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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Ocular Ciliopathies: Genetic and Mechanistic Insights into Developing Therapies

Author(s): Mahesh Shivanna, Manisha Anand, Subhabrata Chakrabarti and Hemant Khanna*

Volume 26 , Issue 17 , 2019

Page: [3120 - 3131] Pages: 12

DOI: 10.2174/0929867325666180917102557

Price: $65


Developing suitable medicines for genetic diseases requires a detailed understanding of not only the pathways that cause the disease, but also the identification of the genetic components involved in disease manifestation. This article focuses on the complexities associated with ocular ciliopathies – a class of debilitating disorders of the eye caused by ciliary dysfunction. Ciliated cell types have been identified in both the anterior and posterior segments of the eye. Photoreceptors (rods and cones) are the most studied ciliated neurons in the retina, which is located in the posterior eye. The photoreceptors contain a specialized lightsensing outer segment, or cilium. Any defects in the development or maintenance of the outer segment can result in severe retinal ciliopathies, such as retinitis pigmentosa and Leber congenital amaurosis. A role of cilia in the cell types involved in regulating aqueous fluid outflow in the anterior segment of the eye has also been recognized. Defects in these cell types are frequently associated with some forms of glaucoma. Here, we will discuss the significance of understanding the genetic heterogeneity and the pathogenesis of ocular ciliopathies to develop suitable treatment strategies for these blinding disorders.

Keywords: Leber congenital amaurosis, photoreceptors, genetic diseases, ocular ciliopathies, photoreceptors, posterior eye, congenital amaurosis.

Dahm, R.; Discovering, D.N. Discovering DNA: Friedrich Miescher and the early years of nucleic acid research. Hum. Genet., 2008, 122(6), 565-581.
[] [PMID: 17901982]
Dunbar, C.E.; High, K.A.; Joung, J.K.; Kohn, D.B.; Ozawa, K.; Sadelain, M. Gene therapy comes of age. Science, 2018, 359(6372), eaan4672.
[] [PMID: 29326244]
Dai, W.J.; Zhu, L.Y.; Yan, Z.Y.; Xu, Y.; Wang, Q.L.; Lu, X.J. CRISPR-Cas9 for in vivo gene therapy: Promise and hurdles. Mol. Ther. Nucleic Acids, 2016, 5, e349.
[] [PMID: 28131272]
Sorokin, S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Biol., 1962, 15, 363-377.
[] [PMID: 13978319]
Singla, V.; Reiter, J.F. The primary cilium as the cell’s antenna: signaling at a sensory organelle. Science, 2006, 313(5787), 629-633.
[] [PMID: 16888132]
Eggenschwiler, J.T.; Anderson, K.V. Cilia and developmental signaling. Annu. Rev. Cell Dev. Biol., 2007, 23, 345-373.
[] [PMID: 17506691]
Rosenbaum, J.L.; Witman, G.B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol., 2002, 3(11), 813-825.
[] [PMID: 12415299]
Nachury, M.V.; Loktev, A.V.; Zhang, Q.; Westlake, C.J.; Peränen, J.; Merdes, A.; Slusarski, D.C.; Scheller, R.H.; Bazan, J.F.; Sheffield, V.C.; Jackson, P.K. A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell, 2007, 129(6), 1201-1213.
[] [PMID: 17574030]
Eguether, T.; San Agustin, J.T.; Keady, B.T.; Jonassen, J.A.; Liang, Y.; Francis, R.; Tobita, K.; Johnson, C.A.; Abdelhamed, Z.A.; Lo, C.W.; Pazour, G.J. IFT27 links the BBSome to IFT for maintenance of the ciliary signaling compartment. Dev. Cell, 2014, 31(3), 279-290.
[] [PMID: 25446516]
Lechtreck, K.F.; Johnson, E.C.; Sakai, T.; Cochran, D.; Ballif, B.A.; Rush, J.; Pazour, G.J.; Ikebe, M.; Witman, G.B. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J. Cell Biol., 2009, 187(7), 1117-1132.
