-function allele worse than the null.
CABP4 (Biallelic variants causing an incomplete CSNB-like phenotype)
Gene: CABP4 hgnc:1386 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CABP4 (hgnc:1386). hgnc:1386 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:42106701 SUPPORT Other
"The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2)."
Lists CABP4 among the CSNB genes associated with the electronegative waveform.
GNAT1 (Dominant and recessive variants causing Riggs CSNB)
Gene: GNAT1 hgnc:4393 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNAT1 (hgnc:4393). hgnc:4393 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:29850563 SUPPORT Human Clinical
"Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype."
Documents a cosegregating GNAT1 variant in a Riggs-type family, assigning the transducin alpha subunit to the phototransduction arm.
GNB3 (Biallelic variants causing a Riggs-like CSNB with cone involvement)
Gene: GNB3 hgnc:4400 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GNB3 (hgnc:4400). hgnc:4400 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:27063057 SUPPORT Human Clinical
"Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity."
Documents the GNB3 phenotype, which uniquely straddles the two arms - the gene modulates both ON-bipolar signalling and cone transducin function.
RHO (Gain-of-function missense variants (G90D, T94I) causing autosomal dominant Riggs CSNB)
Gene: RHO hgnc:10012 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is RHO (hgnc:10012). hgnc:10012 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:29850563 SUPPORT Human Clinical
"Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy."
Supports the general point that only a minority of phototransduction-gene alleles give stationary rather than degenerative disease, which is what distinguishes the CSNB-causing RHO variants from the far commoner RP-causing ones. Marked PARTIAL because this citation makes the cascade-wide point rather than naming the specific RHO alleles.
💊

Medical Actions

2
Refractive Correction and Low-Vision Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Because CSNB is stationary and does not degenerate, management is supportive: correction of the frequently high myopia, management of strabismus and amblyopia risk, low-vision aids where acuity is reduced, and counselling about night-time and low-light safety. There is no approved disease-modifying therapy.
Show evidence (1 reference)
PMID:29390235 SUPPORT Other
"Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
Identifies the refractive and ocular-motor problems that constitute the substance of supportive management in this condition.
AAV Gene Augmentation of the ON-Bipolar Signalplex (Investigational)
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. Ontology label: Gene Therapy NCIT:C15238
Subretinal AAV delivery of the missing signalplex component. Because the retina does not degenerate, the therapeutic window is not closed by childhood: LRIT3 delivered to mature Lrit3-null mouse retina reassembles the depolarizing bipolar cell signalling complex and rescues both retinal function and cortical visual acuity, and functional recovery has been sustained for up to 32 months in a canine LRIT3 model. That canine work also documented off-target transgene expression outside bipolar cells despite an engineered capsid and an ON-bipolar-specific promoter, which the authors identify as requiring optimization before clinical translation. Preclinical only; no human trial.
Mechanism Target:
RESTORES mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip — Supplying the missing signalplex member reassembles the complex at the ON-bipolar dendritic tip, acting on the trigger lesion of the complete form.
Show evidence (1 reference)
PMID:42471459 SUPPORT Model Organism
"We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity."
Demonstrates restoration of the signalling complex itself, not merely a functional readout, and does so in mature retina.
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"While the long-term therapeutic potential of AAVK9#4-shGRM6-cLRIT3-WPRE is promising, we highlight the necessity for further optimization of AAV-LRIT3 therapy in the canine CSNB model prior to its clinical application."
The authors' own conclusion: durable large-animal rescue, but explicit need for further optimization before clinical use. Marked PARTIAL because it establishes preclinical promise rather than clinical efficacy.
🐁

Animal Models

2
Lrit3-null mouse model of complete CSNB
Loss of LRIT3 disassembles the depolarizing bipolar cell signalplex, reproducing the complete CSNB phenotype. Used to show that gene augmentation in the mature retina, rather than during development, is sufficient to restore function.
Species
Mouse
Genotype
Lrit3-/-
Publication
PMID:42471459
Pathograph links
mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip rescues fidelity: moderate Subretinal AAV-LRIT3 in mature Lrit3-null retina restores the signalplex and rescues retinal function and cortical visual acuity, establishing that the defect is correctable after development is complete.
Limitations: Rescue was achieved by expressing LRIT3 in photoreceptors rather than in the ON-bipolar cells where the human signalplex sits, and the mouse lacks a fovea, so the acuity endpoints do not correspond to human central vision.
Readouts
Cortical visual acuity after subretinal AAV-LRIT3
Direction: RESTORED
Interpretation: Functional confirmation that reassembling the signalplex restores vision-guided cortical responses, not merely the electroretinogram.
Show evidence (1 reference)
PMID:42471459 SUPPORT Model Organism
"We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity."
