Nyctalopin Explained

Nyctalopin is a protein located on the surface of photoreceptor-to-ON bipolar cell synapse in the retina. It is composed of 481 amino acids.^[1] and is encoded in human by the NYX gene.^{[2] [3] [4]} This gene is found on the chromosome X^[5] and has two exons. This protein is a leucine-rich proteoglycan^[6] which is expressed in the eye, spleen and brain in mice.^[7] Mutations in this gene cause congenital stationary night blindness in humans (CSNB).^[8] which is a stable retinal disorder. The consequence of this mutation results in an abnormal night vision. Nyctalopin is critical due to the fact that it generates a depolarizing bipolar cell response due to the mutation on the NYX gene. Most of the time, CSNB are associated to hygh myopia which is the result of a mutation on the same gene. Several mutations can occur on the NYX gene resulting on many form of night blindness in humans. Some studies show that these mutations are more present in Asian population than in Caucasian population. A mouse strain called nob (no b-wave) carries a spontaneous mutation leading to a frameshift in this gene. These mice are used as an animal model for congenital stationary night blindness.^[9]

Discovery

The first evidence of the existence of mutation in NYX gene, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness was provided by Richard G. Weleber at the University of Alberta in 2000.

Gene location

The NYX gene is located on the short arm (p) of chromosome X, from base pair 41,447,434 to base pair 41,475,710.^[10]

Protein structure

Nyctalopin contains a N-terminal signal peptide and a C-terminal glycosylphosphatidylinositol (GPI) anchor.^[11] Predicted signal sequence is likely to be processed by a co-translational mechanism.^[12] Nyctalopin does not have two transmembrane domains and the only transmembrane domain is found to be between the amino acid 452 ad 472. In the endoplasmic reticulum, the protein is oriented with the N-terminus in the lumen of the endoplasmic reticulum and the C-terminus is located in the cytoplasm. The central part of the polypeptide encodes 11 consecutive leucines-rich repeats (LRRs). These LRR are flanked by N-terminal and C-terminal rich LRRs Tandem LRRs domains are folded into ß-sheets and α-helices, all joined by loops. According to the cysteine pattern, nyctalopin is part of the class II small leucine-rich proteoglycans. These proteins, are involved in several functions such as cell signalling, growth control, and formation of the extracellular matrix. LRR domains are involved in the protein–protein interaction in small leucine rich repeat proteoglycan family members. Also, LRR domains have a critical role in nyctalopin function. Congenital stationary night blindness in humans appears when a mutation in the LRR domains of nyctalopin occurs.

Mutations

The complete form of congenital stationary night blindness is due to the absence of nyctalopin. This absence is due to a mutation involving an 85 base pair deletion.^[13] In humans, more than 30 mutations are found in the NYX gene and most of them have an impact either on the tertiary structure of the LRR domains of nyctalopin or to truncate the protein.

Further reading

• Musarella MA, Weleber RG, Murphey WH, Young RS, Anson-Cartwright L, Mets M, Kraft SP, Polemeno R, Litt M, Worton RG . Assignment of the gene for complete X-linked congenital stationary night blindness (CSNB1) to Xp11.3 . Genomics . 5 . 4 . 727–37 . November 1989 . 2574143 . 10.1016/0888-7543(89)90114-6 .
• Hardcastle AJ, David-Gray ZK, Jay M, Bird AC, Bhattacharya SS . Localization of CSNBX (CSNB4) between the retinitis pigmentosa loci RP2 and RP3 on proximal Xp . Investigative Ophthalmology & Visual Science . 38 . 13 . 2750–5 . December 1997 . 9418727 .
• Jacobi FK, Andréasson S, Langrova H, Meindl A, Zrenner E, Apfelstedt-Sylla E, Pusch CM . Phenotypic expression of the complete type of X-linked congenital stationary night blindness in patients with different mutations in the NYX gene . Graefe's Archive for Clinical and Experimental Ophthalmology . 240 . 10 . 822–8 . October 2002 . 12397430 . 10.1007/s00417-002-0562-z . 25140284 .
• Gregg RG, Mukhopadhyay S, Candille SI, Ball SL, Pardue MT, McCall MA, Peachey NS . Identification of the gene and the mutation responsible for the mouse nob phenotype . Investigative Ophthalmology & Visual Science . 44 . 1 . 378–84 . January 2003 . 12506099 . 10.1167/iovs.02-0501 . free .
• Zito I, Allen LE, Patel RJ, Meindl A, Bradshaw K, Yates JR, Bird AC, Erskine L, Cheetham ME, Webster AR, Poopalasundaram S, Moore AT, Trump D, Hardcastle AJ . Mutations in the CACNA1F and NYX genes in British CSNBX families . Human Mutation . 21 . 2 . 169 . February 2003 . 12552565 . 10.1002/humu.9106 . 13143864 .
• Zeitz C, Scherthan H, Freier S, Feil S, Suckow V, Schweiger S, Berger W . NYX (nyctalopin on chromosome X), the gene mutated in congenital stationary night blindness, encodes a cell surface protein . Investigative Ophthalmology & Visual Science . 44 . 10 . 4184–91 . October 2003 . 14507859 . 10.1167/iovs.03-0251 . free .
• Khan NW, Kondo M, Hiriyanna KT, Jamison JA, Bush RA, Sieving PA . Primate Retinal Signaling Pathways: Suppressing ON-Pathway Activity in Monkey With Glutamate Analogues Mimics Human CSNB1-NYX Genetic Night Blindness . Journal of Neurophysiology . 93 . 1 . 481–92 . January 2005 . 15331616 . 10.1152/jn.00365.2004 .
• Zeitz C, Minotti R, Feil S, Mátyás G, Cremers FP, Hoyng CB, Berger W . Novel mutations in CACNA1F and NYX in Dutch families with X-linked congenital stationary night blindness . Molecular Vision . 11 . 179–83 . March 2005 . 15761389 .
• Morgans CW, Ren G, Akileswaran L . Localization of nyctalopin in the mammalian retina . The European Journal of Neuroscience . 23 . 5 . 1163–71 . March 2006 . 16553780 . 10.1111/j.1460-9568.2006.04647.x . 40915886 .
• Xiao X, Jia X, Guo X, Li S, Yang Z, Zhang Q . CSNB1 in Chinese families associated with novel mutations in NYX . Journal of Human Genetics . 51 . 7 . 634–40 . 2006 . 16670814 . 10.1007/s10038-006-0406-5 . free .
• Zhang Q, Xiao X, Li S, Jia X, Yang Z, Huang S, Caruso RC, Guan T, Sergeev Y, Guo X, Hejtmancik JF . Mutations in NYX of individuals with high myopia, but without night blindness . Molecular Vision . 13 . 330–6 . March 2007 . 17392683 . 2642916 .

