Biology:Retinoschisin
 Generic protein structure example |
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.[3] 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.[1][5]
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.[1] 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.[6] RS1 also plays a role in the regulation on intracellular MAP kinase signalling.[7]
Structure
The retinoschisin monomer is 224 amino acids long,[3] including a 23-amino acid signal peptide essential for secretion[1] (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,[8] important for the protein's function in cell to cell adhesion.[9] However, its oligomeric structure is a pairing of back-to-back octamers,[4] forming a homo16mer [1]. This structure allows it to adhere to the plasma membrane of retinal cells such as bipolar and photoreceptor cells,[5] 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.[10] 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),[4][1] and defective synapse activity.[1][8] Retinas that lack mature retinoshisin develop these characteristics in up to 1 in 5,000 males.[7] There are over 200 mutations of RS1 recorded in the Retina International Mutation Database, most of which are not pathogenic.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Biology of retinoschisin". Advances in Experimental Medicine and Biology 723: 513–8. 2012. doi:10.1007/978-1-4614-0631-0_64. ISBN 978-1-4614-0630-3. PMID 22183371.
- ↑ Wu WW (October 2005). RS1 structure-function relationships: roles in retinal adhesion and X-linked retinoschisis (Ph.D. thesis). The University of British Columbia.
- ↑ 3.0 3.1 3.2 "Positional cloning of the gene associated with X-linked juvenile retinoschisis". Nature Genetics 17 (2): 164–70. October 1997. doi:10.1038/ng1097-164. PMID 9326935.
- ↑ 4.0 4.1 4.2 "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. doi:10.1073/pnas.1519048113. PMID 27114531. Bibcode: 2016PNAS..113.5287T.
- ↑ 5.0 5.1 5.2 "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. doi:10.1021/bi1007029. PMID 20677810.
- ↑ 6.0 6.1 "Retinoschisin is linked to retinal Na/K-ATPase signaling and localization". Molecular Biology of the Cell 28 (16): 2178–2189. August 2017. doi:10.1091/mbc.e17-01-0064. PMID 28615319.
- ↑ 7.0 7.1 "Pathomechanism of mutated and secreted retinoschisin in X-linked juvenile retinoschisis". Experimental Eye Research 177: 23–34. July 2018. doi:10.1016/j.exer.2018.07.021. PMID 30040949.
- ↑ 8.0 8.1 "Retinoschisin, a photoreceptor-secreted protein, and its interaction with bipolar and muller cells". The Journal of Neuroscience 23 (14): 6030–40. July 2003. doi:10.1523/JNEUROSCI.23-14-06030.2003. PMID 12853421.
- ↑ "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. doi:10.1074/jbc.M302464200. PMID 12746437.
- ↑ "X-Linked Juvenile Retinoschisis". Retinal Degenerations: Biology, Diagnostics, and Therapeutics. Springer Science & Business Media. 2007. pp. 119–135. ISBN 978-1-59745-186-4.
Further reading
- "X-linked retinoschisis: an update". Journal of Medical Genetics 44 (4): 225–32. April 2007. doi:10.1136/jmg.2006.047340. PMID 17172462.
- "Refined localization of the gene causing X-linked juvenile retinoschisis". Genomics 9 (3): 505–10. March 1991. doi:10.1016/0888-7543(91)90417-D. PMID 2032721.
- "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research 6 (9): 791–806. September 1996. doi:10.1101/gr.6.9.791. PMID 8889548.
- "Japanese juvenile retinoschisis is caused by mutations of the XLRS1 gene". Human Genetics 103 (2): 142–4. August 1998. doi:10.1007/pl00008705. PMID 9760195.
- "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. doi:10.1006/bbrc.1999.0323. PMID 10079181.
- "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. doi:10.1002/(SICI)1098-1004(1999)13:4<338::AID-HUMU16>3.0.CO;2-0. PMID 10220153.
- "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. doi:10.1038/sj.ejhg.5200300. PMID 10234514.
- "Assessment of RS1 in X-linked juvenile retinoschisis and sporadic senile retinoschisis". Clinical Genetics 55 (6): 461–5. June 1999. doi:10.1034/j.1399-0004.1999.550611.x. PMID 10450864.
- "Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change". Human Mutation 14 (5): 423–7. 2000. doi:10.1002/(SICI)1098-1004(199911)14:5<423::AID-HUMU8>3.0.CO;2-D. PMID 10533068.
- "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. doi:10.1093/hmg/9.12.1873. PMID 10915776.
- "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. doi:10.1073/pnas.092528599. PMID 11983912. Bibcode: 2002PNAS...99.6222W.
- "Two Japanese patients with mutations in the XLRS1 gene". Retina 22 (3): 354–7. June 2002. doi:10.1097/00006982-200206000-00017. PMID 12055472.
- "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. PMID 12107411.
- "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. doi:10.1016/S0002-9394(02)01592-1. PMID 12383832.
- "Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis". Human Molecular Genetics 11 (24): 3097–105. November 2002. doi:10.1093/hmg/11.24.3097. PMID 12417531.
- "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. doi:10.1016/S0021-5155(02)00539-7. PMID 12457918.
- "Effects of pathological mutations on the stability of a conserved amino acid triad in retinoschisin". FEBS Letters 544 (1–3): 21–6. June 2003. doi:10.1016/S0014-5793(03)00433-2. PMID 12782284.
- "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. doi:10.1159/000072151. PMID 12920343.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
 |