Reports the readout and its restoration directly.
Show evidence (1 reference)
PMID:42471459 SUPPORT Model Organism
"Because of the non-progressive and recessive nature of cCSNB, we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and cortical visual acuity."
States the rationale that makes this model informative for the human mechanism: a stationary recessive disease leaves an intact retina to treat.
Canine LRIT3-CSNB model
A naturally occurring large-animal model of complete CSNB, used for long-term evaluation of ON-bipolar-targeted AAV-LRIT3 gene therapy with follow-up to 32 months.
Species
Dog
Genotype
LRIT3 loss of function
Publication
PMID:37220680
Pathograph links
mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip rescues fidelity: moderate Subretinal ON-bipolar-targeted AAV-LRIT3 produced durable functional recovery and restored the signalplex member TRPM1 in the outer plexiform layer of the treated area.
Limitations: RNA in situ hybridization revealed off-target transgene expression in photoreceptors and in the inner nuclear and ganglion cell layers despite a mutant capsid and an improved ON-bipolar promoter, so the observed rescue cannot be attributed to ON-bipolar transduction alone.
Readouts
TRPM1 restoration in the outer plexiform layer of the treated area
Direction: RESTORED
Interpretation: Molecular evidence that supplying one signalplex member restores another, confirming the interdependence this mechanism node asserts.
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"Following subretinal administration of the therapeutic vector, expression of the LRIT3 transgene, as well as restoration of mGluR6 signaling cascade member TRPM1, were confirmed in the outer plexiform layer (OPL) of the treated area."
Reports the readout and its restoration in the treated retina.
Show evidence (1 reference)
PMID:37220680 SUPPORT Model Organism
"Herein, we demonstrate long-term functional recovery and molecular restoration following subretinal injection of the ON-BC targeting AAV-LRIT3 vector in all eight treated eyes for up to 32 months."
Establishes durable rescue in all treated eyes, supporting this model as informative for the human mechanism.
{ }

Source YAML

click to show 
name: Congenital Stationary Night Blindness
creation_date: "2026-08-22T00:00:00Z"
category: Mendelian
description: >
  Congenital stationary night blindness (CSNB) is a genetically heterogeneous
  group of non-progressive inherited retinal disorders in which the retina is
  structurally normal on fundus examination but cannot signal in dim light. Its
  importance to disease modelling is that a single clinical label covers two
  mechanistically opposite lesions, and the electroretinogram tells them apart.
  In the Riggs form the defect is inside the rod photoreceptor, in the
  phototransduction cascade itself: the rod cannot generate a light response,
  the a-wave is lost, and the b-wave falls with it. In the far commoner
  Schubert-Bornschein form the photoreceptor works and the defect lies at the
  synapse onto the depolarizing (ON) bipolar cell: the a-wave is preserved while
  the b-wave is selectively lost, giving the electronegative waveform. The
  Schubert-Bornschein group divides again by electroretinogram into a complete
  form, in which only the ON pathway fails, and an incomplete form, in which
  both ON and OFF pathways are affected and daytime acuity suffers too. Beyond
  night blindness, patients commonly have high myopia, nystagmus, strabismus and
  reduced acuity. Because the disease is stationary and recessive, the retina
  remains available to treat throughout life, and gene augmentation restores
  function in mature animals rather than only in developing ones.
disease_term:
  preferred_term: congenital stationary night blindness
  term:
    id: MONDO:0016293
    label: congenital stationary night blindness
synonyms:
- CSNB
- night blindness, congenital stationary
- Schubert-Bornschein congenital stationary night blindness
- Riggs congenital stationary night blindness
parents:
- Ophthalmological Disease
- Inherited retinal dystrophy
has_subtypes:
- name: cCSNB
  display_name: Complete CSNB (Schubert-Bornschein, ON pathway)
  subtype_term:
    preferred_term: congenital stationary night blindness 1A
    term:
      id: MONDO:0010690
      label: congenital stationary night blindness 1A
  description: >
    The complete Schubert-Bornschein form, caused by loss of a component of the
    mGluR6 signalplex at the dendritic tips of depolarizing (ON) bipolar cells -
    NYX, GRM6, TRPM1, GPR179 or LRIT3. Rod signalling to the ON pathway is
    abolished, the ON-pathway b-wave is absent, and the OFF pathway is spared.
    Night blindness is profound; there is no retinal degeneration.
  evidence:
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration."
    explanation: >
      Names the five cCSNB signalplex genes and states the defining absence of
      retinal degeneration that separates this from the dystrophies.
