X-linked retinoschisis (XLRS) is a rare X-linked inherited retinal disorder, caused by mutations in retinoschisin 1 (RS1) gene. Three XLRS mice were established, providing ideal systems to study the mechanism and treatment methods for XLRS. RS1 gene mutations can induce abnormal secretion or adhesion function of RS1 protein. In the past year, phase I clinical trials for XLRS has begun in USA, using adeno associated virus (AAV, AAV8 or AAV2)-mediated gene delivery. With the rapid development of new generation of AAV vector that can transduce more retinal cells through intravitreous delivery, gene therapy for XLRS will have a brighter future.
Citation： ZhangYangyang, DaiXufeng, ZhangHua, PangJijing. Molecular genetics and gene therapy of X-linked congenital retinoschisis. Chinese Journal of Ocular Fundus Diseases, 2016, 32(6): 657-660. doi: 10.3670/cma.j.issn.1005-1015.2016.06.027 Copy
| 1. | Haas J. Ueber das zusammenvorkommen von veraen derungen der retina und retina und choroidea[J].Arch Augenheilkd, 1898, 37:343-348. |
| 2. | Wieacker P, Wienker TF, Dallapiccola B, et al. Linkage relationships between Retinoschisis, Xg, and a cloned DNA sequence from the distal short arm of the X chromosome[J].Hum Genet, 1983, 64(2):143-145. |
| 3. | George ND, Yates JR, Moore AT. X linked retinoschisis[J]. Br J Ophthalmol, 1995, 79(7):697-702. |
| 4. | Tantri A, Vrabec TR, Cu-Unjieng A, et al. X-linked retinoschisis:a clinical and molecular genetic review[J].Surv Ophthalmol, 2004, 49(2):214-230. |
| 5. | Forsius H, Krause U, Helve J, et al. Visual acuity in 183 cases of X-chromosomal retinoschisis[J].Can J Ophthalmol, 1973, 8(3):385-393. |
| 6. | Eksandh LC, Ponjavic V, Ayyagari R, et al. Phenotypic expression of juvenile X-linked retinoschisis in Swedish families with different mutations in the XLRS1 gene[J]. Arch Ophthalmol, 2000, 118(8):1098-1104. |
| 7. | George ND, Yates JR, Moore AT. Clinical features in affected males with X-linked retinoschisis[J]. Arch Ophthalmol, 1996, 114(3):274-280. |
| 8. | Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis[J]. Nat Genet, 1997, 17(2):164-170. |
| 9. | Livesey FJ, Furukawa T, Steffen MA, et al. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx[J]. Curr Biol, 2000, 10(6):301-310. |
| 10. | Mears AJ, Kondo M, Swain PK, et al. Nrl is required for rod photoreceptor development[J]. Nat Genet, 2001, 29(4):447-452. |
| 11. | Haider NB, Naggert JK, Nishina PM. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice[J]. Hum Mol Genet, 2001, 10(16):1619-1626. |
| 12. | Cheng H, Khanna H, Oh EC, et al. Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors[J]. Hum Mol Genet, 2004, 13(15):1563-1575. |
| 13. | Swaroop A, Xu JZ, Pawar H, et al. A conserved retina-specific gene encodes a basic motif/leucine zipper domain[J]. Proc Natl Acad Sci USA, 1992, 89(1):266-270. |
| 14. | Swain PK, Hicks D, Mears AJ, et al. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors[J]. J Biol Chem, 2001, 276(39):36824-36830. |
| 15. | Rehemtulla A, Warwar R, Kumar R, et al. The basic motif-leucine zipper transcription factor Nrl can positively regulate rhodopsin gene expression[J]. Proc Natl Acad Sci USA, 1996, 93(1):191-195. |
| 16. | Mitton KP, Swain PK, Chen S, et al. The leucine zipper of NRL interacts with the CRX homeodomain:a possible mechanism of transcriptional synergy in rhodopsin regulation[J]. J Biol Chem, 2000, 275(38):29794-29799. |
| 17. | Chen S, Wang QL, Nie Z, et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes[J]. Neuron, 1997, 19(5):1017-1030. |
| 18. | Furukawa T, Morrow EM, Li T, et al. Retinopathy and attenuated circadian entrainment in Crx-deficient mice[J]. Nat Genet, 1999, 23(4):466-470. |
| 19. | Langmann T, Lai CC, Weigelt K, et al. CRX controls retinal expression of the X-linked juvenile retinoschisis (RS1) gene[J].Nucleic Acids Res, 2008, 36(20):6523-6534. |
