Retinoschisin Explained

Retinoschisin also known as X-linked juvenile retinoschisis protein is a lectin^{[1] [2]} that in humans is encoded by the RS1 gene.^[3]

It is a soluble, cell-surface protein that plays an important role in the maintenance of the retina where it is expressed and secreted by retinal bipolar cells and photoreceptors,^{[4] [5]} as well as in the pineal gland.^[6] Retinoschisin (RS1) is encoded by the gene RS1 located on the X chromosome at p22.1. Young males who have an RS1 mutation are susceptible to retinoschisis, and X-linked eye disease which causes macular degeneration and can lead to a loss of vision.

Function

Retinoschisin is an extracellular protein that plays a crucial role in the cellular organization of the retina: it binds the plasma membranes of various retinal cells tightly to maintain the structure of the retina. In addition to enabling cell-to-cell adhesion, it has been shown that retinoschisin interacts with the sodium/potassium-ATPase (Na/K-ATPase) which resides in the plasma membrane. RS1 also plays a role in the regulation on intracellular MAP kinase signalling.^[7]

Structure

The retinoschisin monomer is 224 amino acids long, including a 23-amino acid signal peptide essential for secretion (this is cleaved off before the protein becomes functional), and a highly conserved sequence motif called the discoidin domain which consists of 157 amino acids, important for the protein's function in cell to cell adhesion.^[8] However, its oligomeric structure is a pairing of back-to-back octamers, forming a homo16mer https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0147653. This structure allows it to adhere to the plasma membrane of retinal cells such as bipolar and photoreceptor cells, joining them together.

Clinical significance

Pathogenic mutations of this gene are responsible for X-linked retinoschisis an early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision.^[9] Female carriers of the RS1 mutation do not show symptoms of X-linked juvenile retinoschisis, except in rare cases where the non-functional protein is expressed due to anomalous X-chromosome inactivation. In young males who carry a gene mutation, the disease presents itself as retinal cavities, splitting of inner retinal layers (also known as foveal schisis), and defective synapse activity.^[10] Retinas that lack mature retinoshisin develop these characteristics in up to 1 in 5,000 males. There are over 200 mutations of RS1 recorded in the Retina International Mutation Database, most of which are not pathogenic.

References

Further reading

• Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D . X-linked retinoschisis: an update . Journal of Medical Genetics . 44 . 4 . 225–32 . April 2007 . 17172462 . 2598044 . 10.1136/jmg.2006.047340 .
• Alitalo T, Kruse TA, de la Chapelle A . Refined localization of the gene causing X-linked juvenile retinoschisis . Genomics . 9 . 3 . 505–10 . March 1991 . 2032721 . 10.1016/0888-7543(91)90417-D .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . September 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Hotta Y, Fujiki K, Hayakawa M, Ohta T, Fujimaki T, Tamaki K, Yokoyama T, Kanai A, Hirakata A, Hida T, Nishina S, Azuma N . Japanese juvenile retinoschisis is caused by mutations of the XLRS1 gene . Human Genetics . 103 . 2 . 142–4 . August 1998 . 9760195 . 10.1007/pl00008705 . 23149265 .
• Shastry BS, Hejtmancik FJ, Trese MT . Recurrent missense (R197C) and nonsense (Y89X) mutations in the XLRS1 gene in families with X-linked retinoschisis . Biochemical and Biophysical Research Communications . 256 . 2 . 317–9 . March 1999 . 10079181 . 10.1006/bbrc.1999.0323 .
• Mashima Y, Shinoda K, Ishida S, Ozawa Y, Kudoh J, Iwata T, Oguchi Y, Shimizu N . Identification of four novel mutations of the XLRS1 gene in Japanese patients with X-linked juvenile retinoschisis. Mutation in brief no. 234. Online . Human Mutation . 13 . 4 . 338 . 1999 . 10220153 . 10.1002/(SICI)1098-1004(1999)13:4<338::AID-HUMU16>3.0.CO;2-0 . free .
• Huopaniemi L, Rantala A, Forsius H, Somer M, de la Chapelle A, Alitalo T . Three widespread founder mutations contribute to high incidence of X-linked juvenile retinoschisis in Finland . European Journal of Human Genetics . 7 . 3 . 368–76 . April 1999 . 10234514 . 10.1038/sj.ejhg.5200300 . free .
• Gehrig A, White K, Lorenz B, Andrassi M, Clemens S, Weber BH . Assessment of RS1 in X-linked juvenile retinoschisis and sporadic senile retinoschisis . Clinical Genetics . 55 . 6 . 461–5 . June 1999 . 10450864 . 10.1034/j.1399-0004.1999.550611.x . 10619184 .
• Hiriyanna KT, Bingham EL, Yashar BM, Ayyagari R, Fishman G, Small KW, Weinberg DV, Weleber RG, Lewis RA, Andreasson S, Richards JE, Sieving PA . Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change . Human Mutation . 14 . 5 . 423–7 . 2000 . 10533068 . 10.1002/(SICI)1098-1004(199911)14:5<423::AID-HUMU8>3.0.CO;2-D . 2027.42/35178 . 26797539 . free .
• Grayson C, Reid SN, Ellis JA, Rutherford A, Sowden JC, Yates JR, Farber DB, Trump D . Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells . Human Molecular Genetics . 9 . 12 . 1873–9 . July 2000 . 10915776 . 10.1093/hmg/9.12.1873 . free .
• Weber BH, Schrewe H, Molday LL, Gehrig A, White KL, Seeliger MW, Jaissle GB, Friedburg C, Tamm E, Molday RS . Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure . Proceedings of the National Academy of Sciences of the United States of America . 99 . 9 . 6222–7 . April 2002 . 11983912 . 122930 . 10.1073/pnas.092528599 . 2002PNAS...99.6222W . free .
• Tuvdendorj D, Isashiki Y, Ohba N, Sonoda S, Izumo S . Two Japanese patients with mutations in the XLRS1 gene . Retina . 22 . 3 . 354–7 . June 2002 . 12055472 . 10.1097/00006982-200206000-00017 .
• Wistow G, Bernstein SL, Wyatt MK, Ray S, Behal A, Touchman JW, Bouffard G, Smith D, Peterson K . Expressed sequence tag analysis of human retina for the NEIBank Project: retbindin, an abundant, novel retinal cDNA and alternative splicing of other retina-preferred gene transcripts . Molecular Vision . 8 . 196–204 . June 2002 . 12107411 .
• Inoue Y, Yamamoto S, Inoue T, Fujikado T, Kusaka S, Ohguro N, Ohji M, Tano Y . Two novel point mutations of the XLRS1 gene in patients with X-linked juvenile retinoschisis . American Journal of Ophthalmology . 134 . 4 . 622–4 . October 2002 . 12383832 . 10.1016/S0002-9394(02)01592-1 .
• Wang T, Waters CT, Rothman AM, Jakins TJ, Römisch K, Trump D . Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis . Human Molecular Genetics . 11 . 24 . 3097–105 . November 2002 . 12417531 . 10.1093/hmg/11.24.3097 . free .
• Tanimoto N, Usui T, Takagi M, Hasegawa S, Abe H, Sekiya K, Miyagawa Y, Nakazawa M . Electroretinographic findings in three family members with X-linked juvenile retinoschisis associated with a novel Pro192Thr mutation of the XLRS1 gene . Japanese Journal of Ophthalmology . 46 . 5 . 568–76 . 2003 . 12457918 . 10.1016/S0021-5155(02)00539-7 .
• Fraternali F, Cavallo L, Musco G . Effects of pathological mutations on the stability of a conserved amino acid triad in retinoschisin . FEBS Letters . 544 . 1–3 . 21–6 . June 2003 . 12782284 . 10.1016/S0014-5793(03)00433-2 . 29279855 . free .
• Sato M, Oshika T, Kaji Y, Nose H . Three novel mutations in the X-linked juvenile retinoschisis (XLRS1) gene in 6 Japanese patients, 1 of whom had Turner's syndrome . Ophthalmic Research . 35 . 5 . 295–300 . 2003 . 12920343 . 10.1159/000072151 . 30631231 .