- name: icCSNB
  display_name: Incomplete CSNB (Schubert-Bornschein, ON and OFF pathways)
  subtype_term:
    preferred_term: congenital stationary night blindness 2A
    term:
      id: MONDO:0010241
      label: congenital stationary night blindness 2A
  description: >
    The incomplete Schubert-Bornschein form, caused most often by CACNA1F
    variants affecting the Cav1.4 calcium channel at the photoreceptor ribbon
    synapse, or by CABP4. Because the lesion is presynaptic it impairs
    transmitter release to both ON and OFF bipolar pathways, so daytime acuity
    and cone function are affected as well as scotopic vision - the reason
    "incomplete" describes a broader, not a milder, deficit.
  evidence:
  - reference: PMID:24466230
    reference_title: "Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in the human CACNA1F gene encoding the α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2)."
    explanation: >
      Assigns CACNA1F to the incomplete form and identifies the channel subunit
      involved.
- name: Riggs
  display_name: Riggs CSNB (rod phototransduction cascade)
  subtype_term:
    preferred_term: congenital stationary night blindness autosomal dominant 1
    term:
      id: MONDO:0012498
      label: congenital stationary night blindness autosomal dominant 1
  description: >
    The rarer Riggs form, in which the lesion is inside the rod photoreceptor
    rather than at its synapse - RHO, GNAT1, PDE6B, GNB3 or SLC24A1 - and the
    rod phototransduction cascade cannot generate or cannot terminate a light
    response. The a-wave is lost with the b-wave, distinguishing it
    electrophysiologically from the Schubert-Bornschein forms, and the fundus
    and daytime vision are normal.
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade"
    explanation: >
      Assigns the Riggs form specifically to the rod phototransduction cascade,
      which is what justifies conforming only this arm to the phototransduction
      module. Evidence source is OTHER because this is a review.
inheritance:
- name: Genetically heterogeneous
  description: >
    CSNB is inherited as an autosomal recessive trait (most complete and
    incomplete Schubert-Bornschein forms), X-linked recessive (NYX in cCSNB,
    CACNA1F in icCSNB), or autosomal dominant (several Riggs-form genes,
    including gain-of-function RHO and GNAT1 alleles). Mode of inheritance
    therefore does not identify the mechanistic arm and cannot substitute for
    electroretinography.
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB)."
    explanation: >
      States the three inheritance modes across the CSNB group. Evidence source
      is OTHER because this is a review.
pathophysiology:
- name: Rod Phototransduction Cascade Defect (Riggs Arm)
  description: >
    In the Riggs form the causative variant sits in the rod phototransduction
    cascade itself - the visual pigment (RHO), the transducin subunits (GNAT1,
    GNB3), the phosphodiesterase (PDE6B), or the sodium-calcium exchanger that
    sets the outer-segment ion balance (SLC24A1). Some are loss-of-function and
    the rod cannot mount a response; some, notably the RHO G90D and T94I
    substitutions, are gain-of-function changes that keep the pigment
    constitutively active in darkness so the rod behaves as though it were
    permanently light-adapted. Either way the rod's own light response is
    abolished or desensitized, and the electroretinographic a-wave goes with it.
  role: trigger
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: rod photoreceptor cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: Phototransduction
    term:
      id: GO:0007602
      label: phototransduction
    modifier: ABNORMAL
  conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade"
    explanation: >
      Directly assigns the Riggs-form genes to the rod phototransduction
      cascade, which is the claim this node and its module conformance rest on.
      Evidence source is OTHER because this is a review.
  - reference: PMID:27063057
    reference_title: "Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade"
    explanation: >
      Independent confirmation, in a gene-discovery paper, that the Riggs form
      is a selective rod photoreceptor cascade defect.
  downstream:
  - target: Loss of Rod Light-Response Generation
    causal_link_type: DIRECT

- name: Loss of Rod Light-Response Generation
  description: >
    The rod fails to convert absorbed photons into the graded hyperpolarization
    that drives the rest of the visual pathway. Because the defect is inside the
    photoreceptor, the summed rod response that generates the scotopic a-wave is
    lost, and the b-wave falls secondarily for want of an input - the pattern
    that distinguishes this arm from the Schubert-Bornschein forms, where the
    a-wave survives.
  role: central_effector
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: rod photoreceptor cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: Detection of light stimulus involved in visual perception
    term:
      id: GO:0050908
      label: detection of light stimulus involved in visual perception
    modifier: DECREASED
  conforms_to: "phototransduction_cascade_dysfunction#Failure of Photoreceptor Light-Response Generation or Timely Recovery"
  evidence:
  - reference: PMID:29850563
    reference_title: "A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves."
    explanation: >
      Ties altered phototransduction to the a-wave-dominant electroretinographic
      signature this node asserts, in a molecularly confirmed adCSNB family.
