Research progress of molecular diagnosis and treatment strategies for <i>RCBTB1</i> gene-related inherited retinal disease_Chinese Journal of Ocular Fundus Diseases

Authors：

Huang Zhiqin ,  Jin Zibing

Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing 100730, China;

Corresponding author：

Jin Zibing, Email: jinzb502@ccmu.edu.cn

Keywords：

RCBTB1; Inherited retinal disease; Induced pluripotent stem cells; Retinal pigment epithelium; Mitochondrial function; Review

DOI：

10.3760/cma.j.cn511434-20230921-00394

Video：

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Abstract Full text Figures/Tables Video References Cited by

RCBTB1 gene associated hereditary retinopathy is an extremely rare inherited retinal disease (IRD) discovered recently. The mutation of RCBTB1 gene can lead to a variety of IRD clinical phenotypes, such as early retinitis pigmentosa and delayed chorioretinal atrophy. The hereditary mode of RCBTB1 gene associated retinopathy is autosomal recessive. RCBTB1 gene plays an important role in maintaining mitochondrial function and anti-oxidative stress defense mechanism of retinal pigment epithelium cells. In the future, it is necessary to further determine whether there is a genotypic and phenotypic correlation in the age of onset of RCBTB1 gene associated retinopathy or multi-organ involvement, and evaluate the safety and efficacy of adeno-associated virus-mediated RCBTB1 gene replacement therapy in animal models, to explore the feasibility of gene replacement therapy and stem cell therapy.

Citation： Huang Zhiqin, Jin Zibing. Research progress of molecular diagnosis and treatment strategies for RCBTB1 gene-related inherited retinal disease. Chinese Journal of Ocular Fundus Diseases, 2024, 40(6): 472-477. doi: 10.3760/cma.j.cn511434-20230921-00394 Copy

