Congenital Stationary Night Blindness

Mendelian MONDO:0016293 Pathograph 30 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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Inheritance

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

Complete CSNB (Schubert-Bornschein, ON pathway)

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. This is an electroretinographic class rather than a MONDO class, so it is left unbound here; the numbered loci that compose it carry the MONDO terms on the CSNB1A, CSNB1B, CSNB1C, CSNB1E and CSNB1F rows below.

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)

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. As with the complete form this is an electroretinographic class with no MONDO term of its own; the CSNB2A and CSNB2B rows below carry the MONDO terms.

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)

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. Like the two Schubert-Bornschein classes this is an electroretinographic grouping with no MONDO term of its own; the CSNBAD1, CSNBAD2, CSNBAD3, CSNB1D, CSNB1G and CSNB1H rows below carry the MONDO terms.

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.

Oguchi disease (failure of rhodopsin shut-off) MONDO:0019152

SAG hgnc:10521 GRK1 hgnc:10013

A recessive form in which the rod generates a light response but cannot terminate it, because the two proteins that shut off activated rhodopsin are lost: rhodopsin kinase (GRK1) and arrestin (SAG). Dark adaptation of rods is extremely retarded while cone adaptation proceeds normally. Oguchi disease is the one arm of this entry in which the fundus is not normal: it shows the Mizuo-Nakamura phenomenon, a golden or gray-white retinal discolouration that appears on light adaptation and disappears in the dark-adapted state, so it is an explicit exception to the normal-fundus generalization the disease-level endpoint node records.

Show evidence (3 references)

PMID:9020843 SUPPORT BACKGROUND Human Clinical

"As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase."

States the shared shut-off function of the two Oguchi genes, which is what makes this a single mechanistic arm rather than two unrelated loci.

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally."

Establishes the rod-selective delay in dark adaptation that distinguishes this arm from a failure of response generation.

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light"

The fundus finding that makes this arm an exception to the normal-fundus generalization the rest of the entry rests on.

CSNB1A - NYX (OMIM:310500) MONDO:0010690

NYX hgnc:8082

X-linked complete CSNB caused by NYX variants. NYX is one of the five genes of the mGluR6 signalling cascade at the ON-bipolar dendritic tip, so this locus sits in the complete Schubert-Bornschein arm.

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."

Places NYX in the mGluR6 signalling cascade that defines the complete form.

CSNB1B - GRM6 (OMIM:257270) MONDO:0009758

GRM6 hgnc:4598

Autosomal recessive complete CSNB caused by biallelic GRM6 variants. GRM6 is the metabotropic glutamate receptor that names the cascade and that keeps the TRPM1 channel closed while the photoreceptor releases glutamate in darkness.

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."

Places GRM6 in the mGluR6 signalling cascade that defines the complete form.

CSNB1C - TRPM1 (OMIM:613216) MONDO:0013183

TRPM1 hgnc:7146

Autosomal recessive complete CSNB caused by biallelic TRPM1 variants. TRPM1 is the effector cation channel of the cascade, the channel that light opens by relieving GRM6 signalling.

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."

Places TRPM1 in the mGluR6 signalling cascade that defines the complete form.

CSNB1D - SLC24A1 (OMIM:613830) MONDO:0013450

SLC24A1 hgnc:10975

Autosomal recessive CSNB caused by biallelic SLC24A1 variants. SLC24A1 encodes NCKX1, the exchanger thought to extrude from the rod outer segment the calcium admitted through the cGMP-gated channels, so the lesion is inside the photoreceptor rather than at the bipolar synapse and this locus is placed in the Riggs arm here. Note that OMIM and MONDO number it within the "complete" series - its MONDO synonym reads "night blindness, congenital stationary (complete), 1D, autosomal recessive" - and that numbering reflects series position rather than the mGluR6 cascade mechanism the other 1-series loci share.

Show evidence (3 references)

PMID:20850105 SUPPORT PRIMARY RESULT Human Clinical

"Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model."

The gene-discovery report: a truncating SLC24A1 allele segregating recessively in a multigeneration night-blindness family.

PMID:26246500 SUPPORT BACKGROUND Model Organism

"It is thought that the concentration of Ca(2+) in rod outer segments is controlled by a dynamic balance between influx via cGMP-gated (CNG) channels and extrusion via Na(+)/Ca(2+), K(+) exchangers (NCKX1)."

The source of the hedged statement about NCKX1's role in the rod outer segment; the authors present it as the prevailing view rather than as a result of their own.

PMID:26246500 SUPPORT PRIMARY RESULT Model Organism

"Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses."

Locates the lesion in the rod outer segment and shows cone responses are spared, which is why this row is placed in the Riggs arm despite its position in the numbered "complete" series.

CSNB1E - GPR179 (OMIM:614565) MONDO:0013807

GPR179 hgnc:31371

Autosomal recessive complete CSNB caused by biallelic GPR179 variants, one of the five members of the mGluR6 signalling cascade at the ON-bipolar dendritic tip.

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."

Places GPR179 in the mGluR6 signalling cascade that defines the complete form.

CSNB1F - LRIT3 (OMIM:615058) MONDO:0014026

LRIT3 hgnc:24783

Autosomal recessive complete CSNB caused by biallelic LRIT3 variants. This is the locus for which gene augmentation has been taken furthest, in both a mouse and a naturally occurring canine model, both curated in this entry's animal_models section.

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 the complete form.

CSNB1G - GNAT1, recessive (OMIM:616389) MONDO:0014614

GNAT1 hgnc:4393

The recessive GNAT1 locus, separate from the dominant GNAT1 locus CSNBAD3. The rod transducin alpha subunit therefore appears twice in the numbered series, once as a recessive locus and once as a dominant one; the mechanistic arm is the same rod phototransduction cascade and only the allele class differs.

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."

Identifies GNAT1 as the transducin alpha subunit gene of the Riggs arm. The family reported here is dominant, so this citation supports the gene and the mechanistic arm rather than the recessive allele class that distinguishes this particular locus.

CSNB1H - GNB3 (OMIM:617024) MONDO:0014872

GNB3 hgnc:4400

Autosomal recessive CSNB caused by biallelic GNB3 variants. The phenotype straddles the two arms of this entry: affected individuals show reduced cone sensitivity together with variable ON-bipolar dysfunction, so it cannot be assigned cleanly to either electroretinographic class.

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 mixed ON-bipolar and cone phenotype that makes this locus hard to assign to a single electroretinographic class.

CSNB1I - GUCY2D (OMIM:618555) MONDO:0032811

GUCY2D hgnc:4689

Biallelic GUCY2D variants, encoding retinal guanylyl cyclase 1, producing a rod-dominant dysfunction with a stable electroretinogram. This is the least securely stationary-night-blindness row in the series and is curated with that reservation: the largest clinical and biochemical series describes the phenotype as a rod-cone dysfunction only similar to rare forms of stationary night blindness, its patients had central macular hypopigmentation and temporal vascular attenuation rather than a normal fundus, and cone responses were variable. Biallelic GUCY2D variants are more usually associated with Leber congenital amaurosis; MONDO files this term under MONDO:0100453 GUCY2D-related recessive retinopathy as well as under congenital stationary night blindness, and the LCA and CORD6 arms of GUCY2D disease are curated in the separate GUCY2D-Related_Retinopathy entry.

Show evidence (2 references)

PMID:40478561 SUPPORT PRIMARY RESULT Human Clinical

"The apparent lack of retinal degeneration, clinical features, predominant and severe rod photoreceptor involvement, and relatively high degree of ERG stability are similar to rare forms of SNB."