  downstream:
  - target: Impaired Scotopic Vision with Normal Fundus
    causal_link_type: DIRECT

- name: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
  description: >
    The complete Schubert-Bornschein arm, and mechanistically NOT a
    phototransduction defect. In darkness photoreceptors release glutamate
    tonically onto depolarizing (ON) bipolar cells, where the metabotropic
    receptor GRM6 keeps the TRPM1 cation channel closed; light, by reducing
    glutamate release, opens TRPM1 and depolarizes the bipolar cell - a
    sign-inverting synapse. NYX, GRM6, TRPM1, GPR179 and LRIT3 form a single
    interdependent signalplex at the ON-bipolar dendritic tip, so loss of any
    one of them disassembles the complex and abolishes the inversion. The
    photoreceptor upstream is entirely normal.
  role: trigger
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: ON-bipolar cell
    term:
      id: CL:0000749
      label: ON-bipolar cell
  biological_processes:
  - preferred_term: G protein-coupled glutamate receptor signaling pathway
    term:
      id: GO:0007216
      label: G protein-coupled glutamate receptor signaling pathway
    modifier: DECREASED
  - preferred_term: Synapse organization
    term:
      id: GO:0050808
      label: synapse organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
    explanation: >
      Localizes the five complete-CSNB genes to the mGluR6 cascade at the
      ON-bipolar dendritic tip, which is the anatomical claim separating this
      node from the Riggs arm.
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes that are part of a large, interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors."
    explanation: >
      Supports the specific claim that these genes act as one interdependent
      complex, which is why losing any single member produces the same
      phenotype.
  downstream:
  - target: Failure of Photoreceptor-to-Bipolar Signal Transmission
    causal_link_type: DIRECT

- name: Presynaptic Calcium Channel Defect at the Photoreceptor Ribbon Synapse
  description: >
    The incomplete Schubert-Bornschein arm. Cav1.4, encoded by CACNA1F, sits at
    the photoreceptor ribbon synapse and does two jobs: it gates the calcium
    influx that drives tonic glutamate release, and it organizes the synapse
    structurally. A loss-of-function variant therefore starves both the ON and
    the OFF bipolar pathways of input, which is why the incomplete form
    compromises daytime acuity and cone function as well as night vision. The
    lesion is presynaptic but still postphototransduction: the rod's light
    response itself is intact.
  role: trigger
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: Calcium ion transmembrane transport
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
    modifier: DECREASED
  - preferred_term: Neurotransmitter secretion
    term:
      id: GO:0007269
      label: neurotransmitter secretion
    modifier: DECREASED
  evidence:
  - reference: PMID:24466230
    reference_title: "Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Light-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses."
    explanation: >
      Establishes the presynaptic function whose loss defines this node, and
      locates it at the ribbon synapse rather than in the outer segment.
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors."
    explanation: >
      Assigns the incomplete-form genes specifically to presynaptic glutamate
      release, distinguishing them from the postsynaptic signalplex genes of the
      complete form. Evidence source is OTHER because this is a review.
  downstream:
  - target: Failure of Photoreceptor-to-Bipolar Signal Transmission
    causal_link_type: DIRECT

- name: Failure of Photoreceptor-to-Bipolar Signal Transmission
  description: >
    Both Schubert-Bornschein arms converge here: the photoreceptor generates a
    normal light response that fails to reach the inner retina. Because the
    a-wave is generated by the photoreceptor and the b-wave by the bipolar cells
    downstream, the result is the electronegative electroretinogram - a b-wave
    that falls below the a-wave. This waveform localizes the lesion to the inner
    retina or the photoreceptor-bipolar synapse, and it is the single most
    informative bedside test in CSNB because it partitions the disease group by
    mechanism before any sequencing is done. It is not specific to CSNB: X-linked
    retinoschisis and KCNV2-associated disease produce it too, by their own
    routes.
  role: central_effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: ON-bipolar cell
    term:
      id: CL:0000749
      label: ON-bipolar cell
  - preferred_term: photoreceptor cell
    term:
      id: CL:0000210
      label: photoreceptor cell
  biological_processes:
  - preferred_term: Chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
    modifier: DECREASED
  evidence:
  - reference: PMID:42106701
    reference_title: "Electronegative electroretinography in inherited retinal disease: a systematic review of genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The electronegative electroretinogram (ERG)-in which the dark-adapted bright-flash b-wave amplitude falls below the a-wave (b: a ratio < 1.0)-localizes dysfunction to the inner retina or photoreceptor-bipolar synapse."
    explanation: >
      Defines the waveform quantitatively and states the anatomical
      localization this node asserts. Evidence source is OTHER because this is a
      systematic review.
  - reference: PMID:42106701
    reference_title: "Electronegative electroretinography in inherited retinal disease: a systematic review of genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2)."
    explanation: >
      Supports the discriminating value of the waveform while establishing the
      specificity caveat this node states. Marked PARTIAL because the same
      review rates the underlying evidence as high risk of bias.