1.	Wu JH, Liu JH, Ko YC, et al. Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy[J]. Hum Mol Genet, 2016, 25(8): 1637-1647. DOI: 10.1093/hmg/ddw041.
2.	Yang J, Xiao X, Sun W, et al. Variants in RCBTB1 are associated with autosomal recessive retinitis pigmentosa but not autosomal dominant FEVR[J]. Curr Eye Res, 2020, 6(6): 839-844. DOI: 10.1080/02713683.2020.1842457.
3.	Huang Z, Zhang D, Thompson JA, et al. Deep clinical phenotyping and gene expression analysis in a patient with RCBTB1-associated retinopathy[J]. Ophthalmic Genet, 2021, 2(3): 266-275. DOI: 10.1080/13816810.2021.1891551.
4.	Catomeris AJ, Ballios BG, Sangermano R, et al. Novel RCBTB1 variants causing later-onset non-syndromic retinal dystrophy with macular chorioretinal atrophy[J]. Ophthalmic Genetics, 2022, 43(3): 332-339. DOI: 10.1080/13816810.2021.2023196.
5.	Coppieters F, Ascari G, Dannhausen K, et al. Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination[J]. Am J Hum Genet, 2016, 99(2): 470-480. DOI: 10.1016/j.ajhg.2016.06.017.
6.	Keenan TD, Agrón E, Domalpally A, et al. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16[J]. Ophthalmology, 2018, 125(12): 1913-1928. DOI: 10.1016/j.ophtha.2018.05.028.
7.	Yang J, Sun W, Zhang Q. Start and end with genetics: RCBTB1 and beyond[J]. Curr Eye Res, 2021, 46(12): 1932-1933. DOI: 10.1080/02713683.2021.1933060.
8.	Birtel J, Von Landenberg C, Gliem M, et al. Mitochondrial retinopathy[J]. Ophthalmol Retina, 2022, 6(1): 65-79. DOI: 10.1016/j.oret.2021.02.017.
9.	Aasen T, Izpisua Belmonte JC. Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells[J]. Nat Protoc, 2010, 5(2): 371-382. DOI: 10.1038/nprot.2009.241.
10.	Oda Y, Yoshimura Y, Ohnishi H, et al. Induction of pluripotent stem cells from human third molar mesenchymal stromal cells[J]. J Biol Chem, 2010, 285(38): 29270-29278. DOI: 10.1074/jbc.M109.055889.
11.	Li G, Xie B, He L, et al. Generation of retinal organoids with mature rods and cones from urine-derived human induced pluripotent stem cells[J/OL]. Stem Cells Int, 2018, 2018: 4968658[2018-06-13]. https://pubmed.ncbi.nlm.nih.gov/30008752/. DOI: 10.1155/2018/4968658.
12.	Loh YH, Agarwal S, Park IH. Generation of induced pluripotent stem cells from human blood[J]. Blood, 2009, 113(22): 5476-5479. DOI: 10.1182/blood-2009-02-204800.
13.	Huang Z, Zhang D, Chen SC, et al. Generation of three induced pluripotent stem cell lines from an isolated inherited retinal dystrophy patient with RCBTB1 frameshifting mutations[J/OL]. Stem Cell Res, 2019, 40: 101549[2019-08-23]. https://pubmed.ncbi.nlm.nih.gov/31494449/. DOI: 10.1016/j.scr.2019.101549.
14.	Carron M, Naert T, Ascari G, et al. Functional characterization of a Xenopus tropicalis knockout and a human cellular model of RCBTB1-associated inherited retinal disease shows involvement of RCBTB1 in the cellular response to oxidative stress[J]. Invest Ophth Vis Sci, 2020, 61(7): 1125.
15.	Huang Z, Zhang D, Chen SC, et al. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with RCBTB1-associated retinopathy[J/OL]. Cells, 2023, 12(10): 1358[2023-05-10]. https://pubmed.ncbi.nlm.nih.gov/37408192/. DOI: 10.3390/cells12101358.
16.	Huang Z, Zhang D, Chen SC, et al. Gene replacement therapy restores RCBTB1 expression and cilium length in patient-derived retinal pigment epithelium[J]. J Cell Mol Med, 2021, 25(21): 10020-10027. DOI: 10.1111/jcmm.16911.
17.	Furuta M, Hori T, Fukagawa T. Chromatin binding of RCC1 during mitosis is important for its nuclear localization in interphase[J]. Mol Biol Cell, 2015, 27(2): 371-381. DOI: 10.1091/mbc.e15-07-0497.
18.	Hadjebi O, Casas-Terradellas E, Garcia-Gonzalo FR, et al. The RCC1 superfamily: from genes, to function, to disease[J]. Biochim Biophys Acta, 2008, 1783(8): 1467-1479. DOI: 10.1016/j.bbamcr.2008.03.015.
19.	Ren X, Jiang K, Zhang F. The multifaceted roles of RCC1 in tumorigenesis[J/OL]. Front Mol Biosci, 2020, 7: 225[2020-09-15]. https://pubmed.ncbi.nlm.nih.gov/33102517/. DOI: 10.3389/fmolb.2020.00225.
20.	Guo DF, Tardif V, Ghelima K, et al. A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells[J]. J Biol Chem, 2004, 279(20): 21109-21120. DOI: 10.1074/jbc.M401544200.
21.	Plafker KS, Singer JD, Plafker SM. The ubiquitin conjugating enzyme, UbcM2, engages in novel interactions with components of cullin-3 based E3 ligases[J]. Biochemistry, 2009, 48(15): 3527-3537. DOI: 10.1021/bi801971m.
22.	Friedman JS, Ray JW, Waseem N, et al. Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa[J]. Am J Hum Genet, 2009, 84(6): 792-800. DOI: 10.1016/j.ajhg.2009.05.007.
23.	Chakarova CF, Khanna H, Shah AZ, et al. TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein[J]. Hum Mol Genet, 2011, 20(5): 975-987. DOI: 10.1093/hmg/ddq543.
24.	Kasai S, Shimizu S, Tatara Y, et al. Regulation of Nrf2 by mitochondrial reactive oxygen species in physiology and pathology[J]. Biomolecules, 2020, 10(2): 320. DOI: 10.3390/biom10020320.
25.	Tonelli C, Chio IIC, Tuveson DA, et al. Transcriptional regulation by Nrf2[J]. Antioxid Redox Signal, 2018, 29(17): 1727-1745. DOI: 10.1089/ars.2017.7342.
26.	Buskin A, Zhu L, Chichagova V, et al. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa[J/OL]. Nat Commun, 2018, 9(1): 4234[2018-10-12]. https://pubmed.ncbi.nlm.nih.gov/30315276/. DOI: 10.1038/s41467-018-06448-y.
27.	Duong TT, Lim J, Vasireddy V, et al. Comparative AAV-eGFP transgene expression using vector serotypes 1-9, 7m8, and 8b in human pluripotent stem cells, RPEs, and human and rat cortical neurons[J/OL]. Stem Cells Int, 2019, 2019: 7281912[2019-01-17]. https://pubmed.ncbi.nlm.nih.gov/30800164. DOI: 10.1155/2019/7281912.
28.	Maeda T, Mandai M, Sugita S, et al. Strategies of pluripotent stem cell-based therapy for retinal degeneration: update and challenges[J]. Trends Mol Med, 2022, 28(5): 388-404. DOI: 10.1016/j.molmed.2022.03.001.