The authors' own framing, which is a similarity claim rather than an identity claim, and the reason this row carries a reservation.

PMID:40478561 SUPPORT PRIMARY RESULT Human Clinical

"Retinal imaging showed central macular hypopigmentation with temporal vascular attenuation."

The fundus finding that separates this row from the normal-fundus generalization the rest of the entry rests on.

CSNB2A - CACNA1F (OMIM:300071) MONDO:0010241

CACNA1F hgnc:1393

X-linked incomplete CSNB caused by CACNA1F variants affecting the Cav1.4 calcium channel at the photoreceptor ribbon synapse, and the commonest cause of the incomplete form. Allele-level curation of the wider CACNA1F spectrum, which also includes cone-rod dystrophy and Aland Island eye disease, lives in the separate CACNA1F-Related_Retinopathy and Aland_Island_Eye_Disease entries. CACNA1F-Related_Retinopathy binds this same MONDO term on its own CSNB2A subtype row, as RHO-Related_Retinopathy does for CSNBAD1 below.

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 names the channel subunit.

CSNB2B / congenital nonprogressive cone-rod synaptic disorder - CABP4 (OMIM:610427) MONDO:0012490

CABP4 hgnc:1386

Autosomal recessive incomplete CSNB caused by biallelic CABP4 variants. MONDO's primary label for this concept is "cone-rod synaptic disorder, congenital nonprogressive", with "night blindness, congenital stationary, type 2B" as a synonym; the synaptic naming is consistent with the incomplete-form genes acting on glutamate release at the photoreceptor terminal, which is why this row sits in the incomplete arm alongside CSNB2A.

Show evidence (2 references)

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. Evidence source is OTHER because this is a systematic review.

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 to presynaptic glutamate release, which is the basis for placing CABP4 with CACNA1F rather than with the postsynaptic signalplex genes. Evidence source is OTHER because this is a review.

CSNBAD1 - RHO (OMIM:610445) MONDO:0012498

RHO hgnc:10012

Autosomal dominant Riggs CSNB caused by RHO missense variants that leave the pigment constitutively active in darkness, of which p.G90D is the classical example. Allele-level curation, including the evidence that p.G90D carriers frequently progress to retinitis pigmentosa, lives in the separate RHO-Related_Retinopathy entry, which binds the same MONDO term on its own CSNBAD1 subtype row.

Show evidence (3 references)

PMID:24760071 SUPPORT BACKGROUND Human Clinical

"In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB."

States the constitutive-activation requirement shared by the three dominant Riggs loci, which is the mechanism this row asserts.

PMID:33669941 SUPPORT BACKGROUND Human Clinical

"Mutation p.G90D has previously been associated with CSNB based on the examination of one family."

Sources the identification of p.G90D as the classical CSNB-causing RHO allele, and records how thin that original basis was.

PMID:33669941 REFUTE PRIMARY RESULT Human Clinical

"The clinical characteristics of the largest p.G90D cohort so far showed a large frequency of progressive retinal degeneration with 53.3% developing RP, contrary to the previous report."

Contradicts the stationary reading of this locus at the allele level: most p.G90D carriers in the largest cohort developed progressive retinitis pigmentosa. It does not contradict the existence of a stationary CSNBAD1 phenotype, which 20% of that cohort had, but it does refute treating p.G90D itself as a reliably stationary allele.

CSNBAD2 - PDE6B (OMIM:163500) MONDO:0008099

PDE6B hgnc:8786

Autosomal dominant Riggs CSNB caused by PDE6B variants. The Rambusch pedigree allele p.His258Asn desensitizes rods, and a later French family carried a truncating allele whose product still binds the inhibitory PDE6 gamma subunit and so relieves inhibition of the normal catalytic subunits. Both routes converge on constitutive activation of the cascade, and both are exceptional among phototransduction-gene alleles, most of which cause progressive rod-cone dystrophy instead.

Show evidence (3 references)

PMID:24760071 SUPPORT BACKGROUND Human Clinical

"The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization."

Names the classical dominant PDE6B allele and its effect on the rod.

PMID:24760071 SUPPORT PRIMARY RESULT Human Clinical

"Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation"

The second reported dominant PDE6B family, which establishes the locus beyond a single pedigree.

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."

Sources the closing clause of the description: alleles in these genes usually cause progressive dystrophy, and the stationary outcome is the exception.

CSNBAD3 - GNAT1, dominant (OMIM:610444) MONDO:0012497

GNAT1 hgnc:4393

Autosomal dominant Riggs CSNB caused by GNAT1 missense variants in the rod transducin alpha subunit, distinct from the recessive GNAT1 locus CSNB1G above.

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 dominant GNAT1 variant in a Riggs-type family.

Oguchi disease-1 - SAG (OMIM:258100) MONDO:0009775

SAG hgnc:10521

Oguchi disease caused by biallelic SAG variants. Arrestin acts in the recovery phase of light transduction; a founder 1147delA allele accounts for most reported Japanese cases.

Show evidence (2 references)

PMID:7670478 SUPPORT PRIMARY RESULT Human Clinical

"in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene"

The gene-discovery report and the source of the founder-allele claim.

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"

Sources the functional role this row attributes to arrestin.

Oguchi disease-2 - GRK1 (OMIM:613411) MONDO:0013259

GRK1 hgnc:10013

Oguchi disease caused by biallelic GRK1 variants. Rhodopsin kinase acts with arrestin to shut off activated rhodopsin, so loss of either protein produces the same failure to quench the light response.

Show evidence (1 reference)

PMID:9020843 SUPPORT PRIMARY RESULT Human Clinical

"Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."

The gene-discovery report establishing GRK1 as the second Oguchi locus.

Discussions and Knowledge Gaps

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

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. GUCY2D, the retinal guanylyl cyclase that resynthesizes the cGMP the cascade hydrolyses, belongs to the same photoreceptor-intrinsic arm: biallelic hypomorphic GUCY2D alleles leave rod electroretinographic components undetectable or severely reduced with a stable course, although that phenotype is not conventionally labelled Riggs and carries macular changes of its own (see the CSNB1I subtype).

rod photoreceptor cell CL:0000604

RHO hgnc:10012 GNAT1 hgnc:4393 GNB3 hgnc:4400 PDE6B hgnc:8786 SLC24A1 hgnc:10975 GUCY2D hgnc:4689

Phototransduction GO:0007602 ⚠ ABNORMAL

Downstream

Loss of Rod Light-Response Generation

Show evidence (5 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.

PMID:24760071 SUPPORT BACKGROUND Human Clinical

"In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB."

Supports the gain-of-function half of this node's claim for the dominant genes bound here, RHO, GNAT1 and PDE6B: what makes the disease stationary rather than degenerative is a cascade left constitutively on.

+ 2 more references

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

Detection of light stimulus involved in visual perception GO:0050908 ↓ 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.

Failure of Rhodopsin Shut-Off in the Rod Outer Segment

The Oguchi arm, and the mirror image of the Riggs arm above: the rod generates a light response but cannot terminate it. Rhodopsin kinase (GRK1) phosphorylates photoactivated rhodopsin and arrestin (SAG) then quenches it, and the two work together, so a null allele in either leaves the pigment signalling after the stimulus has ended. The lesion is in the shutoff arm of the cascade rather than in its activation arm, which is why the electroretinographic and dark-adaptation signature differs from both the Riggs and the Schubert-Bornschein forms.

rod photoreceptor cell CL:0000604

SAG hgnc:10521 GRK1 hgnc:10013

Termination of rod phototransduction signalling GO:0016059 ↓ DECREASED

Downstream

Delayed Rod Dark Adaptation An unquenched pigment keeps the rod effectively light-adapted, so recovery of dark sensitivity is postponed rather than abolished.