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form."
    explanation: >
      States the transmission-versus-photoreceptor contrast that this node's
      placement, and the entry's selective module conformance, depend on.
      Evidence source is OTHER because this is a review.
  - reference: PMID:20301423
    reference_title: "X-Linked Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Characteristic ERG findings can help distinguish between complete X-linked CSNB and incomplete X-linked CSNB."
    explanation: >
      Confirms independently that electroretinography, not genotype or symptom
      profile, is what separates the complete from the incomplete form - the
      claim this entry rests its subtype structure on. Evidence source is OTHER
      because GeneReviews is an expert-curated clinical synthesis.
  downstream:
  - target: Impaired Scotopic Vision with Normal Fundus
    causal_link_type: DIRECT

- name: Impaired Scotopic Vision with Normal Fundus
  description: >
    The shared clinical endpoint. Vision in dim light is impaired from birth and
    stays that way - the disease is stationary, and the fundus is essentially
    normal, which is why CSNB is missed or misattributed when
    electroretinography is not done. Accompanying signs are common and are what
    usually bring the child to attention: high myopia, nystagmus, strabismus and
    reduced acuity, the last most marked in the incomplete form where the cone
    pathway is involved too. There is no retinal degeneration, which both
    defines the group and, because the retina stays intact, keeps it treatable
    into adulthood.

    This node deliberately carries NO conforms_to. It is the shared endpoint of
    all three arms - the Riggs cascade lesion above it and both
    Schubert-Bornschein transmission lesions - so wiring it to
    phototransduction_cascade_dysfunction would silently readmit the very forms
    that module's scope note excludes, and would assert "photoreceptor
    dysfunction" of arms in which the photoreceptor is intact and the synapse is
    what fails. Module conformance for this entry is therefore confined to the
    two Riggs-arm nodes upstream, which is where the module's key conformance
    target sits.
  role: consequence
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: Visual perception
    term:
      id: GO:0007601
      label: visual perception
    modifier: DECREASED
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
    explanation: >
      Enumerates the accompanying ocular signs this node lists. Evidence source
      is OTHER because this is a review.
  - reference: PMID:20301423
    reference_title: "X-Linked Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia"
    explanation: >
      GeneReviews supplies the acuity range and confirms the non-progressive
      character and normal fundus that define this node, for the X-linked forms.
      Evidence source is OTHER because GeneReviews is an expert-curated clinical
      synthesis rather than a primary study.
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These genes include NYX, GRM6, TRPM1, GPR179, and LRIT3, and the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration."
    explanation: >
      Supports the combination of impaired low-light vision with myopia and
      nystagmus, and the explicit absence of degeneration that this node treats
      as defining.
phenotypes:
- category: Ocular
  name: Night Blindness
  description: >
    Impaired vision in dim light, present from birth or early infancy and
    non-progressive. The cardinal symptom of the disorder.
  phenotype_term:
    preferred_term: Nyctalopia
    term:
      id: HP:0000662
      label: Nyctalopia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Congenital stationary night blindness (CSNB) is a group of inherited retinal diseases in which either rod-to-ON-bipolar cell (ON-BC) signaling, or rod function is affected leading to impaired vision under low light conditions."
    explanation: >
      States impaired low-light vision as the defining consequence common to
      both mechanistic arms. VERY_FREQUENT is a Pattern C mapping of that
      definitional framing (docs/frequency-evidence-guidelines.md); no
      proportion is reported, and the band is defensible because impaired
      low-light vision is what defines membership of the group.
- category: Ocular
  name: Electronegative Electroretinogram
  description: >
    A dark-adapted bright-flash b-wave amplitude below the a-wave, the
    characteristic finding of the Schubert-Bornschein forms and the test that
    separates them from the Riggs form, in which both waves are reduced
    together.
  subtype: cCSNB
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:42106701
    reference_title: "Electronegative electroretinography in inherited retinal disease: a systematic review of genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Electronegative ERG patterns were commonly described across the CSNB and XLRS literature, with the greatest consistency for complete CSNB and KCNV2."
    explanation: >
      Supports both the association and the specific point that consistency is
      greatest for the complete form, which is why this phenotype is scoped to
      the cCSNB subtype.
- category: Ocular
  name: Myopia
  description: >
    Refractive error, often high, particularly characteristic of the
    Schubert-Bornschein forms.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:27063057
    reference_title: "Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus."
    explanation: >
      Establishes the association across both Schubert-Bornschein subtypes
      rather than in the complete form alone. No frequency band is asserted:
      the source reports "variable degrees" without a proportion, and this
      entry spans three mechanistically distinct subtypes whose refractive and
      ocular-motor profiles differ, so a single disease-level band would not be
      supportable.