[] [PMID: 20038682]
Nager, A. R.; Goldstein, J. S.; Herranz-Perez, V.; Portran, D.; Ye, F.; Garcia-Verdugo, J. M.; Nachury, M. V. An actin network dispatches ciliary GPCRs into extracellular vesicles to modulate signaling Cell., 2017, 168(1-2), 252-263 e14..
Salinas, R.Y.; Pearring, J.N.; Ding, J.D.; Spencer, W.J.; Hao, Y.; Arshavsky, V.Y. Photoreceptor discs form through peripherin-dependent suppression of ciliary ectosome release. J. Cell Biol., 2017, 216(5), 1489-1499.
[] [PMID: 28381413]
Wheway, G.; Schmidts, M.; Mans, D.A.; Szymanska, K.; Nguyen, T.T.; Racher, H.; Phelps, I.G.; Toedt, G.; Kennedy, J.; Wunderlich, K.A.; Sorusch, N.; Abdelhamed, Z.A.; Natarajan, S.; Herridge, W.; van Reeuwijk, J.; Horn, N.; Boldt, K.; Parry, D.A.; Letteboer, S.J.; Roosing, S.; Adams, M.; Bell, S.M.; Bond, J.; Higgins, J.; Morrison, E.E.; Tomlinson, D.C.; Slaats, G.G.; van Dam, T.J.; Huang, L.; Kessler, K.; Giessl, A.; Logan, C.V.; Boyle, E.A.; Shendure, J.; Anazi, S.; Aldahmesh, M.; Al Hazzaa, S.; Hegele, R.A.; Ober, C.; Frosk, P.; Mhanni, A.A.; Chodirker, B.N.; Chudley, A.E.; Lamont, R.; Bernier, F.P.; Beaulieu, C.L.; Gordon, P.; Pon, R.T.; Donahue, C.; Barkovich, A.J.; Wolf, L.; Toomes, C.; Thiel, C.T.; Boycott, K.M.; McKibbin, M.; Inglehearn, C.F.; Stewart, F.; Omran, H.; Huynen, M.A.; Sergouniotis, P.I.; Alkuraya, F.S.; Parboosingh, J.S.; Innes, A.M.; Willoughby, C.E.; Giles, R.H.; Webster, A.R.; Ueffing, M.; Blacque, O.; Gleeson, J.G.; Wolfrum, U.; Beales, P.L.; Gibson, T.; Doherty, D.; Mitchison, H.M.; Roepman, R.; Johnson, C.A. An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes. Nat. Cell Biol., 2015, 17(8), 1074-1087.
[] [PMID: 26167768]
Reiter, J.F. A cilium is not a cilium is not a cilium: signaling contributes to ciliary morphological diversity. Dev. Cell, 2008, 14(5), 635-636.
[] [PMID: 18477443]
Sharma, N.; Berbari, N.F.; Yoder, B.K. Ciliary dysfunction in developmental abnormalities and diseases. Curr. Top. Dev. Biol., 2008, 85, 371-427.
[] [PMID: 19147012]
Hildebrandt, F.; Benzing, T.; Katsanis, N. Ciliopathies. N. Engl. J. Med., 2011, 364(16), 1533-1543.
[] [PMID: 21506742]
Wheway, G.; Parry, D.A.; Johnson, C.A. The role of primary cilia in the development and disease of the retina. Organogenesis, 2014, 10(1), 69-85.
[] [PMID: 24162842]
Khanna, H. Photoreceptor sensory cilium: traversing the ciliary gate. Cells, 2015, 4(4), 674-686.
[] [PMID: 26501325]
Badano, J.L.; Mitsuma, N.; Beales, P.L.; Katsanis, N. The ciliopathies: an emerging class of human genetic disorders. Annu. Rev. Genomics Hum. Genet., 2006, 7, 125-148.
[] [PMID: 16722803]
Reiter, J.F.; Leroux, M.R. Genes and molecular pathways underpinning ciliopathies. Nat. Rev. Mol. Cell Biol., 2017, 18(9), 533-547.