| 20. | Wang T, Waters CT, Rothman AM, et al. Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis[J]. Hum Mol Genet, 2002, 11(24):3097-3105. |
| 21. | Takada Y, Fariss RN, Muller M, et al. Retinoschisin expression and localization in rodent and human pineal and consequences of mouse RS1 gene knockout[J]. Mol Vis, 2006, 12:1108-1116. |
| 22. | Zeng Y, Takada Y, Kjellstrom S, et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis[J]. Invest Ophthalmol Vis Sci, 2004, 45(9):3279-3285. |
| 23. | Weber BH, Schrewe H, Molday LL, et al. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure[J]. Proc Natl Acad Sci USA, 2002, 99(9):6222-6227. |
| 24. | Jablonski MM, Dalke C, Wang X, et al. An ENU-induced mutation in Rs1h causes disruption of retinal structure and function[J]. Mol Vis, 2005, 11:569-581. |
| 25. | Condon GP, Brownstein S, Wang NS, et al. Congenital hereditary (juvenile X-linked) retinoschisis:histopathologic and ultrastructural findings in three eyes[J]. Arch Ophthalmol, 1986, 104(4):576-583. |
| 26. | Kirsch LS, Brownstein S, de Wolff-Rouendaal D. A histopathological, ultrastructural and immunohistochemical study of congenital hereditary retinoschisis[J]. Can J Ophthalmol, 1996, 31(6):301-310. |
| 27. | Mooy CM, Van Den Born LI, Baarsma S, et al. Hereditary X-linked juvenile retinoschisis:a review of the role of Müller cells[J]. Arch Ophthalmol, 2002, 120(7):979-984. |
| 28. | Azzolini C, Pierro L, Codenotti M, et al. OCT images and surgery of juvenile Macular retinoschisis[J]. Eur J Ophthalmol, 1997, 7(2):196-200. |
| 29. | Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis:clinical diagnosis, genetic analysis, and molecular mechanisms[J]. Prog Retin Eye Res, 2012, 31(3):195-212.DOI:10.1016/j.preteyeres.2011.12.002. |
| 30. | Sergeev YV, Caruso RC, Meltzer MR, et al. Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis[J]. Hum Mol Genet, 2010, 19(7):1302-1313.DOI:10.1093/hmg/ddq006. |
| 31. | Sergeev YV, Vitale S, Sieving PA, et al. Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes[J]. Hum Mol Genet, 2013, 22(23):4756-4767.DOI:10.1093/hmg/ddt329. |
| 32. | Wu WW, Molday RS. Defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin are primary mechanisms responsible for X-linked retinoschisis[J]. J Biol Chem, 2003, 278(30):28139-28146. |
| 33. | Hiriyanna KT, Bingham EL, Yashar BM, et al. Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change[J]. Hum Mutat, 1999, 14(5):423-427. |
| 34. | Molday LL, Wu WW, Molday RS. Retinoschisin (RS1), the protein encoded by the X-linked retinoschisis gene, is anchored to the surface of retinal photoreceptor and bipolar cells through its interactions with a Na/K ATPase-SARM1 complex[J]. J Biol Chem, 2007, 282(45):32792-32801. |
| 35. | Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18(3):643-650. DOI:10.1038/mt.2009.277. |
| 36. | Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous[J].Sci Transl Med, 2013, 5(189):189ra76.DOI:10.1126/scitranslmed. 3005708. |
| 37. | Du W, Tao Y, Deng WT, et al. Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia[J]. Hum Mol Genet, 2015, 24(13):3699-3707.DOI:10.1093/hmg/ddv114. |
| 38. | Marangoni D, Wu Z, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4):202-211.DOI:10. 1089/humc.2014.067. |
| 39. | Bennett J, Duan D, Engelhardt JF, et al. Real-time, noninvasive in vivo assessment of adeno-associated virus-mediated retinal transduction[J]. Invest Ophthalmol Vis Sci, 1997, 38(13):2857-2863. |
| 40. | Park TK, Wu Z, Kjellstrom S, et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse[J].Gene Ther, 2009, 16(7):916-926.DOI:10.1038/gt.2009.61. |
- 1. Haas J. Ueber das zusammenvorkommen von veraen derungen der retina und retina und choroidea[J].Arch Augenheilkd, 1898, 37:343-348.