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration"
    explanation: >
      Corroborates the association specifically in the complete form, whose
      description names myopia as a characteristic feature.
- category: Ocular
  name: Nystagmus
  description: >
    Infantile nystagmus, common in the Schubert-Bornschein forms and often the
    presenting sign in infancy before night blindness can be reported.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:27063057
    reference_title: "Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus."
    explanation: >
      Establishes the association across both Schubert-Bornschein subtypes
      rather than in the complete form alone. No frequency band is asserted:
      the source reports "variable degrees" without a proportion, and this
      entry spans three mechanistically distinct subtypes whose refractive and
      ocular-motor profiles differ, so a single disease-level band would not be
      supportable.
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the resulting cCSNB phenotype is characterized by abnormally low-light vision, myopia, and nystagmus, but does not include retinal degeneration"
    explanation: >
      Corroborates the association specifically in the complete form, whose
      description names nystagmus among the characteristic features.
- category: Ocular
  name: Strabismus
  description: >
    Ocular misalignment, reported among the additional ocular signs of the CSNB
    group.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
    explanation: >
      Lists strabismus among the additional ocular signs. Evidence source is
      OTHER because this is a review.
- category: Ocular
  name: Reduced Visual Acuity
  description: >
    Subnormal daytime acuity, characteristic of the incomplete form where both
    ON and OFF pathways are affected, and generally preserved in the complete
    and Riggs forms.
  subtype: icCSNB
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well."
    explanation: >
      States that acuity is affected specifically in the incomplete form because
      both pathways are involved, which is why this phenotype is scoped to that
      subtype.
genetic:
- name: NYX
  association: Loss-of-function variants causing complete CSNB (X-linked)
  subtype: cCSNB
  gene_term:
    preferred_term: NYX
    term:
      id: hgnc:8082
      label: NYX
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
    explanation: >
      Assigns NYX to the mGluR6 signalplex of the complete form.
- name: GRM6
  association: Biallelic loss-of-function variants causing complete CSNB
  subtype: cCSNB
  gene_term:
    preferred_term: GRM6
    term:
      id: hgnc:4598
      label: GRM6
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
    explanation: >
      Assigns GRM6, the metabotropic glutamate receptor that names the cascade,
      to the complete form.
- name: TRPM1
  association: Biallelic loss-of-function variants causing complete CSNB
  subtype: cCSNB
  gene_term:
    preferred_term: TRPM1
    term:
      id: hgnc:7146
      label: TRPM1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
    explanation: >
      Assigns TRPM1, the effector cation channel of the cascade, to the
      complete form.
- name: LRIT3
  association: Biallelic loss-of-function variants causing complete CSNB
  subtype: cCSNB
  gene_term:
    preferred_term: LRIT3
    term:
      id: hgnc:24783
      label: LRIT3
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:42471459
    reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We used a mouse model of cCSNB caused by LRIT3 loss to evaluate the efficacy of a single subretinal injection of an rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity."
    explanation: >
      Establishes LRIT3 loss as a cause of complete CSNB, and is the gene whose
      restoration rescued function in the model.
- name: GPR179
  association: Biallelic loss-of-function variants causing complete CSNB
  subtype: cCSNB
  gene_term:
    preferred_term: GPR179
    term:
      id: hgnc:31371
      label: GPR179
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips."
    explanation: >
      Assigns GPR179 to the mGluR6 signalplex of the complete form.
- name: CACNA1F
  association: Hemizygous variants causing incomplete CSNB (X-linked)
  subtype: icCSNB
  notes: >
    Most CACNA1F variants are loss of function, but some alter channel gating.
    A gain-of-function allele (human I745T, modelled as murine I756T) shifting
    the voltage dependence of activation was found in a family with an unusually
    severe phenotype, and the corresponding mouse showed more severe
    photoreceptor degeneration than a loss-of-function line - a caution against
    treating incomplete CSNB as uniformly stationary.
  gene_term:
    preferred_term: CACNA1F
    term:
      id: hgnc:1393
      label: CACNA1F
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:24466230
    reference_title: "Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Mutations in the human CACNA1F gene encoding the α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2)."
    explanation: >
      Assigns CACNA1F to the incomplete form.
  - reference: PMID:24466230
    reference_title: "Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both mutants showed a progressive photoreceptor loss, but degeneration was more severe and significantly enhanced in the I756T mutants compared to the ΔEx14-17 mutants."
    explanation: >
      Supports the notes' caution that some CACNA1F alleles produce progressive
      degeneration, with the gain-of-function allele worse than the null.