[] [PMID: 28698599]
Khanna, H. Ciliary trafficking in vertebrate photoreceptors; Bentham, 2017.
Besharse, J.C.; Baker, S.A.; Luby-Phelps, K.; Pazour, G.J. Photoreceptor intersegmental transport and retinal degeneration: a conserved pathway common to motile and sensory cilia. Adv. Exp. Med. Biol., 2003, 533, 157-164.
[] [PMID: 15180260]
Besharse, J.C.; Bok, D. The retina and its disorders. Academic Press: Amsterdam ; Boston., 2011, p xvi, 912.
Nathans, J. The evolution and physiology of human color vision: insights from molecular genetic studies of visual pigments. Neuron, 1999, 24(2), 299-312.
[] [PMID: 10571225]
Anand, M.; Khanna, H. Ciliary transition zone (TZ) proteins RPGR and CEP290: role in photoreceptor cilia and degenerative diseases. Expert Opin. Ther. Targets, 2012, 16(6), 541-551.
[] [PMID: 22563985]
Dona, M.; Bachmann-Gagescu, R.; Texier, Y.; Toedt, G.; Hetterschijt, L.; Tonnaer, E.L.; Peters, T.A.; van Beersum, S.E.; Bergboer, J.G.; Horn, N.; de Vrieze, E.; Slijkerman, R.W.; van Reeuwijk, J.; Flik, G.; Keunen, J.E.; Ueffing, M.; Gibson, T.J.; Roepman, R.; Boldt, K.; Kremer, H.; van Wijk, E. NINL and DZANK1 Co-function in vesicle transport and are essential for photoreceptor development in zebrafish. PLoS Genet., 2015, 11(10), e1005574.
[] [PMID: 26485514]
Fogerty, J.; Denton, K.; Perkins, B.D. Mutations in the Dynein1 Complex are permissible for basal body migration in photoreceptors but alter rab6 localization. Adv. Exp. Med. Biol., 2016, 854, 209-215.
[] [PMID: 26427413]
Barbelanne, M.; Hossain, D.; Chan, D.P.; Peränen, J.; Tsang, W.Y. Nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. Hum. Mol. Genet., 2015, 24(8), 2185-2200.
[] [PMID: 25552655]
Barbelanne, M.; Song, J.; Ahmadzai, M.; Tsang, W.Y. Pathogenic NPHP5 mutations impair protein interaction with Cep290, a prerequisite for ciliogenesis. Hum. Mol. Genet., 2013, 22(12), 2482-2494.
[] [PMID: 23446637]
Khanna, H.; Davis, E.E.; Murga-Zamalloa, C.A.; Estrada-Cuzcano, A.; Lopez, I.; den Hollander, A.I.; Zonneveld, M.N.; Othman, M.I.; Waseem, N.; Chakarova, C.F.; Maubaret, C.; Diaz-Font, A.; MacDonald, I.; Muzny, D.M.; Wheeler, D.A.; Morgan, M.; Lewis, L.R.; Logan, C.V.; Tan, P.L.; Beer, M.A.; Inglehearn, C.F.; Lewis, R.A.; Jacobson, S.G.; Bergmann, C.; Beales, P.L.; Attié-Bitach, T.; Johnson, C.A.; Otto, E.A.; Bhattacharya, S.S.; Hildebrandt, F.; Gibbs, R.A.; Koenekoop, R.K.; Swaroop, A.; Katsanis, N. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nat. Genet., 2009, 41(6), 739-745.
[] [PMID: 19430481]
Murga-Zamalloa, C.; Swaroop, A.; Khanna, H. Multiprotein complexes of Retinitis Pigmentosa GTPase regulator (RPGR), a ciliary protein mutated in X-linked Retinitis Pigmentosa (XLRP). Adv. Exp. Med. Biol., 2010, 664, 105-114.
[] [PMID: 20238008]
Murga-Zamalloa, C.A.; Desai, N.J.; Hildebrandt, F.; Khanna, H. Interaction of ciliary disease protein retinitis pigmentosa GTPase regulator with nephronophthisis-associated proteins in mammalian retinas. Mol. Vis., 2010, 16, 1373-1381.