Show evidence (3 references)

PMID:9020843 SUPPORT BACKGROUND Human Clinical

States the shared shut-off function of the two genes bound on this node, which is the mechanism the node asserts and the reason a lesion in either gene produces one phenotype.

PMID:9020843 SUPPORT PRIMARY RESULT Human Clinical

"Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."

Establishes GRK1 null alleles as causal, and explicitly as an addition to the genetic heterogeneity of congenital stationary night blindness.

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"

Assigns arrestin to the recovery rather than the activation phase of transduction, which is what places this node in the shutoff arm.

Delayed Rod Dark Adaptation

The rod recovers its dark sensitivity only after a prolonged period in darkness, while cone dark adaptation proceeds on its normal timescale. This rod-selective delay, rather than an absent rod response, is what distinguishes Oguchi disease from the Riggs arm: the rod can respond, but it cannot reset.

rod photoreceptor cell CL:0000604

Dark adaptation GO:1990603 ↓ DECREASED

Downstream

Mizuo-Nakamura Phenomenon The light-adapted retina takes on a golden or gray-white discolouration that clears once the eye has been in darkness long enough for the rods to recover.

Night Blindness A rod that cannot reset cannot signal in dim light, so the Oguchi arm reaches the same cardinal symptom as the other three arms by its own route.

Show evidence (1 reference)

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally."

States both halves of this node: the rod delay and the normal cone course that makes it rod-selective.

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

NYX hgnc:8082 GRM6 hgnc:4598 TRPM1 hgnc:7146 GPR179 hgnc:31371 LRIT3 hgnc:24783

G protein-coupled glutamate receptor signaling pathway GO:0007216 ↓ DECREASED Synapse organization GO:0050808 ⚠ 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

CACNA1F hgnc:1393 CABP4 hgnc:1386

Calcium ion transmembrane transport GO:0070588 ↓ DECREASED Neurotransmitter secretion GO:0007269 ↓ DECREASED

Downstream

Failure of Photoreceptor-to-Bipolar Signal Transmission

Reduced Visual Acuity Because the lesion starves the OFF as well as the ON bipolar pathway, the incomplete form compromises daytime acuity, which the complete and Riggs forms generally spare.

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 photoreceptor cell CL:0000210

Chemical synaptic transmission GO:0007268 ↓ DECREASED

Downstream

Impaired Scotopic Vision with Normal Fundus

Electronegative Electroretinogram The b-wave is generated downstream of the transmission failure while the a-wave is generated upstream of it, so the waveform inverts and the bright-flash b:a ratio falls below one.

Show evidence (5 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

Supports the discriminating value of the waveform while establishing the specificity caveat this node states. The same review rates the underlying evidence as at high risk of bias, so read it as a consistency claim rather than a precision estimate.

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.

+ 2 more references

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 ↓ DECREASED

Downstream

Night Blindness The shared clinical endpoint of the Riggs and both Schubert-Bornschein arms presents as impaired vision in dim light.

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

Supports the combination of impaired low-light vision with myopia and nystagmus, and the explicit absence of degeneration that this node treats as defining.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Night Blindness VERY_FREQUENT Ocular HP:0000662

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

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.

Mizuo-Nakamura Phenomenon Ocular HP:0030824

Show evidence (2 references)

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light"

Describes the sign and its dependence on adaptation state, which is what the HPO term denotes.

PMID:9020843 SUPPORT BACKGROUND Human Clinical

"Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon."

Independent description naming the phenomenon, in the paper that identified the second Oguchi gene.

Myopia Ocular HP:0000545

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

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."

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

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

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.

🧬

Genetic Associations

NYX (Loss-of-function variants causing complete CSNB (X-linked))

Gene: NYX hgnc:8082 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 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 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 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:42471459 SUPPORT Model Organism

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 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 gene page 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 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:42106701 SUPPORT Other

Lists CABP4 among the CSNB genes associated with the electronegative waveform.

GNAT1 (Dominant and recessive variants causing Riggs CSNB)

Gene: GNAT1 hgnc:4393 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 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 gene page 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. The citation makes the cascade-wide point rather than naming the specific RHO alleles, so it supports the claim indirectly.

SAG (Biallelic loss-of-function variants causing Oguchi disease type 1)

Gene: SAG hgnc:10521 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:7670478 SUPPORT PRIMARY RESULT Human Clinical

"in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene"

The gene-discovery report, and the source of the founder-allele statement in the notes.

PMID:7670478 SUPPORT BACKGROUND Human Clinical

"arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"

Sources the recovery-phase role the notes attribute to arrestin.

GRK1 (Biallelic loss-of-function variants causing Oguchi disease type 2)

Gene: GRK1 hgnc:10013 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:9020843 SUPPORT PRIMARY RESULT Human Clinical

"Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."

The gene-discovery report establishing GRK1 as the second Oguchi locus.

PMID:9020843 SUPPORT BACKGROUND Human Clinical

Sources the shared shut-off function that unites the two Oguchi loci.

SLC24A1 (Biallelic loss-of-function variants causing CSNB1D)

Gene: SLC24A1 hgnc:10975 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20850105 SUPPORT PRIMARY RESULT Human Clinical

The gene-discovery report, with recessive segregation in a multigeneration family.

PMID:26246500 SUPPORT PRIMARY RESULT Model Organism

"The compensating loss of CNG channel function in the absence of NCKX1-mediated Ca(2+) extrusion may prevent toxic Ca(2+) buildup and provides an explanation for the stationary nature of the associated disorder in humans."

The authors' proposed account of why this locus is stationary, recorded in the notes as their proposal rather than as an established mechanism.

PDE6B (Heterozygous variants causing autosomal dominant CSNB (CSNBAD2))

Gene: PDE6B hgnc:8786 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:24760071 SUPPORT BACKGROUND Human Clinical

"The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization."

Names the classical dominant allele and its effect on the rod.

PMID:24760071 SUPPORT PRIMARY RESULT Human Clinical

"Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation"

The second dominant PDE6B family, establishing the locus beyond one pedigree.

PMID:24760071 SUPPORT PRIMARY RESULT In Vitro

"We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation."

The authors' mechanistic account of the truncating allele, which the notes records as their hypothesis.

GUCY2D (Biallelic hypomorphic variants causing CSNB1I, a rod-dominant dysfunction only partly matching CSNB)

Gene: GUCY2D hgnc:4689 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:40478561 SUPPORT PRIMARY RESULT Human Clinical

"Molecular analyses revealed biallelic variants of GUCY2D in all patients, four of which are clinically and biochemically characterized for the first time, to our knowledge."

Establishes the gene-phenotype association in the case series that defines this locus clinically.

PMID:40478561 SUPPORT PRIMARY RESULT Human Clinical

"The apparent lack of retinal degeneration, clinical features, predominant and severe rod photoreceptor involvement, and relatively high degree of ERG stability are similar to rare forms of SNB."

The authors' framing is a similarity claim, which is what the first reservation in the notes records.

PMID:33109612 REFUTE PRIMARY RESULT In Vitro

"The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB."

Refutes the mechanistic half of this record's claim, not the association: the measured loss of guanylyl cyclase activation by GCAPs accounts for the cone-rod and LCA phenotypes but not for a rod-selective one, so a phototransduction-activation account of CSNB1I is unsupported.