- name: CABP4
  association: Biallelic variants causing an incomplete CSNB-like phenotype
  subtype: icCSNB
  gene_term:
    preferred_term: CABP4
    term:
      id: hgnc:1386
      label: CABP4
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:42106701
    reference_title: "Electronegative electroretinography in inherited retinal disease: a systematic review of genotype-phenotype correlations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2)."
    explanation: >
      Lists CABP4 among the CSNB genes associated with the electronegative
      waveform.
- name: GNAT1
  association: Dominant and recessive variants causing Riggs CSNB
  subtype: Riggs
  gene_term:
    preferred_term: GNAT1
    term:
      id: hgnc:4393
      label: GNAT1
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:29850563
    reference_title: "A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype."
    explanation: >
      Documents a cosegregating GNAT1 variant in a Riggs-type family, assigning
      the transducin alpha subunit to the phototransduction arm.
- name: GNB3
  association: Biallelic variants causing a Riggs-like CSNB with cone involvement
  subtype: Riggs
  gene_term:
    preferred_term: GNB3
    term:
      id: hgnc:4400
      label: GNB3
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:27063057
    reference_title: "Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity."
    explanation: >
      Documents the GNB3 phenotype, which uniquely straddles the two arms -
      the gene modulates both ON-bipolar signalling and cone transducin
      function.
- name: RHO
  association: Gain-of-function missense variants (G90D, T94I) causing autosomal dominant Riggs CSNB
  subtype: Riggs
  gene_term:
    preferred_term: RHO
    term:
      id: hgnc:10012
      label: RHO
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:29850563
    reference_title: "A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy."
    explanation: >
      Supports the general point that only a minority of phototransduction-gene
      alleles give stationary rather than degenerative disease, which is what
      distinguishes the CSNB-causing RHO variants from the far commoner
      RP-causing ones. Marked PARTIAL because this citation makes the
      cascade-wide point rather than naming the specific RHO alleles.
treatments:
- name: Refractive Correction and Low-Vision Support
  description: >
    Because CSNB is stationary and does not degenerate, management is
    supportive: correction of the frequently high myopia, management of
    strabismus and amblyopia risk, low-vision aids where acuity is reduced, and
    counselling about night-time and low-light safety. There is no approved
    disease-modifying therapy.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:29390235
    reference_title: "[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity."
    explanation: >
      Identifies the refractive and ocular-motor problems that constitute the
      substance of supportive management in this condition.
- name: AAV Gene Augmentation of the ON-Bipolar Signalplex (Investigational)
  description: >
    Subretinal AAV delivery of the missing signalplex component. Because the
    retina does not degenerate, the therapeutic window is not closed by
    childhood: LRIT3 delivered to mature Lrit3-null mouse retina reassembles the
    depolarizing bipolar cell signalling complex and rescues both retinal
    function and cortical visual acuity, and functional recovery has been
    sustained for up to 32 months in a canine LRIT3 model. That canine work also
    documented off-target transgene expression outside bipolar cells despite an
    engineered capsid and an ON-bipolar-specific promoter, which the authors
    identify as requiring optimization before clinical translation. Preclinical
    only; no human trial.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
    treatment_effect: RESTORES
    description: >
      Supplying the missing signalplex member reassembles the complex at the
      ON-bipolar dendritic tip, acting on the trigger lesion of the complete
      form.
    evidence:
    - reference: PMID:42471459
      reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity."
      explanation: >
        Demonstrates restoration of the signalling complex itself, not merely a
        functional readout, and does so in mature retina.
  evidence:
  - reference: PMID:37220680
    reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "While the long-term therapeutic potential of AAVK9#4-shGRM6-cLRIT3-WPRE is promising, we highlight the necessity for further optimization of AAV-LRIT3 therapy in the canine CSNB model prior to its clinical application."
    explanation: >
      The authors' own conclusion: durable large-animal rescue, but explicit
      need for further optimization before clinical use. Marked PARTIAL because
      it establishes preclinical promise rather than clinical efficacy.
animal_models:
- name: Lrit3-null mouse model of complete CSNB
  species: Mouse
  genotype: Lrit3-/-
  description: >
    Loss of LRIT3 disassembles the depolarizing bipolar cell signalplex,
    reproducing the complete CSNB phenotype. Used to show that gene augmentation
    in the mature retina, rather than during development, is sufficient to
    restore function.
  publication: PMID:42471459
  modeled_mechanisms:
  - target: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
    relationship: RESCUES
    fidelity: MODERATE
    description: >
      Subretinal AAV-LRIT3 in mature Lrit3-null retina restores the signalplex
      and rescues retinal function and cortical visual acuity, establishing that
      the defect is correctable after development is complete.
    limitations: >
      Rescue was achieved by expressing LRIT3 in photoreceptors rather than in
      the ON-bipolar cells where the human signalplex sits, and the mouse lacks
      a fovea, so the acuity endpoints do not correspond to human central
      vision.