[PMID: 20664800]
Omori, Y.; Chaya, T.; Katoh, K.; Kajimura, N.; Sato, S.; Muraoka, K.; Ueno, S.; Koyasu, T.; Kondo, M.; Furukawa, T. Negative regulation of ciliary length by ciliary male germ cell-associated kinase (Mak) is required for retinal photoreceptor survival. Proc. Natl. Acad. Sci. USA, 2010, 107(52), 22671-22676.
[] [PMID: 21148103]
Rachel, R.A.; Li, T.; Swaroop, A. Photoreceptor sensory cilia and ciliopathies: focus on CEP290, RPGR and their interacting proteins. Cilia, 2012, 1(1), 22.
[] [PMID: 23351659]
Wang, R.; Wiggs, J.L. Common and rare genetic risk factors for glaucoma. Cold Spring Harb. Perspect. Med., 2014, 4(12), a017244.
[] [PMID: 25237143]
Luo, N.; Conwell, M.D.; Chen, X.; Kettenhofen, C.I.; Westlake, C.J.; Cantor, L.B.; Wells, C.D.; Weinreb, R.N.; Corson, T.W.; Spandau, D.F.; Joos, K.M.; Iomini, C.; Obukhov, A.G.; Sun, Y. Primary cilia signaling mediates intraocular pressure sensation. Proc. Natl. Acad. Sci. USA, 2014, 111(35), 12871-12876.
[] [PMID: 25143588]
Luo, N.; West, C.C.; Murga-Zamalloa, C.A.; Sun, L.; Anderson, R.M.; Wells, C.D.; Weinreb, R.N.; Travers, J.B.; Khanna, H.; Sun, Y. OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. Hum. Mol. Genet., 2012, 21(15), 3333-3344.
[] [PMID: 22543976]
Goetz, J.G.; Steed, E.; Ferreira, R.R.; Roth, S.; Ramspacher, C.; Boselli, F.; Charvin, G.; Liebling, M.; Wyart, C.; Schwab, Y.; Vermot, J. Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Reports, 2014, 6(5), 799-808.
[] [PMID: 24561257]
Klagsbrun, M.; D’Amore, P.A. Angiogenesis: biology and pathology. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, N.Y., 2012, xiv, 522.
Souma, T.; Tompson, S.W.; Thomson, B.R.; Siggs, O.M.; Kizhatil, K.; Yamaguchi, S.; Feng, L.; Limviphuvadh, V.; Whisenhunt, K.N.; Maurer-Stroh, S.; Yanovitch, T.L.; Kalaydjieva, L.; Azmanov, D.N.; Finzi, S.; Mauri, L.; Javadiyan, S.; Souzeau, E.; Zhou, T.; Hewitt, A.W.; Kloss, B.; Burdon, K.P.; Mackey, D.A.; Allen, K.F.; Ruddle, J.B.; Lim, S.H.; Rozen, S.; Tran-Viet, K.N.; Liu, X.; John, S.; Wiggs, J.L.; Pasutto, F.; Craig, J.E.; Jin, J.; Quaggin, S.E.; Young, T.L. Angiopoietin receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J. Clin. Invest., 2016, 126(7), 2575-2587.
[] [PMID: 27270174]
Thomson, B.R.; Souma, T.; Tompson, S.W.; Onay, T.; Kizhatil, K.; Siggs, O.M.; Feng, L.; Whisenhunt, K.N.; Yanovitch, T.L.; Kalaydjieva, L.; Azmanov, D.N.; Finzi, S.; Tanna, C.E.; Hewitt, A.W.; Mackey, D.A.; Bradfield, Y.S.; Souzeau, E.; Javadiyan, S.; Wiggs, J.L.; Pasutto, F.; Liu, X.; John, S.W.; Craig, J.E.; Jin, J.; Young, T.L.; Quaggin, S.E. Angiopoietin-1 is required for Schlemm’s canal development in mice and humans. J. Clin. Invest., 2017, 127(12), 4421-4436.