- 2. Wieacker P, Wienker TF, Dallapiccola B, et al. Linkage relationships between Retinoschisis, Xg, and a cloned DNA sequence from the distal short arm of the X chromosome[J].Hum Genet, 1983, 64(2):143-145.
- 3. George ND, Yates JR, Moore AT. X linked retinoschisis[J]. Br J Ophthalmol, 1995, 79(7):697-702.
- 4. Tantri A, Vrabec TR, Cu-Unjieng A, et al. X-linked retinoschisis:a clinical and molecular genetic review[J].Surv Ophthalmol, 2004, 49(2):214-230.
- 5. Forsius H, Krause U, Helve J, et al. Visual acuity in 183 cases of X-chromosomal retinoschisis[J].Can J Ophthalmol, 1973, 8(3):385-393.
- 6. Eksandh LC, Ponjavic V, Ayyagari R, et al. Phenotypic expression of juvenile X-linked retinoschisis in Swedish families with different mutations in the XLRS1 gene[J]. Arch Ophthalmol, 2000, 118(8):1098-1104.
- 7. George ND, Yates JR, Moore AT. Clinical features in affected males with X-linked retinoschisis[J]. Arch Ophthalmol, 1996, 114(3):274-280.
- 8. Sauer CG, Gehrig A, Warneke-Wittstock R, et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis[J]. Nat Genet, 1997, 17(2):164-170.
- 9. Livesey FJ, Furukawa T, Steffen MA, et al. Microarray analysis of the transcriptional network controlled by the photoreceptor homeobox gene Crx[J]. Curr Biol, 2000, 10(6):301-310.
- 10. Mears AJ, Kondo M, Swain PK, et al. Nrl is required for rod photoreceptor development[J]. Nat Genet, 2001, 29(4):447-452.
- 11. Haider NB, Naggert JK, Nishina PM. Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice[J]. Hum Mol Genet, 2001, 10(16):1619-1626.
- 12. Cheng H, Khanna H, Oh EC, et al. Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors[J]. Hum Mol Genet, 2004, 13(15):1563-1575.
- 13. Swaroop A, Xu JZ, Pawar H, et al. A conserved retina-specific gene encodes a basic motif/leucine zipper domain[J]. Proc Natl Acad Sci USA, 1992, 89(1):266-270.
- 14. Swain PK, Hicks D, Mears AJ, et al. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors[J]. J Biol Chem, 2001, 276(39):36824-36830.
- 15. Rehemtulla A, Warwar R, Kumar R, et al. The basic motif-leucine zipper transcription factor Nrl can positively regulate rhodopsin gene expression[J]. Proc Natl Acad Sci USA, 1996, 93(1):191-195.
- 16. Mitton KP, Swain PK, Chen S, et al. The leucine zipper of NRL interacts with the CRX homeodomain:a possible mechanism of transcriptional synergy in rhodopsin regulation[J]. J Biol Chem, 2000, 275(38):29794-29799.
- 17. Chen S, Wang QL, Nie Z, et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes[J]. Neuron, 1997, 19(5):1017-1030.
- 18. Furukawa T, Morrow EM, Li T, et al. Retinopathy and attenuated circadian entrainment in Crx-deficient mice[J]. Nat Genet, 1999, 23(4):466-470.
- 19. Langmann T, Lai CC, Weigelt K, et al. CRX controls retinal expression of the X-linked juvenile retinoschisis (RS1) gene[J].Nucleic Acids Res, 2008, 36(20):6523-6534.
- 20. Wang T, Waters CT, Rothman AM, et al. Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis[J]. Hum Mol Genet, 2002, 11(24):3097-3105.
- 21. Takada Y, Fariss RN, Muller M, et al. Retinoschisin expression and localization in rodent and human pineal and consequences of mouse RS1 gene knockout[J]. Mol Vis, 2006, 12:1108-1116.
- 22. Zeng Y, Takada Y, Kjellstrom S, et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis[J]. Invest Ophthalmol Vis Sci, 2004, 45(9):3279-3285.