    readouts:
    - name: Cortical visual acuity after subretinal AAV-LRIT3
      target: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
      direction: RESTORED
      interpretation: >
        Functional confirmation that reassembling the signalplex restores
        vision-guided cortical responses, not merely the electroretinogram.
      evidence:
      - reference: PMID:42471459
        reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We show that gene augmentation by expressing LRIT3 in Lrit3-/- retinas of mature mice restores the DBC synaptic signaling complex and is sufficient to rescue retinal function and improve visual acuity."
        explanation: >
          Reports the readout and its restoration directly.
    evidence:
    - reference: PMID:42471459
      reference_title: "Gene augmentation therapy successfully treats mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Because of the non-progressive and recessive nature of cCSNB, we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and cortical visual acuity."
      explanation: >
        States the rationale that makes this model informative for the human
        mechanism: a stationary recessive disease leaves an intact retina to
        treat.
- name: Canine LRIT3-CSNB model
  species: Dog
  genotype: LRIT3 loss of function
  description: >
    A naturally occurring large-animal model of complete CSNB, used for
    long-term evaluation of ON-bipolar-targeted AAV-LRIT3 gene therapy with
    follow-up to 32 months.
  publication: PMID:37220680
  modeled_mechanisms:
  - target: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
    relationship: RESCUES
    fidelity: MODERATE
    description: >
      Subretinal ON-bipolar-targeted AAV-LRIT3 produced durable functional
      recovery and restored the signalplex member TRPM1 in the outer plexiform
      layer of the treated area.
    limitations: >
      RNA in situ hybridization revealed off-target transgene expression in
      photoreceptors and in the inner nuclear and ganglion cell layers despite a
      mutant capsid and an improved ON-bipolar promoter, so the observed rescue
      cannot be attributed to ON-bipolar transduction alone.
    readouts:
    - name: TRPM1 restoration in the outer plexiform layer of the treated area
      target: mGluR6 Signalplex Defect at the ON-Bipolar Dendritic Tip
      direction: RESTORED
      interpretation: >
        Molecular evidence that supplying one signalplex member restores
        another, confirming the interdependence this mechanism node asserts.
      evidence:
      - reference: PMID:37220680
        reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Following subretinal administration of the therapeutic vector, expression of the LRIT3 transgene, as well as restoration of mGluR6 signaling cascade member TRPM1, were confirmed in the outer plexiform layer (OPL) of the treated area."
        explanation: >
          Reports the readout and its restoration in the treated retina.
    evidence:
    - reference: PMID:37220680
      reference_title: "Extended functional rescue following AAV gene therapy in a canine model of LRIT3-congenital stationary night blindness."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Herein, we demonstrate long-term functional recovery and molecular restoration following subretinal injection of the ON-BC targeting AAV-LRIT3 vector in all eight treated eyes for up to 32 months."
      explanation: >
        Establishes durable rescue in all treated eyes, supporting this model as
        informative for the human mechanism.
discussions:
- discussion_id: csnb_stationary_label_versus_progressive_alleles
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is "stationary" a safe description of every CSNB genotype, given that some
    alleles in CSNB genes produce progressive photoreceptor degeneration?
  attaches_to:
  - "pathophysiology#Presynaptic Calcium Channel Defect at the Photoreceptor Ribbon Synapse"
  - "pathophysiology#Impaired Scotopic Vision with Normal Fundus"
  rationale: >-
    The absence of degeneration is treated as definitional for CSNB and is the
    basis for the claim that the retina remains treatable into adulthood. Yet
    both mouse models of CSNB2 - a loss-of-function Cacna1f line and a
    gain-of-function I756T line - showed progressive photoreceptor loss, worse
    in the gain-of-function line, and CACNA1F variants in humans present either
    as incomplete CSNB or as progressive cone-rod dystrophy. GNAT1 shows the
    same allelic split between stationary and degenerative outcomes. If
    stationarity is an allele-level rather than a gene-level property, then a
    CSNB diagnosis alone does not license indefinite deferral of intervention,
    and the therapeutic window argument needs qualifying per genotype.
  proposed_experiments:
  - experiment_id: csnb_longitudinal_oct_by_allele_class
    name: Longitudinal outer-retinal imaging in CSNB stratified by allele class
    description: >
      Follow molecularly defined CSNB cohorts with serial optical coherence
      tomography of the outer nuclear layer and ellipsoid zone, stratified by
      whether the variant is predicted loss of function or gating-altering, to
      test whether measurable photoreceptor loss occurs in any subgroup over a
      decade.
references:
- reference: PMID:20301423
  title: X-Linked Congenital Stationary Night Blindness.
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301423
X-Linked Congenital Stationary Night Blindness.
No top-level findings curated for this source.