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.[1]
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.[2][3] 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.[4] 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.
Mutation | Position | References | |
---|---|---|---|
Nucleotide | Amino acid | ||
c.?-1_?-61del | 1_20del | Signal sequence | [3] |
Splicing | Intron 1 | [5] | |
c.?-63_1443-?del | 21_481del | [3] | |
c.48_64del | L18RfsX108 | Signal sequence | [5] |
c.85_108del | R29_A36del | N-terminal LRR | [2] |
c.G91C | C31S | LRRNT | [3] |
c.C105A | C35X | LRRNT | [3] |
c.C169A | P57T | LRRNT | |
c.C191A | A64E | LRR1 | [6] |
c.G281C | R94P | LRR2 | [7] |
c.301_303del | I101del | LRR2 | [3] |
c.T302C | I101T | LRR2 | [7] |
c.340_351del | E114_A118del | LRR3 | [3][5] |
c.G427C | A143P | LRR4 | [3] |
c.C452T | P151L | LRR4 | [2] |
c.464_465insAGCGTGCCCGAGCGCCTCCTG | S149_V150dup+P151_L155dup | LRR4 | [2] |
c.C524G | P175R | LRR5 | [3] |
c.T551C | L184P | LRR6 | [2] |
c.556_618delins | H186?fsX260 | LRR6 | [2] |
c.559_560delinsAA | A187K | LRR6 | [3] |
c.613_621dup | 205_207dup | LRR7 | [2][3] |
c.628_629ins | R209_S210insCLR | LRR7 | [2] |
c.T638A | L213Q | LRR7 | [2] |
c.A647G | N216S | LRR7 | [2][5] |
c.T695C | L232P | LRR8 | [2] |
c.727_738del | 243_246del | LRR8 | [3] |
c.C792G | N264K | LRR9 | [2] |
c.T854C | L285P | LRR10 | [2] |
c.T893C | F298S | LRR10 | [2] |
c.C895T | Q299X | LRR10 | [5] |
c.T920C | L307P | LRR11 | [3] |
c.A935G | N312S | LRR11 | [3] |
c.T1040C | L347P | LRRCT | [3] |
c.G1049A | W350X | LRRCT | [2] |
c.G1109T | G370V | LRRCT | [3] |
c.1122_1457del | S374RfsX383 | LRRCT | [3][5] |
c.1306del | L437WfsX559 | C-terminus | [5] |
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.[8][9] 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.[10] This has been demonstrated in CACNA1F mutant mice that have markedly reduced photoreceptor calcium signals.[11] 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.
Mutation | Position | Effect | References | |
---|---|---|---|---|
Nucleotide | Amino Acid | |||
c.C148T | R50X | N-terminus | ||
c.151_155delAGAAA | R51PfsX115 | N-terminus | [12] | |
c.T220C | C74R | N-terminus | [12] | |
c.C244T | R82X | N-terminus | [13][12] | |
c.466_469delinsGTAGGGGTGCT CCACCCCGTAGGGGTGCTCCACC | S156VdelPinsGVKHOVGVLH | D1S2-3 | [13][14][15] | |
Splicing | Intron 4 | [13] | ||
c.T685C | S229P | D1S4-5 | [12] | |
c.G781A | G261R | D1-pore | [12] | |
c.G832T | E278X | D1-pore | ||
c.904insG | R302AfsX314 | D1-pore | [14] | |
c.951_953delCTT | F318del | D1-pore | [13] | |
c.G1106A | G369D | D1S6 | Activates ~20mV more negative than wild-type, increases time to peak current and decreases inactivation, increased Ca2+ permeability. | [8][10][13][12][16] |
c.1218delC | W407GfsX443 | D1-2 | [9][13][17] | |
c.C1315T | Q439X | D1-2 | [12] | |
c.G1556A | R519Q | D1-2 | Decreased expression | [8][18] |
c.C1873T | R625X | D2S4 | [13][12] | |
c.G2021A | G674D | D2S5 | [10][13][14] | |
c.C2071T | R691X | D2-pore | [6] | |
c.T2258G | F753C | D2S6 | [12] | |
c.T2267C | I756T | D2S6 | Activates ~35mV more negative than wild-type, inactivates more slowly | |
Splicing | Intron 19 | [12] | ||
c.T2579C | L860P | D2-3 | [12] | |
c.C2683T | R895X | D3S1-2 | [5][6][9][13] | |
Splicing | Intron 22 | [12][14] | ||
Splicing | Intron 22 | [12] | ||
c.C2783A | A928D | D3S2-3 | [10][13] | |
c.C2905T | R969X | D3S4 | [8][12] | |
c.C2914T | R972X | D3S4 | [17] | |
Splicing | Intron24 | [13] | ||
c.C2932T | R978X | D3S4 | [14] | |
c.3006_3008delCAT | I1003del | D3S4-5 | [13] | |
c.G3052A | G1018R | D3S5 | [12] | |
c.3125delG | G1042AfsX1076 | D3-pore | [13] | |
c.3166insC | L1056PfsX1066 | D3-pore | [8][9][13][12] | |
c.C3178T | R1060W | D3-pore | [8][12] | |
c.T3236C | L1079P | D3-pore | Does not open without BayK, activates ~5mV more negative than wild-type | [12][16] |
c.3672delC | L1225SfsX1266 | D4S2 | [9][13] | |
c.3691_3702del | G1231_T1234del | D4S2 | [8][12] | |
c.G3794T | S1265I | D4S3 | [6] | |
c.C3886A | R1296S | D4S4 | [6] | |
c.C3895T | R1299X | D4S4 | [9][13][12] | |
Splicing | Intron 32 | [12] | ||
c.C4075T | Q1359X | D4-pore | [8][12] | |
c.T4124A | L1375H | D4-pore | Decreased expression | [8][12][18] |
Splicing | Intron 35 | [12] | ||
c.G4353A | W1451X | C-terminus | Non-functional | [9][10][13][16] |
c.T4495C | C1499R | C-terminus | [12] | |
c.C4499G | P1500R | C-terminus | [12] | |
c.T4523C | L1508P | C-terminus | [12] | |
Splicing | intron 40 | [13] | ||
c.4581delC | F1528LfsX1535 | C-terminus | ||
c.A4804T | K1602X | C-terminus | [8][12] | |
c.C5479T | R1827X | C-terminus | [12] | |
c.5663delG | S1888TfsX1931 | C-terminus | [13] | |
c.G5789A | R1930H | C-terminus | [6] |
Only three rhodopsin mutations have been found associated with congenital stationary night blindness (CSNB).[19] 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 [20] and the Thr94Ile, which has been the most recent one reported.[21] 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.[22] 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.[23]
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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/x-linked-congenital-stationary-night-blindness