1. Wu JH, Liu JH, Ko YC, et al. Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy[J]. Hum Mol Genet, 2016, 25(8): 1637-1647. DOI: 10.1093/hmg/ddw041.
2. Yang J, Xiao X, Sun W, et al. Variants in RCBTB1 are associated with autosomal recessive retinitis pigmentosa but not autosomal dominant FEVR[J]. Curr Eye Res, 2020, 6(6): 839-844. DOI: 10.1080/02713683.2020.1842457.
3. Huang Z, Zhang D, Thompson JA, et al. Deep clinical phenotyping and gene expression analysis in a patient with RCBTB1-associated retinopathy[J]. Ophthalmic Genet, 2021, 2(3): 266-275. DOI: 10.1080/13816810.2021.1891551.
4. Catomeris AJ, Ballios BG, Sangermano R, et al. Novel RCBTB1 variants causing later-onset non-syndromic retinal dystrophy with macular chorioretinal atrophy[J]. Ophthalmic Genetics, 2022, 43(3): 332-339. DOI: 10.1080/13816810.2021.2023196.
5. Coppieters F, Ascari G, Dannhausen K, et al. Isolated and syndromic retinal dystrophy caused by biallelic mutations in RCBTB1, a gene implicated in ubiquitination[J]. Am J Hum Genet, 2016, 99(2): 470-480. DOI: 10.1016/j.ajhg.2016.06.017.
6. Keenan TD, Agrón E, Domalpally A, et al. Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16[J]. Ophthalmology, 2018, 125(12): 1913-1928. DOI: 10.1016/j.ophtha.2018.05.028.
7. Yang J, Sun W, Zhang Q. Start and end with genetics: RCBTB1 and beyond[J]. Curr Eye Res, 2021, 46(12): 1932-1933. DOI: 10.1080/02713683.2021.1933060.
8. Birtel J, Von Landenberg C, Gliem M, et al. Mitochondrial retinopathy[J]. Ophthalmol Retina, 2022, 6(1): 65-79. DOI: 10.1016/j.oret.2021.02.017.
9. Aasen T, Izpisua Belmonte JC. Isolation and cultivation of human keratinocytes from skin or plucked hair for the generation of induced pluripotent stem cells[J]. Nat Protoc, 2010, 5(2): 371-382. DOI: 10.1038/nprot.2009.241.
10. Oda Y, Yoshimura Y, Ohnishi H, et al. Induction of pluripotent stem cells from human third molar mesenchymal stromal cells[J]. J Biol Chem, 2010, 285(38): 29270-29278. DOI: 10.1074/jbc.M109.055889.
11. Li G, Xie B, He L, et al. Generation of retinal organoids with mature rods and cones from urine-derived human induced pluripotent stem cells[J/OL]. Stem Cells Int, 2018, 2018: 4968658[2018-06-13]. https://pubmed.ncbi.nlm.nih.gov/30008752/. DOI: 10.1155/2018/4968658.
12. Loh YH, Agarwal S, Park IH. Generation of induced pluripotent stem cells from human blood[J]. Blood, 2009, 113(22): 5476-5479. DOI: 10.1182/blood-2009-02-204800.
13. Huang Z, Zhang D, Chen SC, et al. Generation of three induced pluripotent stem cell lines from an isolated inherited retinal dystrophy patient with RCBTB1 frameshifting mutations[J/OL]. Stem Cell Res, 2019, 40: 101549[2019-08-23]. https://pubmed.ncbi.nlm.nih.gov/31494449/. DOI: 10.1016/j.scr.2019.101549.
14. Carron M, Naert T, Ascari G, et al. Functional characterization of a Xenopus tropicalis knockout and a human cellular model of RCBTB1-associated inherited retinal disease shows involvement of RCBTB1 in the cellular response to oxidative stress[J]. Invest Ophth Vis Sci, 2020, 61(7): 1125.