💊

Medical Actions

Refractive Correction and Low-Vision Support

Action: Supportive Care NCIT:C15747

Platform: Other

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 therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

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. It establishes preclinical promise rather than clinical efficacy.

🐁

Animal Models

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

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
notes: >-
  SUBTYPE STRUCTURE. This entry now carries two layers of subtype row, and the
  distinction matters. The first four rows (cCSNB, icCSNB, Riggs, Oguchi) are
  mechanistic arms: cCSNB, icCSNB and Riggs are electroretinographic classes with
  no MONDO term of their own and are deliberately left unbound, while Oguchi
  disease does have one (MONDO:0019152) and carries it. The remaining rows are the
  individual numbered loci, each bound to its own MONDO term, each carrying the
  gene it names, and each assigned to one of the arms through the `subtype:`
  foreign keys on the `genetic:` records. An earlier version of this entry bound a
  numbered leaf on each of the three arms (CSNB1A on cCSNB, CSNB2A on icCSNB,
  CSNBAD1 on Riggs), which asserted that the arm was that one locus; those
  bindings were moved onto their own rows.

  MONDO DESCENDANT RECONCILIATION (OLS4, 2026-09-25). MONDO:0016293 has 18
  hierarchical descendants. Seventeen are curated here as bound subtype rows. The
  eighteenth, MONDO:0044749 X-linked congenital stationary night blindness, is a
  mode-of-inheritance grouping over the two X-linked loci that already have rows
  (CSNB1A/NYX and CSNB2A/CACNA1F), so it is not curated separately.

  Two of those seventeen are not in this issue's gap list because MONDO records no
  causal gene edge on them, and both are nonetheless gene-defined in the
  literature: MONDO:0032811 (CSNB1I) has no gene edge but is filed under
  MONDO:0100453 GUCY2D-related recessive retinopathy, and MONDO:0019152 (Oguchi
  disease) is the umbrella over the two gene-bearing Oguchi leaves. A gene-keyed
  diff against MONDO therefore under-reports this entry's genetics rather than
  over-reporting it.