[] [PMID: 29106382]
Kim, J.; Park, D.Y.; Bae, H.; Park, D.Y.; Kim, D.; Lee, C.K.; Song, S.; Chung, T.Y.; Lim, D.H.; Kubota, Y.; Hong, Y.K.; He, Y.; Augustin, H.G.; Oliver, G.; Koh, G.Y. Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma. J. Clin. Invest., 2017, 127(10), 3877-3896.
[] [PMID: 28920924]
Kabra, M.; Zhang, W.; Rathi, S.; Mandal, A.K.; Senthil, S.; Pyatla, G.; Ramappa, M.; Banerjee, S.; Shekhar, K.; Marmamula, S.; Mettla, A.L.; Kaur, I.; Khanna, R.C.; Khanna, H.; Chakrabarti, S. Angiopoietin receptor TEK interacts with CYP1B1 in primary congenital glaucoma. Hum. Genet., 2017, 136(8), 941-949.
[] [PMID: 28620713]
Biswas, P.; Duncan, J.L.; Ali, M.; Matsui, H.; Naeem, M.A.; Raghavendra, P.B.; Frazer, K.A.; Arts, H.H.; Riazuddin, S.; Akram, J.; Hejtmancik, J.F.; Riazuddin, S.A.; Ayyagari, R. A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Hum. Mol. Genet., 2017, 26(23), 4741-4751.
[] [PMID: 28973684]
Bujakowska, K.M.; Zhang, Q.; Siemiatkowska, A.M.; Liu, Q.; Place, E.; Falk, M.J.; Consugar, M.; Lancelot, M.E.; Antonio, A.; Lonjou, C.; Carpentier, W.; Mohand-Saïd, S.; den Hollander, A.I.; Cremers, F.P.; Leroy, B.P.; Gai, X.; Sahel, J.A.; van den Born, L.I.; Collin, R.W.; Zeitz, C.; Audo, I.; Pierce, E.A. Mutations in IFT172 cause isolated retinal degeneration and Bardet-Biedl syndrome. Hum. Mol. Genet., 2015, 24(1), 230-242.
[] [PMID: 25168386]
den Hollander, A.I.; Koenekoop, R.K.; Yzer, S.; Lopez, I.; Arends, M.L.; Voesenek, K.E.; Zonneveld, M.N.; Strom, T.M.; Meitinger, T.; Brunner, H.G.; Hoyng, C.B.; van den Born, L.I.; Rohrschneider, K.; Cremers, F.P. Mutations in the CEP290 (NPHP6) gene are a frequent cause of Leber congenital amaurosis. Am. J. Hum. Genet., 2006, 79(3), 556-561.
[] [PMID: 16909394]
Pretorius, P.R.; Baye, L.M.; Nishimura, D.Y.; Searby, C.C.; Bugge, K.; Yang, B.; Mullins, R.F.; Stone, E.M.; Sheffield, V.C.; Slusarski, D.C. Identification and functional analysis of the vision-specific BBS3 (ARL6) long isoform. PLoS Genet., 2010, 6(3), e1000884.
[] [PMID: 20333246]
Zhang, Y.; Seo, S.; Bhattarai, S.; Bugge, K.; Searby, C.C.; Zhang, Q.; Drack, A.V.; Stone, E.M.; Sheffield, V.C. BBS mutations modify phenotypic expression of CEP290-related ciliopathies. Hum. Mol. Genet., 2014, 23(1), 40-51.
[] [PMID: 23943788]
Rachel, R.A.; May-Simera, H.L.; Veleri, S.; Gotoh, N.; Choi, B.Y.; Murga-Zamalloa, C.; McIntyre, J.C.; Marek, J.; Lopez, I.; Hackett, A.N.; Zhang, J.; Brooks, M.; den Hollander, A.I.; Beales, P.L.; Li, T.; Jacobson, S.G.; Sood, R.; Martens, J.R.; Liu, P.; Friedman, T.B.; Khanna, H.; Koenekoop, R.K.; Kelley, M.W.; Swaroop, A. Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis. J. Clin. Invest., 2012, 122(4), 1233-1245.