- 23. Weber BH, Schrewe H, Molday LL, et al. Inactivation of the murine X-linked juvenile retinoschisis gene, Rs1h, suggests a role of retinoschisin in retinal cell layer organization and synaptic structure[J]. Proc Natl Acad Sci USA, 2002, 99(9):6222-6227.
- 24. Jablonski MM, Dalke C, Wang X, et al. An ENU-induced mutation in Rs1h causes disruption of retinal structure and function[J]. Mol Vis, 2005, 11:569-581.
- 25. Condon GP, Brownstein S, Wang NS, et al. Congenital hereditary (juvenile X-linked) retinoschisis:histopathologic and ultrastructural findings in three eyes[J]. Arch Ophthalmol, 1986, 104(4):576-583.
- 26. Kirsch LS, Brownstein S, de Wolff-Rouendaal D. A histopathological, ultrastructural and immunohistochemical study of congenital hereditary retinoschisis[J]. Can J Ophthalmol, 1996, 31(6):301-310.
- 27. Mooy CM, Van Den Born LI, Baarsma S, et al. Hereditary X-linked juvenile retinoschisis:a review of the role of Müller cells[J]. Arch Ophthalmol, 2002, 120(7):979-984.
- 28. Azzolini C, Pierro L, Codenotti M, et al. OCT images and surgery of juvenile Macular retinoschisis[J]. Eur J Ophthalmol, 1997, 7(2):196-200.
- 29. Molday RS, Kellner U, Weber BH. X-linked juvenile retinoschisis:clinical diagnosis, genetic analysis, and molecular mechanisms[J]. Prog Retin Eye Res, 2012, 31(3):195-212.DOI:10.1016/j.preteyeres.2011.12.002.
- 30. Sergeev YV, Caruso RC, Meltzer MR, et al. Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis[J]. Hum Mol Genet, 2010, 19(7):1302-1313.DOI:10.1093/hmg/ddq006.
- 31. Sergeev YV, Vitale S, Sieving PA, et al. Molecular modeling indicates distinct classes of missense variants with mild and severe XLRS phenotypes[J]. Hum Mol Genet, 2013, 22(23):4756-4767.DOI:10.1093/hmg/ddt329.
- 32. Wu WW, Molday RS. Defective discoidin domain structure, subunit assembly, and endoplasmic reticulum processing of retinoschisin are primary mechanisms responsible for X-linked retinoschisis[J]. J Biol Chem, 2003, 278(30):28139-28146.
- 33. Hiriyanna KT, Bingham EL, Yashar BM, et al. Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change[J]. Hum Mutat, 1999, 14(5):423-427.
- 34. Molday LL, Wu WW, Molday RS. Retinoschisin (RS1), the protein encoded by the X-linked retinoschisis gene, is anchored to the surface of retinal photoreceptor and bipolar cells through its interactions with a Na/K ATPase-SARM1 complex[J]. J Biol Chem, 2007, 282(45):32792-32801.
- 35. Simonelli F, Maguire AM, Testa F, et al. Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration[J]. Mol Ther, 2010, 18(3):643-650. DOI:10.1038/mt.2009.277.
- 36. Dalkara D, Byrne LC, Klimczak RR, et al. In vivo-directed evolution of a new adeno-associated virus for therapeutic outer retinal gene delivery from the vitreous[J].Sci Transl Med, 2013, 5(189):189ra76.DOI:10.1126/scitranslmed. 3005708.
- 37. Du W, Tao Y, Deng WT, et al. Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia[J]. Hum Mol Genet, 2015, 24(13):3699-3707.DOI:10.1093/hmg/ddv114.
- 38. Marangoni D, Wu Z, Wiley HE, et al. Preclinical safety evaluation of a recombinant AAV8 vector for X-linked retinoschisis after intravitreal administration in rabbits[J]. Hum Gene Ther Clin Dev, 2014, 25(4):202-211.DOI:10. 1089/humc.2014.067.
- 39. Bennett J, Duan D, Engelhardt JF, et al. Real-time, noninvasive in vivo assessment of adeno-associated virus-mediated retinal transduction[J]. Invest Ophthalmol Vis Sci, 1997, 38(13):2857-2863.
- 40. Park TK, Wu Z, Kjellstrom S, et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse[J].Gene Ther, 2009, 16(7):916-926.DOI:10.1038/gt.2009.61.