  DOUBLE-BOUND MONDO TERMS. Two terms bound on rows here are also bound on subtype
  rows of gene-scoped entries: MONDO:0010241 (CSNB2A) in CACNA1F-Related_Retinopathy
  and MONDO:0012498 (CSNBAD1) in RHO-Related_Retinopathy. That is deliberate - this
  entry models the CSNB phenotype across genes and those entries model one gene's
  allelic spectrum across phenotypes - and each row says so, but it is a lump/split
  decision a reviewer should see rather than infer.
parents:
- Ophthalmological Disease
- Inherited retinal dystrophy
has_subtypes:
- name: cCSNB
  display_name: Complete CSNB (Schubert-Bornschein, ON pathway)
  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. This is an
    electroretinographic class rather than a MONDO class, so it is left unbound
    here; the numbered loci that compose it carry the MONDO terms on the CSNB1A,
    CSNB1B, CSNB1C, CSNB1E and CSNB1F rows below.
  review_notes: >
    MONDO has no class term for the complete form as such. Synonym-inclusive OLS4
    searches of MONDO for "complete congenital stationary night blindness" return
    only the numbered leaves CSNB1A to CSNB1F, whose own synonyms embed the word
    "complete" (for example MONDO:0009758 carries "night blindness, congenital
    stationary (complete), 1B, autosomal recessive"); a search for
    "Schubert-Bornschein" returns nothing. Run 2026-09-25.
  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)
  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. As with the complete
    form this is an electroretinographic class with no MONDO term of its own; the
    CSNB2A and CSNB2B rows below carry the MONDO terms.
  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)
  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. Like the two Schubert-Bornschein classes this
    is an electroretinographic grouping with no MONDO term of its own; the
    CSNBAD1, CSNBAD2, CSNBAD3, CSNB1D, CSNB1G and CSNB1H rows below carry the
    MONDO terms.
  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.
- name: Oguchi
  display_name: Oguchi disease (failure of rhodopsin shut-off)
  subtype_term:
    preferred_term: Oguchi disease
    term:
      id: MONDO:0019152
      label: Oguchi disease
  description: >
    A recessive form in which the rod generates a light response but cannot
    terminate it, because the two proteins that shut off activated rhodopsin are
    lost: rhodopsin kinase (GRK1) and arrestin (SAG). Dark adaptation of rods is
    extremely retarded while cone adaptation proceeds normally. Oguchi disease is
    the one arm of this entry in which the fundus is not normal: it shows the
    Mizuo-Nakamura phenomenon, a golden or gray-white retinal discolouration that
    appears on light adaptation and disappears in the dark-adapted state, so it is
    an explicit exception to the normal-fundus generalization the disease-level
    endpoint node records.
  genes:
  - preferred_term: SAG
    term:
      id: hgnc:10521
      label: SAG
  - preferred_term: GRK1
    term:
      id: hgnc:10013
      label: GRK1
  evidence:
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase."
    quote_role: BACKGROUND
    explanation: >
      States the shared shut-off function of the two Oguchi genes, which is what
      makes this a single mechanistic arm rather than two unrelated loci.
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally."
    quote_role: BACKGROUND
    explanation: >
      Establishes the rod-selective delay in dark adaptation that distinguishes
      this arm from a failure of response generation.
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light"
    quote_role: BACKGROUND
    explanation: >
      The fundus finding that makes this arm an exception to the normal-fundus
      generalization the rest of the entry rests on.
- name: CSNB1A
  display_name: CSNB1A - NYX (OMIM:310500)
  subtype_term:
    preferred_term: congenital stationary night blindness 1A
    term:
      id: MONDO:0010690
      label: congenital stationary night blindness 1A
  description: >
    X-linked complete CSNB caused by NYX variants. NYX is one of the five genes
    of the mGluR6 signalling cascade at the ON-bipolar dendritic tip, so this
    locus sits in the complete Schubert-Bornschein arm.
  genes:
  - preferred_term: NYX
    term:
      id: hgnc:8082
      label: NYX
  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: Places NYX in the mGluR6 signalling cascade that defines the complete form.
- name: CSNB1B
  display_name: CSNB1B - GRM6 (OMIM:257270)
  subtype_term:
    preferred_term: congenital stationary night blindness 1B
    term:
      id: MONDO:0009758
      label: congenital stationary night blindness 1B
  description: >
    Autosomal recessive complete CSNB caused by biallelic GRM6 variants. GRM6 is
    the metabotropic glutamate receptor that names the cascade and that keeps the
    TRPM1 channel closed while the photoreceptor releases glutamate in darkness.
  genes:
  - preferred_term: GRM6
    term:
      id: hgnc:4598
      label: GRM6
  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: Places GRM6 in the mGluR6 signalling cascade that defines the complete form.
- name: CSNB1C
  display_name: CSNB1C - TRPM1 (OMIM:613216)
  subtype_term:
    preferred_term: congenital stationary night blindness 1C
    term:
      id: MONDO:0013183
      label: congenital stationary night blindness 1C
  description: >
    Autosomal recessive complete CSNB caused by biallelic TRPM1 variants. TRPM1
    is the effector cation channel of the cascade, the channel that light opens
    by relieving GRM6 signalling.
  genes:
  - preferred_term: TRPM1
    term:
      id: hgnc:7146
      label: TRPM1
  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: Places TRPM1 in the mGluR6 signalling cascade that defines the complete form.
- name: CSNB1D
  display_name: CSNB1D - SLC24A1 (OMIM:613830)
  subtype_term:
    preferred_term: congenital stationary night blindness 1D
    term:
      id: MONDO:0013450
      label: congenital stationary night blindness 1D
  description: >
    Autosomal recessive CSNB caused by biallelic SLC24A1 variants. SLC24A1
    encodes NCKX1, the exchanger thought to extrude from the rod outer segment
    the calcium admitted through the cGMP-gated channels, so the lesion is inside
    the photoreceptor rather than at the bipolar synapse and this locus is placed
    in the Riggs arm here. Note that OMIM and MONDO number it within the
    "complete" series - its MONDO synonym reads "night blindness, congenital
    stationary (complete), 1D, autosomal recessive" - and that numbering reflects
    series position rather than the mGluR6 cascade mechanism the other 1-series
    loci share.
  genes:
  - preferred_term: SLC24A1
    term:
      id: hgnc:10975
      label: SLC24A1
  evidence:
  - reference: PMID:20850105
    reference_title: A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model."
    quote_role: PRIMARY_RESULT
    explanation: >
      The gene-discovery report: a truncating SLC24A1 allele segregating
      recessively in a multigeneration night-blindness family.
  - reference: PMID:26246500
    reference_title: A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "It is thought that the concentration of Ca(2+) in rod outer segments is controlled by a dynamic balance between influx via cGMP-gated (CNG) channels and extrusion via Na(+)/Ca(2+), K(+) exchangers (NCKX1)."
    quote_role: BACKGROUND
    explanation: >
      The source of the hedged statement about NCKX1's role in the rod outer
      segment; the authors present it as the prevailing view rather than as a
      result of their own.
  - reference: PMID:26246500
    reference_title: A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses."
    quote_role: PRIMARY_RESULT
    explanation: >
      Locates the lesion in the rod outer segment and shows cone responses are
      spared, which is why this row is placed in the Riggs arm despite its
      position in the numbered "complete" series.
- name: CSNB1E
  display_name: CSNB1E - GPR179 (OMIM:614565)
  subtype_term:
    preferred_term: congenital stationary night blindness 1E
    term:
      id: MONDO:0013807
      label: congenital stationary night blindness 1E
  description: >
    Autosomal recessive complete CSNB caused by biallelic GPR179 variants, one of
    the five members of the mGluR6 signalling cascade at the ON-bipolar dendritic
    tip.
  genes:
  - preferred_term: GPR179
    term:
      id: hgnc:31371
      label: GPR179
  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: Places GPR179 in the mGluR6 signalling cascade that defines the complete form.
- name: CSNB1F
  display_name: CSNB1F - LRIT3 (OMIM:615058)
  subtype_term:
    preferred_term: congenital stationary night blindness 1F
    term:
      id: MONDO:0014026
      label: congenital stationary night blindness 1F
  description: >
    Autosomal recessive complete CSNB caused by biallelic LRIT3 variants. This is
    the locus for which gene augmentation has been taken furthest, in both a
    mouse and a naturally occurring canine model, both curated in this entry's
    animal_models section.
  genes:
  - preferred_term: LRIT3
    term:
      id: hgnc:24783
      label: LRIT3
  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 the complete form.
- name: CSNB1G
  display_name: CSNB1G - GNAT1, recessive (OMIM:616389)
  subtype_term:
    preferred_term: congenital stationary night blindness 1G
    term:
      id: MONDO:0014614
      label: congenital stationary night blindness 1G
  description: >
    The recessive GNAT1 locus, separate from the dominant GNAT1 locus CSNBAD3.
    The rod transducin alpha subunit therefore appears twice in the numbered
    series, once as a recessive locus and once as a dominant one; the mechanistic
    arm is the same rod phototransduction cascade and only the allele class
    differs.
  genes:
  - preferred_term: GNAT1
    term:
      id: hgnc:4393
      label: GNAT1
  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: >
      Identifies GNAT1 as the transducin alpha subunit gene of the Riggs arm.
      The family reported here is dominant, so this citation supports the gene
      and the mechanistic arm rather than the recessive allele class that
      distinguishes this particular locus.
- name: CSNB1H
  display_name: CSNB1H - GNB3 (OMIM:617024)
  subtype_term:
    preferred_term: congenital stationary night blindness 1H
    term:
      id: MONDO:0014872
      label: congenital stationary night blindness 1H
  description: >
    Autosomal recessive CSNB caused by biallelic GNB3 variants. The phenotype
    straddles the two arms of this entry: affected individuals show reduced cone
    sensitivity together with variable ON-bipolar dysfunction, so it cannot be
    assigned cleanly to either electroretinographic class.
  genes:
  - preferred_term: GNB3
    term:
      id: hgnc:4400
      label: GNB3
  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 mixed ON-bipolar and cone phenotype that makes this locus
      hard to assign to a single electroretinographic class.
- name: CSNB1I
  display_name: CSNB1I - GUCY2D (OMIM:618555)
  subtype_term:
    preferred_term: night blindness, congenital stationary, type 1I
    term:
      id: MONDO:0032811
      label: night blindness, congenital stationary, type1i
  description: >
    Biallelic GUCY2D variants, encoding retinal guanylyl cyclase 1, producing a
    rod-dominant dysfunction with a stable electroretinogram. This is the least
    securely stationary-night-blindness row in the series and is curated with that
    reservation: the largest clinical and biochemical series describes the
    phenotype as a rod-cone dysfunction only similar to rare forms of stationary
    night blindness, its patients had central macular hypopigmentation and
    temporal vascular attenuation rather than a normal fundus, and cone responses
    were variable. Biallelic GUCY2D variants are more usually associated with
    Leber congenital amaurosis; MONDO files this term under
    MONDO:0100453 GUCY2D-related recessive retinopathy as well as under
    congenital stationary night blindness, and the LCA and CORD6 arms of GUCY2D
    disease are curated in the separate GUCY2D-Related_Retinopathy entry.
  genes:
  - preferred_term: GUCY2D
    term:
      id: hgnc:4689
      label: GUCY2D
  evidence:
  - reference: PMID:40478561
    reference_title: "Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The apparent lack of retinal degeneration, clinical features, predominant and severe rod photoreceptor involvement, and relatively high degree of ERG stability are similar to rare forms of SNB."
    quote_role: PRIMARY_RESULT
    explanation: >
      The authors' own framing, which is a similarity claim rather than an
      identity claim, and the reason this row carries a reservation.
  - reference: PMID:40478561
    reference_title: "Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Retinal imaging showed central macular hypopigmentation with temporal vascular attenuation."
    quote_role: PRIMARY_RESULT
    explanation: >
      The fundus finding that separates this row from the normal-fundus
      generalization the rest of the entry rests on.
- name: CSNB2A
  display_name: CSNB2A - CACNA1F (OMIM:300071)
  subtype_term:
    preferred_term: congenital stationary night blindness 2A
    term:
      id: MONDO:0010241
      label: congenital stationary night blindness 2A
  description: >
    X-linked incomplete CSNB caused by CACNA1F variants affecting the Cav1.4
    calcium channel at the photoreceptor ribbon synapse, and the commonest cause
    of the incomplete form. Allele-level curation of the wider CACNA1F spectrum,
    which also includes cone-rod dystrophy and Aland Island eye disease, lives in
    the separate CACNA1F-Related_Retinopathy and Aland_Island_Eye_Disease entries.
    CACNA1F-Related_Retinopathy binds this same MONDO term on its own CSNB2A
    subtype row, as RHO-Related_Retinopathy does for CSNBAD1 below.
  genes:
  - preferred_term: CACNA1F
    term:
      id: hgnc:1393
      label: CACNA1F
  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 names the channel subunit.
- name: CSNB2B
  display_name: CSNB2B / congenital nonprogressive cone-rod synaptic disorder - CABP4 (OMIM:610427)
  subtype_term:
    preferred_term: cone-rod synaptic disorder, congenital nonprogressive
    term:
      id: MONDO:0012490
      label: cone-rod synaptic disorder, congenital nonprogressive
  description: >
    Autosomal recessive incomplete CSNB caused by biallelic CABP4 variants.
    MONDO's primary label for this concept is "cone-rod synaptic disorder,
    congenital nonprogressive", with "night blindness, congenital stationary,
    type 2B" as a synonym; the synaptic naming is consistent with the
    incomplete-form genes acting on glutamate release at the photoreceptor
    terminal, which is why this row sits in the incomplete arm alongside CSNB2A.
  genes:
  - preferred_term: CABP4
    term:
      id: hgnc:1386
      label: CABP4
  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. Evidence source is OTHER because this is a systematic review.
  - 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 to presynaptic glutamate release, which
      is the basis for placing CABP4 with CACNA1F rather than with the
      postsynaptic signalplex genes. Evidence source is OTHER because this is a
      review.
- name: CSNBAD1
  display_name: CSNBAD1 - RHO (OMIM:610445)
  subtype_term:
    preferred_term: congenital stationary night blindness autosomal dominant 1
    term:
      id: MONDO:0012498
      label: congenital stationary night blindness autosomal dominant 1
  description: >
    Autosomal dominant Riggs CSNB caused by RHO missense variants that leave the
    pigment constitutively active in darkness, of which p.G90D is the classical
    example. Allele-level curation, including the evidence that p.G90D carriers
    frequently progress to retinitis pigmentosa, lives in the separate
    RHO-Related_Retinopathy entry, which binds the same MONDO term on its own
    CSNBAD1 subtype row.
  genes:
  - preferred_term: RHO
    term:
      id: hgnc:10012
      label: RHO
  evidence:
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB."
    quote_role: BACKGROUND
    explanation: >
      States the constitutive-activation requirement shared by the three
      dominant Riggs loci, which is the mechanism this row asserts.
  - reference: PMID:33669941
    reference_title: "Stationary and Progressive Phenotypes Caused by the p.G90D Mutation in Rhodopsin Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation p.G90D has previously been associated with CSNB based on the examination of one family."
    quote_role: BACKGROUND
    explanation: >
      Sources the identification of p.G90D as the classical CSNB-causing RHO
      allele, and records how thin that original basis was.
  - reference: PMID:33669941
    reference_title: "Stationary and Progressive Phenotypes Caused by the p.G90D Mutation in Rhodopsin Gene."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical characteristics of the largest p.G90D cohort so far showed a large frequency of progressive retinal degeneration with 53.3% developing RP, contrary to the previous report."
    quote_role: PRIMARY_RESULT
    explanation: >
      Contradicts the stationary reading of this locus at the allele level: most
      p.G90D carriers in the largest cohort developed progressive retinitis
      pigmentosa. It does not contradict the existence of a stationary CSNBAD1
      phenotype, which 20% of that cohort had, but it does refute treating
      p.G90D itself as a reliably stationary allele.
- name: CSNBAD2
  display_name: CSNBAD2 - PDE6B (OMIM:163500)
  subtype_term:
    preferred_term: congenital stationary night blindness autosomal dominant 2
    term:
      id: MONDO:0008099
      label: congenital stationary night blindness autosomal dominant 2
  description: >
    Autosomal dominant Riggs CSNB caused by PDE6B variants. The Rambusch pedigree
    allele p.His258Asn desensitizes rods, and a later French family carried a
    truncating allele whose product still binds the inhibitory PDE6 gamma subunit
    and so relieves inhibition of the normal catalytic subunits. Both routes
    converge on constitutive activation of the cascade, and both are exceptional
    among phototransduction-gene alleles, most of which cause progressive
    rod-cone dystrophy instead.
  genes:
  - preferred_term: PDE6B
    term:
      id: hgnc:8786
      label: PDE6B
  evidence:
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization."
    quote_role: BACKGROUND
    explanation: Names the classical dominant PDE6B allele and its effect on the rod.
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation"
    quote_role: PRIMARY_RESULT
    explanation: >
      The second reported dominant PDE6B family, which establishes the locus
      beyond a single pedigree.
  - 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: >
      Sources the closing clause of the description: alleles in these genes
      usually cause progressive dystrophy, and the stationary outcome is the
      exception.
- name: CSNBAD3
  display_name: CSNBAD3 - GNAT1, dominant (OMIM:610444)
  subtype_term:
    preferred_term: congenital stationary night blindness autosomal dominant 3
    term:
      id: MONDO:0012497
      label: congenital stationary night blindness autosomal dominant 3
  description: >
    Autosomal dominant Riggs CSNB caused by GNAT1 missense variants in the rod
    transducin alpha subunit, distinct from the recessive GNAT1 locus CSNB1G
    above.
  genes:
  - preferred_term: GNAT1
    term:
      id: hgnc:4393
      label: GNAT1
  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 dominant GNAT1 variant in a Riggs-type family.
- name: Oguchi1
  display_name: Oguchi disease-1 - SAG (OMIM:258100)
  subtype_term:
    preferred_term: Oguchi disease-1
    term:
      id: MONDO:0009775
      label: Oguchi disease-1
  description: >
    Oguchi disease caused by biallelic SAG variants. Arrestin acts in the
    recovery phase of light transduction; a founder 1147delA allele accounts for
    most reported Japanese cases.
  genes:
  - preferred_term: SAG
    term:
      id: hgnc:10521
      label: SAG
  evidence:
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene"
    quote_role: PRIMARY_RESULT
    explanation: The gene-discovery report and the source of the founder-allele claim.
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"
    quote_role: BACKGROUND
    explanation: Sources the functional role this row attributes to arrestin.
- name: Oguchi2
  display_name: Oguchi disease-2 - GRK1 (OMIM:613411)
  subtype_term:
    preferred_term: Oguchi disease-2
    term:
      id: MONDO:0013259
      label: Oguchi disease-2
  description: >
    Oguchi disease caused by biallelic GRK1 variants. Rhodopsin kinase acts with
    arrestin to shut off activated rhodopsin, so loss of either protein produces
    the same failure to quench the light response.
  genes:
  - preferred_term: GRK1
    term:
      id: hgnc:10013
      label: GRK1
  evidence:
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."
    quote_role: PRIMARY_RESULT
    explanation: The gene-discovery report establishing GRK1 as the second Oguchi locus.
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.
    GUCY2D, the retinal guanylyl cyclase that resynthesizes the cGMP the cascade
    hydrolyses, belongs to the same photoreceptor-intrinsic arm: biallelic
    hypomorphic GUCY2D alleles leave rod electroretinographic components
    undetectable or severely reduced with a stable course, although that
    phenotype is not conventionally labelled Riggs and carries macular changes of
    its own (see the CSNB1I subtype).
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: RHO
    term:
      id: hgnc:10012
      label: RHO
  - preferred_term: GNAT1
    term:
      id: hgnc:4393
      label: GNAT1
  - preferred_term: GNB3
    term:
      id: hgnc:4400
      label: GNB3
  - preferred_term: PDE6B
    term:
      id: hgnc:8786
      label: PDE6B
  - preferred_term: SLC24A1
    term:
      id: hgnc:10975
      label: SLC24A1
  - preferred_term: GUCY2D
    term:
      id: hgnc:4689
      label: GUCY2D
  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.
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB."
    explanation: >
      Supports the gain-of-function half of this node's claim for the dominant
      genes bound here, RHO, GNAT1 and PDE6B: what makes the disease stationary
      rather than degenerative is a cascade left constitutively on.
  - reference: PMID:26246500
    reference_title: A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses."
    explanation: >
      Places SLC24A1, bound on this node, inside the rod outer segment with cone
      responses spared, which is what assigns it to this arm rather than to the
      synaptic arms.
  - reference: PMID:40478561
    reference_title: "Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Rod photoreceptor-mediated electroretinogram (ERG) components were undetectable or severely reduced in all but one case, and cone-mediated responses were variable."
    explanation: >
      Supports the GUCY2D sentence in this node's description: the rod-dominant
      electroretinographic deficit that places biallelic GUCY2D alleles in the
      photoreceptor-intrinsic arm, together with the variable cone involvement
      that keeps them from being called Riggs.
  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: Failure of Rhodopsin Shut-Off in the Rod Outer Segment
  description: >
    The Oguchi arm, and the mirror image of the Riggs arm above: the rod
    generates a light response but cannot terminate it. Rhodopsin kinase (GRK1)
    phosphorylates photoactivated rhodopsin and arrestin (SAG) then quenches it,
    and the two work together, so a null allele in either leaves the pigment
    signalling after the stimulus has ended. The lesion is in the shutoff arm of
    the cascade rather than in its activation arm, which is why the
    electroretinographic and dark-adaptation signature differs from both the
    Riggs and the Schubert-Bornschein forms.
  role: trigger
  biological_scale: MOLECULAR
  genes:
  - preferred_term: SAG
    term:
      id: hgnc:10521
      label: SAG
  - preferred_term: GRK1
    term:
      id: hgnc:10013
      label: GRK1
  cell_types:
  - preferred_term: rod photoreceptor cell
    term:
      id: CL:0000604
      label: retinal rod cell
  biological_processes:
  - preferred_term: Termination of rod phototransduction signalling
    term:
      id: GO:0016059
      label: negative regulation of opsin-mediated signaling pathway
    modifier: DECREASED
  conforms_to: "phototransduction_cascade_dysfunction#Phototransduction Cascade Component Defect"
  evidence:
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase."
    explanation: >
      States the shared shut-off function of the two genes bound on this node,
      which is the mechanism the node asserts and the reason a lesion in either
      gene produces one phenotype.
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."
    explanation: >
      Establishes GRK1 null alleles as causal, and explicitly as an addition to
      the genetic heterogeneity of congenital stationary night blindness.
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"
    explanation: >
      Assigns arrestin to the recovery rather than the activation phase of
      transduction, which is what places this node in the shutoff arm.
  downstream:
  - target: Delayed Rod Dark Adaptation
    causal_link_type: DIRECT
    description: >
      An unquenched pigment keeps the rod effectively light-adapted, so recovery
      of dark sensitivity is postponed rather than abolished.