[] [PMID: 22446187]
Rao, K.N.; Zhang, W.; Li, L.; Ronquillo, C.; Baehr, W.; Khanna, H. Ciliopathy-associated protein CEP290 modifies the severity of retinal degeneration due to loss of RPGR. Hum. Mol. Genet., 2016, 25(10), 2005-2012.
[] [PMID: 26936822]
Louie, C.M.; Caridi, G.; Lopes, V.S.; Brancati, F.; Kispert, A.; Lancaster, M.A.; Schlossman, A.M.; Otto, E.A.; Leitges, M.; Gröne, H.J.; Lopez, I.; Gudiseva, H.V.; O’Toole, J.F.; Vallespin, E.; Ayyagari, R.; Ayuso, C.; Cremers, F.P.; den Hollander, A.I.; Koenekoop, R.K.; Dallapiccola, B.; Ghiggeri, G.M.; Hildebrandt, F.; Valente, E.M.; Williams, D.S.; Gleeson, J.G. AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat. Genet., 2010, 42(2), 175-180.
[] [PMID: 20081859]
Bird, A.C. Clinical investigation of Retinitis pigmentosa. Prog. Clin. Biol. Res., 1987, 247, 3-20.
[PMID: 3317446]
Heckenlively, J.R.; Yoser, S.L.; Friedman, L.H.; Oversier, J.J. Clinical findings and common symptoms in Retinitis pigmentosa. Am. J. Ophthalmol., 1988, 105(5), 504-511.
[] [PMID: 3259404]
Daiger, S.P. RetNet. The retinal information network; The Univ. of Texas Health Science Center at Houston, 1996.
Daiger, S.P.; Bowne, S.J.; Sullivan, L.S. Perspective on genes and mutations causing Retinitis pigmentosa. Arch. Ophthalmol., 2007, 125(2), 151-158.
[] [PMID: 17296890]
Wright, A.F.; Chakarova, C.F.; Abd El-Aziz, M.M.; Bhattacharya, S.S. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat. Rev. Genet., 2010, 11(4), 273-284.
[] [PMID: 20212494]
Chakarova, C.F.; Khanna, H.; Shah, A.Z.; Patil, S.B.; Sedmak, T.; Murga-Zamalloa, C.A.; Papaioannou, M.G.; Nagel-Wolfrum, K.; Lopez, I.; Munro, P.; Cheetham, M.; Koenekoop, R.K.; Rios, R.M.; Matter, K.; Wolfrum, U.; Swaroop, A.; Bhattacharya, S.S. TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein. Hum. Mol. Genet., 2011, 20(5), 975-987.
[] [PMID: 21159800]
Ghosh, A.K.; Murga-Zamalloa, C.A.; Chan, L.; Hitchcock, P.F.; Swaroop, A.; Khanna, H. Human retinopathy-associated ciliary protein Retinitis pigmentosa GTPase regulator mediates cilia-dependent vertebrate development. Hum. Mol. Genet., 2010, 19(1), 90-98.
[] [PMID: 19815619]
Li, L.; Rao, K.N.; Zheng-Le, Y.; Hurd, T.W.; Lillo, C.; Khanna, H. Loss of Retinitis pigmentosa 2 (RP2) protein affects cone photoreceptor sensory cilium elongation in mice. Cytoskeleton (Hoboken), 2015, 72(9), 447-454.
[] [PMID: 26383048]
Liu, Q.; Zuo, J.; Pierce, E.A. The Retinitis pigmentosa 1 protein is a photoreceptor microtubule-associated protein. J. Neurosci., 2004, 24(29), 6427-6436.