15. Huang Z, Zhang D, Chen SC, et al. Mitochondrial dysfunction and impaired antioxidant responses in retinal pigment epithelial cells derived from a patient with RCBTB1-associated retinopathy[J/OL]. Cells, 2023, 12(10): 1358[2023-05-10]. https://pubmed.ncbi.nlm.nih.gov/37408192/. DOI: 10.3390/cells12101358.
16. Huang Z, Zhang D, Chen SC, et al. Gene replacement therapy restores RCBTB1 expression and cilium length in patient-derived retinal pigment epithelium[J]. J Cell Mol Med, 2021, 25(21): 10020-10027. DOI: 10.1111/jcmm.16911.
17. Furuta M, Hori T, Fukagawa T. Chromatin binding of RCC1 during mitosis is important for its nuclear localization in interphase[J]. Mol Biol Cell, 2015, 27(2): 371-381. DOI: 10.1091/mbc.e15-07-0497.
18. Hadjebi O, Casas-Terradellas E, Garcia-Gonzalo FR, et al. The RCC1 superfamily: from genes, to function, to disease[J]. Biochim Biophys Acta, 2008, 1783(8): 1467-1479. DOI: 10.1016/j.bbamcr.2008.03.015.
19. Ren X, Jiang K, Zhang F. The multifaceted roles of RCC1 in tumorigenesis[J/OL]. Front Mol Biosci, 2020, 7: 225[2020-09-15]. https://pubmed.ncbi.nlm.nih.gov/33102517/. DOI: 10.3389/fmolb.2020.00225.
20. Guo DF, Tardif V, Ghelima K, et al. A novel angiotensin II type 1 receptor-associated protein induces cellular hypertrophy in rat vascular smooth muscle and renal proximal tubular cells[J]. J Biol Chem, 2004, 279(20): 21109-21120. DOI: 10.1074/jbc.M401544200.
21. Plafker KS, Singer JD, Plafker SM. The ubiquitin conjugating enzyme, UbcM2, engages in novel interactions with components of cullin-3 based E3 ligases[J]. Biochemistry, 2009, 48(15): 3527-3537. DOI: 10.1021/bi801971m.
22. Friedman JS, Ray JW, Waseem N, et al. Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa[J]. Am J Hum Genet, 2009, 84(6): 792-800. DOI: 10.1016/j.ajhg.2009.05.007.
23. Chakarova CF, Khanna H, Shah AZ, et al. TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein[J]. Hum Mol Genet, 2011, 20(5): 975-987. DOI: 10.1093/hmg/ddq543.
24. Kasai S, Shimizu S, Tatara Y, et al. Regulation of Nrf2 by mitochondrial reactive oxygen species in physiology and pathology[J]. Biomolecules, 2020, 10(2): 320. DOI: 10.3390/biom10020320.
25. Tonelli C, Chio IIC, Tuveson DA, et al. Transcriptional regulation by Nrf2[J]. Antioxid Redox Signal, 2018, 29(17): 1727-1745. DOI: 10.1089/ars.2017.7342.
26. Buskin A, Zhu L, Chichagova V, et al. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa[J/OL]. Nat Commun, 2018, 9(1): 4234[2018-10-12]. https://pubmed.ncbi.nlm.nih.gov/30315276/. DOI: 10.1038/s41467-018-06448-y.
27. Duong TT, Lim J, Vasireddy V, et al. Comparative AAV-eGFP transgene expression using vector serotypes 1-9, 7m8, and 8b in human pluripotent stem cells, RPEs, and human and rat cortical neurons[J/OL]. Stem Cells Int, 2019, 2019: 7281912[2019-01-17]. https://pubmed.ncbi.nlm.nih.gov/30800164. DOI: 10.1155/2019/7281912.
28. Maeda T, Mandai M, Sugita S, et al. Strategies of pluripotent stem cell-based therapy for retinal degeneration: update and challenges[J]. Trends Mol Med, 2022, 28(5): 388-404. DOI: 10.1016/j.molmed.2022.03.001.

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