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|X-linked congenital stationary night blindness|
|Classification and external resources|
Malfunction in transmission from the photoreceptors in the outer nuclear layer to bipolar cells in the inner nuclear layer underlies CSNB.
X-linked congenital stationary night blindness (CSNB) is a form of nyctalopia and is a rare X-linked non-progressive retinal disorder. It has two forms, complete, also known as type-1 (CSNB1), and incomplete, also known as type-2 (CSNB2), depending on severity. In the complete form (CSNB1), there is no measurable rod cell response to light, whereas this response is measurable in the incomplete form. Patients with this disorder have difficulty adapting to low light situations due to impaired photoreceptor transmission. These patients also often have reduced visual acuity, myopia, nystagmus, and strabismus. CSNB1 is caused by mutations in the gene NYX, which encodes a protein involved in retinal synapse formation or synaptic transmission. CSNB2 is caused by mutations in the gene CACNA1F, which encodes a voltage-gated calcium channel CaV1.4.
The X-linked varieties of congenital stationary night blindness (CSNB) can be differentiated from the autosomal forms by the presence of myopia, which is typically absent in the autosomal forms. Patients with CSNB often have impaired night vision, myopia, reduced visual acuity, strabismus, and nystagmus. Individuals with the complete form of CSNB (CSNB1) have highly impaired rod sensitivity (reduced ~300x) as well as cone dysfunction. Patients with the incomplete form can present with either myopia or hyperopia.
CSNB was originally believed to be caused by malfunction in neurotransmission from rods to bipolar cells in the retina. This is due to electroretinogram (ERG) measurements on CSNB patients which show a drastic decrease in the size of the scotopic b-wave in comparison to the a-wave, in CSNB2, or a complete loss of both in CSNB1. The a-wave is believed to represent the response of rods to visual input and remains largely unchanged in CSNB2 patients. The b-wave, however, is believed to result from electrical activity of bipolar cells and is decreased or non-existent in both CSNB1 and 2. CSNB1 patients also show mildly altered cone activity. Further study has demonstrated that the defects found in CSNB patients are better explained by more general defects in both the rod and cone ON-signaling pathways.
The complete form of X-linked congenital stationary night blindness, also known as nyctalopia, is caused by mutations in the NYX gene (Nyctalopin on X-chromosome), which encodes a small leucine-rich repeat (LRR) family protein of unknown function. This protein consists of an N-terminal signal peptide and 11 LRRs (LRR1-11) flanked by cysteine-rich LRRs (LRRNT and LRRCT). At the C-terminus of the protein there is a putative GPI anchor site. Although the function of NYX is yet to be fully understood, it is believed to be located extracellularly. A naturally occurring deletion of 85 bases in NYX in some mice leads to the "nob" (no b-wave) phenotype, which is highly similar to that seen in CSNB1 patients. NYX is expressed primarily in the rod and cone cells of the retina. There are currently almost 40 known mutations in NYX associated with CSNB1, Table 1., located throughout the protein. As the function of the nyctalopin protein is unknown, these mutations have not been further characterized. However, many of them are predicted to lead to truncated proteins that, presumably, are non-functional.
|LRR: leucine-rich repeat, LRRNT and LRRCT: N- and C-terminal cysteine-rich LRRs.|
The incomplete form of X-linked congenital stationary night blindness (CSNB2) is caused by mutations in the CACNA1F gene, which encodes the voltage-gated calcium channel CaV1.4 expressed heavily in retina. One of the important properties of this channel is that it inactivates at an extremely low rate. This allows it to produce sustained Ca2+ entry upon depolarization. As photoreceptors depolarize in the absence of light, CaV1.4 channels operate to provide sustained neurotransmitter release upon depolarization. This has been demonstrated in CACNA1F mutant mice that have markedly reduced photoreceptor calcium signals. There are currently 55 mutations in CACNA1F located throughout the channel, Table 2 and Figure 1. While most of these mutations result in truncated and, likely, non-functional channels, it is expected that they prevent the ability of light to hyperpolarize photoreceptors. Of the mutations with known functional consequences, 4 produce channels that are either completely non-functional, and two that result in channels which open at far more hyperpolarized potentials than wild-type. This will result in photoreceptors that continue to release neurotransmitter even after light-induced hyperpolarization.
|S156VdelPinsGVKHOVGVLH||D1S2-3||, , |
|c.G1106A||G369D||D1S6||Activates ~20mV more negative than wild-type, increases time to peak current and decreases inactivation, increased Ca2+ permeability.||, , , , |
|c.1218delC||W407GfsX443||D1-2||, , |
|c.G1556A||R519Q||D1-2||Decreased expression||, |
|c.G2021A||G674D||D2S5||, , |
|c.T2267C||I756T||D2S6||Activates ~35mV more negative than wild-type, inactivates more slowly|||
|c.C2683T||R895X||D3S1-2||, , , |
|Splicing||Intron 22||, |
|c.3166insC||L1056PfsX1066||D3-pore||, , , |
|c.T3236C||L1079P||D3-pore||Does not open without BayK, activates ~5mV more negative than wild-type||, |
|c.C3895T||R1299X||D4S4||, , |
|c.T4124A||L1375H||D4-pore||Decreased expression||, , |
|c.G4353A||W1451X||C-terminus||Non-functional||, , , |
Only three rhodopsin mutations have been found associated with congenital stationary night blindness (CSNB). Two of these mutations are found in the second transmembrane helix of rhodopsin at Gly-90 and Thr-94. Specifically, these mutations are the Gly90Asp  and the Thr94Ile, which has been the most recent one reported. The third mutation is Ala292Glu, and it is located in the seventh transmembrane helix, in proximity to the site of retinal attachment at Lys-296. Mutations associated with CSNB affect amino acid residues near the protonated Schiff base (PSB) linkage. They are associated with changes in conformational stability and the protonated status of the PSB nitrogen.
- Boycott K, Pearce W, Musarella M, Weleber R, Maybaum T, Birch D, Miyake Y, Young R, Bech-Hansen N (1998). Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet 62 (4): 865–875.
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- Pusch C, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi F, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A (2000). The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26 (3): 324–327.
- Gregg R, Mukhopadhyay S, Candille S, Ball S, Pardue M, McCall M, Peachey N (2003). Identification of the gene and the mutation responsible for the mouse nob phenotype. Invest Ophthalmol Vis Sci 44 (1): 378–384.
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- Bech-Hansen N, Naylor M, Maybaum T, Pearce W, Koop B, Fishman G, Mets M, Musarella M, Boycott K (1998). Loss-of-function mutations in a calcium-channel alpha1-subunit gene in Xp11.23 cause incomplete X-linked congenital stationary night blindness. Nat Genet 19 (3): 264–267.
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- Allen L, Zito I, Bradshaw K, Patel R, Bird A, Fitzke F, Yates J, Trump D, Hardcastle A, Moore A (2003). Genotype-phenotype correlation in British families with X linked congenital stationary night blindness. Br J Ophthalmol 87 (11): 1413–1420.
- Hoda J, Zaghetto F, Koschak A, Striessnig J (2005). Congenital stationary night blindness type 2 mutations S229P, G369D, L1068P, and W1440X alter channel gating or functional expression of Ca(v)1.4 L-type Ca2+ channels. J Neurosci 25 (1): 252–259.
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Genetic disorder, membrane: Channelopathy
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TRPC6 (FSGS2) · TRPML1 (Mucolipidosis type IV)
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AQP2 (Nephrogenic diabetes insipidus 2)
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