[] [PMID: 15269252]
Bedoni, N.; Haer-Wigman, L.; Vaclavik, V.; Tran, V.H.; Farinelli, P.; Balzano, S.; Royer-Bertrand, B.; El-Asrag, M.E.; Bonny, O.; Ikonomidis, C.; Litzistorf, Y.; Nikopoulos, K.; Yioti, G.G.; Stefaniotou, M.I.; McKibbin, M.; Booth, A.P.; Ellingford, J.M.; Black, G.C.; Toomes, C.; Inglehearn, C.F.; Hoyng, C.B.; Bax, N.; Klaver, C.C.; Thiadens, A.A.; Murisier, F.; Schorderet, D.F.; Ali, M.; Cremers, F.P.; Andréasson, S.; Munier, F.L.; Rivolta, C. Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility. Hum. Mol. Genet., 2016, 25(20), 4546-4555.
[PMID: 28173158]
Das, R.G.; Marinho, F.P.; Iwabe, S.; Santana, E.; McDaid, K.S.; Aguirre, G.D.; Miyadera, K. Variabilities in retinal function and structure in a canine model of cone-rod dystrophy associated with RPGRIP1 support multigenic etiology. Sci. Rep., 2017, 7(1), 12823.
[] [PMID: 28993665]
Sharon, D.; Sandberg, M.A.; Rabe, V.W.; Stillberger, M.; Dryja, T.P.; Berson, E.L. RP2 and RPGR mutations and clinical correlations in patients with X-linked Retinitis pigmentosa. Am. J. Hum. Genet., 2003, 73(5), 1131-1146.
[] [PMID: 14564670]
Beltran, W.A.; Hammond, P.; Acland, G.M.; Aguirre, G.D. A frameshift mutation in RPGR exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci., 2006, 47(4), 1669-1681.
[] [PMID: 16565408]
Rao, K.N.; Li, L.; Zhang, W.; Brush, R.S.; Rajala, R.V.; Khanna, H. Loss of human disease protein Retinitis pigmentosa GTPase regulator (RPGR) differentially affects rod or cone-enriched retina. Hum. Mol. Genet., 2016, 25(7), 1345-1356.
[] [PMID: 26908598]
Zhang, Q.; Acland, G.M.; Wu, W.X.; Johnson, J.L.; Pearce-Kelling, S.; Tulloch, B.; Vervoort, R.; Wright, A.F.; Aguirre, G.D. Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration. Hum. Mol. Genet., 2002, 11(9), 993-1003.
[] [PMID: 11978759]
Li, L.; Khan, N.; Hurd, T.; Ghosh, A.K.; Cheng, C.; Molday, R.; Heckenlively, J.R.; Swaroop, A.; Khanna, H. Ablation of the X-linked Retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci., 2013, 54(7), 4503-4511.
[] [PMID: 23745007]
Sharon, D.; Bruns, G.A.; McGee, T.L.; Sandberg, M.A.; Berson, E.L.; Dryja, T.P. X-linked retinitis pigmentosa: mutation spectrum of the RPGR and RP2 genes and correlation with visual function. Invest. Ophthalmol. Vis. Sci., 2000, 41(9), 2712-2721.
[PMID: 10937588]
Breuer, D.K.; Yashar, B.M.; Filippova, E.; Hiriyanna, S.; Lyons, R.H.; Mears, A.J.; Asaye, B.; Acar, C.; Vervoort, R.; Wright, A.F.; Musarella, M.A.; Wheeler, P.; MacDonald, I.; Iannaccone, A.; Birch, D.; Hoffman, D.R.; Fishman, G.A.; Heckenlively, J.R.; Jacobson, S.G.; Sieving, P.A.; Swaroop, A. A comprehensive mutation analysis of RP2 and RPGR in a North American cohort of families with X-linked retinitis pigmentosa. Am. J. Hum. Genet., 2002, 70(6), 1545-1554.
[] [PMID: 11992260]
Patil, S.B.; Hurd, T.W.; Ghosh, A.K.; Murga-Zamalloa, C.A.; Khanna, H. Functional analysis of retinitis pigmentosa 2 (RP2) protein reveals variable pathogenic potential of disease-associated missense variants. PLoS One, 2011, 6(6), e21379.
[] [PMID: 21738648]
Lamb, T.D. Evolution of phototransduction, vertebrate photoreceptors and retina. Prog. Retin. Eye Res., 2013, 36, 52-119.