- name: Delayed Rod Dark Adaptation
  description: >
    The rod recovers its dark sensitivity only after a prolonged period in
    darkness, while cone dark adaptation proceeds on its normal timescale. This
    rod-selective delay, rather than an absent rod response, is what distinguishes
    Oguchi disease from the Riggs arm: the rod can respond, but it cannot reset.
  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: Dark adaptation
    term:
      id: GO:1990603
      label: dark adaptation
    modifier: DECREASED
  conforms_to: "phototransduction_cascade_dysfunction#Failure of Photoreceptor Light-Response Generation or Timely Recovery"
  evidence:
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The course of dark adaptation of rod photoreceptors is extremely retarded in Oguchi disease while that of cones appears to proceed normally."
    explanation: >
      States both halves of this node: the rod delay and the normal cone course
      that makes it rod-selective.
  downstream:
  - target: Mizuo-Nakamura Phenomenon
    causal_link_type: DIRECT
    description: >
      The light-adapted retina takes on a golden or gray-white discolouration
      that clears once the eye has been in darkness long enough for the rods to
      recover.
    evidence:
    - reference: PMID:7670478
      reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light"
      explanation: >
        Ties the fundus sign to the light and dark adaptation state, which is
        the causal claim this edge makes.
  - target: Night Blindness
    causal_link_type: DIRECT
    description: >
      A rod that cannot reset cannot signal in dim light, so the Oguchi arm
      reaches the same cardinal symptom as the other three arms by its own route.
    evidence:
    - reference: PMID:7670478
      reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: "Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness with all other visual functions, including visual acuity, visual field, and colour vision being usually normal."
      explanation: >
        Establishes night blindness as the presenting and essentially isolated
        deficit in this arm.