External links

• GeneReviews/NCBI/NIH/UW entry on X-Linked Congenital Stationary Night Blindness

Notes and References

1. Yip SP, Li CC, Yiu WC, Hung WH, Lam WW, Lai MC, Ng PW, Fung WY, Chu PH, Jiang B, Chan HH, Yap MK . A novel missense mutation in the NYX gene associated with high myopia . Ophthalmic & Physiological Optics . 33 . 3 . 346–53 . May 2013 . 23406521 . 10.1111/opo.12036 . 8851666 . free .
2. Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, Bergen AA, Prinsen CF, Polomeno RC, Gal A, Drack AV, Musarella MA, Jacobson SG, Young RS, Weleber RG . Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness . Nature Genetics . 26 . 3 . 319–23 . November 2000 . 11062471 . 10.1038/81619 . 10223880 .
3. Pusch CM, Zeitz C, Brandau O, Pesch K, Achatz H, Feil S, Scharfe C, Maurer J, Jacobi FK, Pinckers A, Andreasson S, Hardcastle A, Wissinger B, Berger W, Meindl A . The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein . Nature Genetics . 26 . 3 . 324–7 . November 2000 . 11062472 . 10.1038/81627 . 42428370 .
4. Web site: Entrez Gene: NYX nyctalopin.
5. Jacobi FK, Andréasson S, Langrova H, Meindl A, Zrenner E, Apfelstedt-Sylla E, Pusch CM . Phenotypic expression of the complete type of X-linked congenital stationary night blindness in patients with different mutations in the NYX gene . Graefe's Archive for Clinical and Experimental Ophthalmology . 240 . 10 . 822–8 . October 2002 . 12397430 . 10.1007/s00417-002-0562-z . 25140284 .
6. Pearring JN, Bojang P, Shen Y, Koike C, Furukawa T, Nawy S, Gregg RG . A role for nyctalopin, a small leucine-rich repeat protein, in localizing the TRP melastatin 1 channel to retinal depolarizing bipolar cell dendrites . The Journal of Neuroscience . 31 . 27 . 10060–6 . July 2011 . 21734298 . 3139999 . 10.1523/JNEUROSCI.1014-11.2011 .
7. Pesch K, Zeitz C, Fries JE, Münscher S, Pusch CM, Kohler K, Berger W, Wissinger B . Isolation of the mouse nyctalopin gene nyx and expression studies in mouse and rat retina . Investigative Ophthalmology & Visual Science . 44 . 5 . 2260–6 . May 2003 . 12714669 . 10.1167/iovs.02-0115 . free .
8. Zhou L, Li T, Song X, Li Y, Li H, Dan H . NYX mutations in four families with high myopia with or without CSNB1 . Molecular Vision . 21 . 213–23 . 2015 . 25802485 . 4357032 .
9. Pardue MT, McCall MA, LaVail MM, Gregg RG, Peachey NS . A naturally occurring mouse model of X-linked congenital stationary night blindness . Investigative Ophthalmology & Visual Science . 39 . 12 . 2443–9 . November 1998 . 9804152 .
10. Web site: NYX gene.
11. Gregg RG, Kamermans M, Klooster J, Lukasiewicz PD, Peachey NS, Vessey KA, McCall MA . Nyctalopin expression in retinal bipolar cells restores visual function in a mouse model of complete X-linked congenital stationary night blindness . en . Journal of Neurophysiology . 98 . 5 . 3023–33 . November 2007 . 17881478 . 10.1152/jn.00608.2007 . 2933657.
12. Bojang P, Gregg RG . Topological analysis of small leucine-rich repeat proteoglycan nyctalopin . PLOS ONE . 7 . 4 . e33137 . 2012 . 22485138 . 3317652 . 10.1371/journal.pone.0033137 . 2012PLoSO...733137B . free .
13. Gregg RG, Mukhopadhyay S, Candille SI, Ball SL, Pardue MT, McCall MA, Peachey NS . Identification of the gene and the mutation responsible for the mouse nob phenotype . Investigative Ophthalmology & Visual Science . 44 . 1 . 378–84 . January 2003 . 12506099 . 10.1167/iovs.02-0501. free .