[] [PMID: 23792002]
Prosseda, P.P.; Luo, N.; Wang, B.; Alvarado, J.A.; Hu, Y.; Sun, Y. Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. J. Cell Sci., 2017, 130(20), 3447-3454.
[] [PMID: 28871046]
Collin, R.W.; den Hollander, A.I.; van der Velde-Visser, S.D.; Bennicelli, J.; Bennett, J.; Cremers, F.P. Antisense oligonucleotide (AON)-based therapy for leber congenital amaurosis caused by a frequent mutation in CEP290. Mol. Ther. Nucleic Acids, 2012, 1, e14.
[] [PMID: 23343883]
Garanto, A.; Chung, D.C.; Duijkers, L.; Corral-Serrano, J.C.; Messchaert, M.; Xiao, R.; Bennett, J.; Vandenberghe, L.H.; Collin, R.W. In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. Hum. Mol. Genet., 2016, 25(12), 2552-2563.
[PMID: 27106101]
Grayson, C.; Chapple, J.P.; Willison, K.R.; Webster, A.R.; Hardcastle, A.J.; Cheetham, M.E. In vitro analysis of aminoglycoside therapy for the Arg120stop nonsense mutation in RP2 patients. J. Med. Genet., 2002, 39(1), 62-67.
[] [PMID: 11826029]
Vandenberghe, L.H.; Wilson, J.M.; Gao, G. Tailoring the AAV vector capsid for gene therapy. Gene Ther., 2009, 16(3), 311-319.
[] [PMID: 19052631]
Beltran, W.A.; Cideciyan, A.V.; Lewin, A.S.; Iwabe, S.; Khanna, H.; Sumaroka, A.; Chiodo, V.A.; Fajardo, D.S.; Román, A.J.; Deng, W.T.; Swider, M.; Alemán, T.S.; Boye, S.L.; Genini, S.; Swaroop, A.; Hauswirth, W.W.; Jacobson, S.G.; Aguirre, G.D. Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked Retinitis pigmentosa. Proc. Natl. Acad. Sci. USA, 2012, 109(6), 2132-2137.
[] [PMID: 22308428]
Mookherjee, S.; Hiriyanna, S.; Kaneshiro, K.; Li, L.; Li, Y.; Li, W.; Qian, H.; Li, T.; Khanna, H.; Colosi, P.; Swaroop, A.; Wu, Z. Long-term rescue of cone photoreceptor degeneration in Retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy. Hum. Mol. Genet., 2015, 24(22), 6446-6458.
[] [PMID: 26358772]
Simons, D.L.; Boye, S.L.; Hauswirth, W.W.; Wu, S.M. Gene therapy prevents photoreceptor death and preserves retinal function in a Bardet-Biedl syndrome mouse model. Proc. Natl. Acad. Sci. USA, 2011, 108(15), 6276-6281.
[] [PMID: 21444805]
Allocca, M.; Doria, M.; Petrillo, M.; Colella, P.; Garcia-Hoyos, M.; Gibbs, D.; Kim, S.R.; Maguire, A.; Rex, T.S.; Di Vicino, U.; Cutillo, L.; Sparrow, J.R.; Williams, D.S.; Bennett, J.; Auricchio, A. Serotype-dependent packaging of large genes in adeno-associated viral vectors results in effective gene delivery in mice. J. Clin. Invest., 2008, 118(5), 1955-1964.
[] [PMID: 18414684]
Zhang, W.; Li, L.; Su, Q.; Gao, G.; Khanna, H. Gene therapy using a miniCEP290 fragment delays photoreceptor degeneration in a mouse model of leber congenital amaurosis. Hum. Gene Ther., 2018, 29(1), 42-50.
[] [PMID: 28679290]
Kalouda, P.; Keskini, C.; Anastasopoulos, E.; Topouzis, F. Achievements and limits of current medical therapy of glaucoma. Dev. Ophthalmol., 2017, 59, 1-14.
[] [PMID: 28442683]

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