- 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
  genes:
  - preferred_term: NYX
    term:
      id: hgnc:8082
      label: NYX
  - preferred_term: GRM6
    term:
      id: hgnc:4598
      label: GRM6
  - preferred_term: TRPM1
    term:
      id: hgnc:7146
      label: TRPM1
  - preferred_term: GPR179
    term:
      id: hgnc:31371
      label: GPR179
  - preferred_term: LRIT3
    term:
      id: hgnc:24783
      label: LRIT3
  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
  genes:
  - preferred_term: CACNA1F
    term:
      id: hgnc:1393
      label: CACNA1F
  - preferred_term: CABP4
    term:
      id: hgnc:1386
      label: CABP4
  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
  - target: Reduced Visual Acuity
    causal_link_type: DIRECT
    description: >
      Because the lesion starves the OFF as well as the ON bipolar pathway, the
      incomplete form compromises daytime acuity, which the complete and Riggs
      forms generally spare.
    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 in the incomplete form specifically, and
        attributes it to the joint ON and OFF involvement this node produces.
        Evidence source is OTHER because this is a review.

- 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. The same review rates the underlying
      evidence as at high risk of bias, so read it as a consistency claim rather
      than a precision estimate.
  - 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: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 the edge from this node to the electronegative waveform, and
      records that the association is most consistent for the complete form.
      Evidence source is OTHER because this is a systematic 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
  - target: Electronegative Electroretinogram
    causal_link_type: DIRECT
    description: >
      The b-wave is generated downstream of the transmission failure while the
      a-wave is generated upstream of it, so the waveform inverts and the
      bright-flash b:a ratio falls below one.
    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 localizes it to the
        photoreceptor-bipolar synapse, which is what this edge asserts.
        Evidence source is OTHER because this is a systematic review.