External links

• GeneReview/NCBI/NIH/UW entry on X-Linked Juvenile Retinoschisis

Notes and References

1. Book: Vijayasarathy C, Ziccardi L, Sieving PA . Retinal Degenerative Diseases . Biology of Retinoschisin . Advances in Experimental Medicine and Biology . 723 . 513–8 . 2012 . 22183371 . 3475158 . 10.1007/978-1-4614-0631-0_64 . 978-1-4614-0630-3 .
2. Wu WW . RS1 structure-function relationships: roles in retinal adhesion and X-linked retinoschisis . Ph.D. . The University of British Columbia . October 2005 .
3. Sauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A, Lorenz B, Jurklies B, Weber BH . Positional cloning of the gene associated with X-linked juvenile retinoschisis . Nature Genetics . 17 . 2 . 164–70 . October 1997 . 9326935 . 10.1038/ng1097-164 . 7829510 .
4. Tolun G, Vijayasarathy C, Huang R, Zeng Y, Li Y, Steven AC, Sieving PA, Heymann JB . Paired octamer rings of retinoschisin suggest a junctional model for cell-cell adhesion in the retina . Proceedings of the National Academy of Sciences of the United States of America . 113 . 19 . 5287–92 . May 2016 . 27114531 . 4868477 . 10.1073/pnas.1519048113 . 2016PNAS..113.5287T . free .
5. Kotova S, Vijayasarathy C, Dimitriadis EK, Ikonomou L, Jaffe H, Sieving PA . Retinoschisin (RS1) interacts with negatively charged lipid bilayers in the presence of Ca2+: an atomic force microscopy study . Biochemistry . 49 . 33 . 7023–32 . August 2010 . 20677810 . 2929131 . 10.1021/bi1007029 .
6. Plössl K, Royer M, Bernklau S, Tavraz NN, Friedrich T, Wild J, Weber BH, Friedrich U . Retinoschisin is linked to retinal Na/K-ATPase signaling and localization . Molecular Biology of the Cell . 28 . 16 . 2178–2189 . August 2017 . 28615319 . 5531734 . 10.1091/mbc.e17-01-0064 .
7. Plössl K, Schmid V, Straub K, Schmid C, Ammon M, Merkl R, Weber BH, Friedrich U . Pathomechanism of mutated and secreted retinoschisin in X-linked juvenile retinoschisis . Experimental Eye Research . 177 . 23–34 . July 2018 . 30040949 . 10.1016/j.exer.2018.07.021 . 51717282 .
8. Wu WW, Molday RS . Defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin are primary mechanisms responsible for X-linked retinoschisis . The Journal of Biological Chemistry . 278 . 30 . 28139–46 . July 2003 . 12746437 . 10.1074/jbc.M302464200 . free .
9. Book: Weber BH, Kellner U . X-Linked Juvenile Retinoschisis . Tombran-Tink J, Barnstable C . Retinal Degenerations: Biology, Diagnostics, and Therapeutics . 2007 . 119–135 . Springer Science & Business Media . 978-1-59745-186-4 .
10. Reid SN, Yamashita C, Farber DB . Retinoschisin, a photoreceptor-secreted protein, and its interaction with bipolar and muller cells . The Journal of Neuroscience . 23 . 14 . 6030–40 . July 2003 . 12853421 . 6740352 . 10.1523/JNEUROSCI.23-14-06030.2003 .