- 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.
  downstream:
  - target: Night Blindness
    causal_link_type: DIRECT
    description: >
      The shared clinical endpoint of the Riggs and both Schubert-Bornschein arms
      presents as impaired vision in dim light.
    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 that both the transmission and the rod-function lesions lead to
        impaired low-light vision, which is the edge this asserts.
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: Mizuo-Nakamura Phenomenon
  subtype: Oguchi
  description: >
    A golden or gray-white discolouration of the fundus seen in the light-adapted
    eye that clears after prolonged dark adaptation. Confined to Oguchi disease
    within this entry, and the reason Oguchi disease is the one arm in which the
    fundus is not normal.
  phenotype_term:
    preferred_term: Mizuo-Nakamura phenomenon
    term:
      id: HP:0030824
      label: Mizuo phenomenon
  evidence:
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "A typical clinical feature of the disorder is a golden or gray-white discolouration of the fundus which disappears in the dark-adapted state and reappears shortly after the onset of light"
    explanation: >
      Describes the sign and its dependence on adaptation state, which is what
      the HPO term denotes.
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon."
    explanation: >
      Independent description naming the phenomenon, in the paper that
      identified the second Oguchi gene.
- 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. The citation makes the cascade-wide point rather than
      naming the specific RHO alleles, so it supports the claim indirectly.
- name: SAG
  association: Biallelic loss-of-function variants causing Oguchi disease type 1
  subtype: Oguchi
  gene_term:
    preferred_term: SAG
    term:
      id: hgnc:10521
      label: SAG
  relationship_type: CAUSATIVE
  notes: >
    SAG encodes arrestin-1, which quenches photoactivated rhodopsin after
    rhodopsin kinase has phosphorylated it. A 1147delA frameshift is a founder
    allele accounting for most reported Japanese cases. Because the lesion is in
    the shutoff rather than the activation arm of the cascade, the rod response is
    generated and then fails to terminate, which is why Oguchi disease is
    curated here as a fourth mechanistic arm rather than inside the Riggs arm.
  evidence:
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "in five out of six unrelated Japanese patients with Oguchi disease, we have identified a homozygous deletion of nucleotide 1147 (1147delA) in codon 309 of the arrestin gene"
    explanation: >
      The gene-discovery report, and the source of the founder-allele statement
      in the notes.
  - reference: PMID:7670478
    reference_title: A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "arrestin, an intrinsic rod photoreceptor protein implicated in the recovery phase of light transduction"
    explanation: Sources the recovery-phase role the notes attribute to arrestin.
- name: GRK1
  association: Biallelic loss-of-function variants causing Oguchi disease type 2
  subtype: Oguchi
  gene_term:
    preferred_term: GRK1
    term:
      id: hgnc:10013
      label: GRK1
  relationship_type: CAUSATIVE
  notes: >
    GRK1 encodes rhodopsin kinase, the enzyme that phosphorylates photoactivated
    rhodopsin and so allows arrestin to bind it. HGNC records RHOK as a previous
    symbol for this gene, which is worth knowing when reading the older Oguchi
    literature. Loss of either GRK1 or SAG produces the same failure to quench,
    which is why the two loci share one mechanistic arm.
  evidence:
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness."
    explanation: The gene-discovery report establishing GRK1 as the second Oguchi locus.
  - reference: PMID:9020843
    reference_title: Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase."
    explanation: Sources the shared shut-off function that unites the two Oguchi loci.
- name: SLC24A1
  association: Biallelic loss-of-function variants causing CSNB1D
  subtype: Riggs
  gene_term:
    preferred_term: SLC24A1
    term:
      id: hgnc:10975
      label: SLC24A1
  relationship_type: CAUSATIVE
  notes: >
    SLC24A1 encodes NCKX1, the sodium-calcium-potassium exchanger that is thought
    to extrude from the rod outer segment the calcium admitted through the
    cGMP-gated channels. The mouse knockout has malformed outer-segment disks,
    reduced CNG channel function and a hundredfold reduction in rod responses with
    cone responses preserved, and its authors propose that the compensating loss
    of CNG channel function is what keeps the disorder stationary rather than
    degenerative.
  evidence:
  - reference: PMID:20850105
    reference_title: A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model."
    explanation: The gene-discovery report, with recessive segregation in a multigeneration family.
  - reference: PMID:26246500
    reference_title: A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "The compensating loss of CNG channel function in the absence of NCKX1-mediated Ca(2+) extrusion may prevent toxic Ca(2+) buildup and provides an explanation for the stationary nature of the associated disorder in humans."
    explanation: >
      The authors' proposed account of why this locus is stationary, recorded in
      the notes as their proposal rather than as an established mechanism.
- name: PDE6B
  association: Heterozygous variants causing autosomal dominant CSNB (CSNBAD2)
  subtype: Riggs
  gene_term:
    preferred_term: PDE6B
    term:
      id: hgnc:8786
      label: PDE6B
  relationship_type: CAUSATIVE
  notes: >
    PDE6B encodes the beta catalytic subunit of rod cGMP phosphodiesterase. The
    dominant CSNB alleles are exceptional for this gene: the Rambusch p.His258Asn
    substitution desensitizes rods, and a truncating allele reported in a French
    family yields a product that still binds the inhibitory gamma subunit and so
    relieves inhibition of the normal catalytic subunits. Both leave the cascade
    constitutively active. HGNC records CSNBAD2 as an alias symbol for this gene,
    and PDEB as a previous symbol.
  evidence:
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization."
    explanation: Names the classical dominant allele and its effect on the rod.
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation"
    explanation: The second dominant PDE6B family, establishing the locus beyond one pedigree.
  - reference: PMID:24760071
    reference_title: A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation."
    explanation: >
      The authors' mechanistic account of the truncating allele, which the notes
      records as their hypothesis.
- name: GUCY2D
  association: Biallelic hypomorphic variants causing CSNB1I, a rod-dominant dysfunction only partly matching CSNB
  gene_term:
    preferred_term: GUCY2D
    term:
      id: hgnc:4689
      label: GUCY2D
  relationship_type: CAUSATIVE
  notes: >
    MONDO records GUCY2D as the causal gene of MONDO:0032811 congenital stationary
    night blindness type 1I (OMIM:618555), and the clinical series behind that
    term is real: six patients from five families with longstanding night
    blindness, biallelic GUCY2D variants, absent or severely reduced rod
    electroretinographic components, and a stable course. Two reservations are
    recorded rather than resolved here. First, the authors describe the phenotype
    as a rod-cone dysfunction only similar to rare forms of stationary night
    blindness, and their patients had central macular hypopigmentation and
    temporal vascular attenuation, so the normal fundus that defines the rest of
    this entry does not hold. Second, an earlier biochemical study of the
    CSNB-associated alleles concluded that the loss of guanylyl cyclase activation
    it measured cannot account for a rod-selective deficit, so the mechanism
    linking these alleles to a rod-only phenotype is unexplained. No subtype
    foreign key is set because this locus belongs to none of the four
    electroretinographic arms this entry models. The Leber congenital amaurosis
    and CORD6 arms of GUCY2D disease are curated in GUCY2D-Related_Retinopathy.
  evidence:
  - reference: PMID:40478561
    reference_title: "Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Molecular analyses revealed biallelic variants of GUCY2D in all patients, four of which are clinically and biochemically characterized for the first time, to our knowledge."
    explanation: >
      Establishes the gene-phenotype association in the case series that defines
      this locus clinically.
  - reference: PMID:40478561
    reference_title: "Clinical and Biochemical Characterization of Specific GUCY2D Alleles Associated With a Rare Form of Night Blindness."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The apparent lack of retinal degeneration, clinical features, predominant and severe rod photoreceptor involvement, and relatively high degree of ERG stability are similar to rare forms of SNB."
    explanation: >
      The authors' framing is a similarity claim, which is what the first
      reservation in the notes records.
  - reference: PMID:33109612
    reference_title: "GUCY2D mutations in retinal guanylyl cyclase 1 provide biochemical reasons for dominant cone-rod dystrophy but not for stationary night blindness."
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "The observed biochemical changes can explain the dominant CORD6 blindness and recessive LCA1 blindness, both of which affect rods and cones, but they cannot explain the selective loss of rod function in recessive CSNB."
    explanation: >
      Refutes the mechanistic half of this record's claim, not the association:
      the measured loss of guanylyl cyclase activation by GCAPs accounts for the
      cone-rod and LCA phenotypes but not for a rod-selective one, so a
      phototransduction-activation account of CSNB1I is unsupported.
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. 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: []

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PMID:20301423

X-Linked Congenital Stationary Night Blindness.

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