Rinki Ratnapriya, Samuel G. Jacobson, Artur V. Cideciyan, Milton A. English, Alejandro J. Roman, Alexander Sumaroka, Rebecca Sheplock, Anand Swaroop | Frontiers in Cell and Developmental Biology | 16 August 2021 |
Volume 9 | 2021 | https://doi.org/10.3389/fcell.2021.720782
Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.
Introduction
Emerging from the era of ungenotyped inherited retinal degenerations (IRDs), we are now aware of the heterogeneous basis of these blinding diseases (Bramall et al., 2010; Wright et al., 2010; Ratnapriya and Swaroop, 2013; Verbakel et al., 2018; Garafalo et al., 2020). From the linkage mapping of disease loci to the identification of causative genes and mutations, there was a steady increase in the number of genes associated with IRDs in the three decades from 1990 onward (RetNet, the Retinal Information Network)1. Yet, there remain many IRD patients and families with unknown genetic diagnosis (at least 30%; Birtel et al., 2018; Garafalo et al., 2020; Hejtmancik and Daiger, 2020). The largest percentage of these molecularly unresolved Mendelian IRDs has been the simplex/multiplex or presumed autosomal recessively inherited diseases (Garafalo et al., 2020).
We have been investigating patients and families with non-syndromic retinal degeneration, and whenever a genetic cause for an autosomal dominant IRD was identified, the family was screened for known mutations. In recent years, the next-generation sequencing technologies, especially targeted and whole exome sequencing, have expedited the molecular diagnosis efforts (Booij et al., 2011; O’Sullivan et al., 2012; Ratnapriya and Swaroop, 2013; Beryozkin et al., 2015; Roberts et al., 2016). In the current study, we applied whole exome sequencing to a multi-generation dominant IRD family which was initially screened for known mutations but gave negative results. We analyzed all genes associated with IRDs as reported in the RetNet database and identified a novel, rare, heterozygous variant p.Asp67Val in ARL3 as a causative mutation. ARL3 encodes ADP-ribosylation factor, (Arf)-like protein 3. This soluble small GTPase has been localized to photoreceptors, and mutations in the ARL3 gene are considered to cause retinal ciliopathy (Frederick et al., 2020; Sánchez-Bellver et al., 2021).
A missense variant in ARL3 has previously been associated with non-syndromic autosomal dominant retinitis pigmentosa (OMIM 604695; Fahim et al., 2000). Specifically, the c.269A > G (p.Tyr90Cys) variant was determined to be a de novo mutation in two unrelated families, each with two generations of affected members (Strom et al., 2016; Holtan et al., 2019). ARL3 has also been implicated as an autosomal recessive cause of Joubert syndrome and non-syndromic retinal degeneration (Alkanderi et al., 2018; Sheikh et al., 2019; Fu et al., 2021).
The identification of causal genes underlying human diseases has clear clinical and research utility, and there has been recent progress toward therapy in dominant forms of IRD (Sudharsan and Beltran, 2019; Kruczek et al., 2021). Further, specifically considering the ARL3 gene, there are studies in patient-derived cell lines and animal models that can be the foundation for understanding the mechanism and devising the therapeutic strategies (Grayson et al., 2002; Evans et al., 2010; Schwarz et al., 2012; Hanke-Gogokhia et al., 2016; Kruczek and Swaroop, 2020).
References
Aleman, T. S., Soumittra, N., Cideciyan, A. V., Sumaroka, A. M., Ramprasad, V. L., Herrera, W., et al. (2009). CERKL mutations cause an autosomal recessive cone-rod dystrophy with inner retinopathy. Invest. Ophthalmol. Vis. Sci. 50, 5944–5954. doi: 10.1167/iovs.09-3982
Alkanderi, S., Molinari, E., Shaheen, R., Elmaghloob, Y., Stephen, L. A., Sammut, V., et al. (2018). ARL3 mutations cause joubert syndrome by disrupting ciliary protein composition. Am. J. Hum. Genet. 103, 612–620. doi: 10.1016/j.ajhg.2018.08.015
Audo, I., Robson, A. G., Holder, G. E., and Moore, A. T. (2008). The negative ERG: clinical phenotypes and disease mechanisms of inner retinal dysfunction. Surv. Ophthalmol. 53, 16–40. doi: 10.1016/j.survophthal.2007.10.010
Azari, A. A., Aleman, T. S., Cideciyan, A. V., Schwartz, S. B., Windsor, E. A., Sumaroka, A., et al. (2006). Retinal disease expression in bardet-biedl syndrome-1 (BBS1) is a spectrum from maculopathy to retina-wide degeneration. Invest. Ophthalmol. Vis. Sci. 47, 5004–5010. doi: 10.1167/iovs.06-0517
Bartolini, F., Bhamidipati, A., Thomas, S., Schwahn, U., Lewis, S. A., and Cowan, N. J. (2002). Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C. J. Biol. Chem. 277, 14629–14634. doi: 10.1074/jbc.M200128200
Beryozkin, A., Shevah, E., Kimchi, A., Mizrahi-Meissonnier, L., Khateb, S., Ratnapriya, R., et al. (2015). Whole exome sequencing reveals mutations in known retinal disease genes in 33 out of 68 Israeli families with inherited retinopathies. Sci. Rep. 5:13187. doi: 10.1038/srep13187
Birtel, J., Gliem, M., Mangold, E., Müller, P. L., Holz, F. G., Neuhaus, C., et al. (2018). Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PloS One 13:e0207958. doi: 10.1371/journal.pone.0207958
Bolger, A. M., Lohse, M., and Usadel, B. (2014). Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics 30, 2114–2120. doi: 10.1093/bioinformatics/btu170
Booij, J. C., Bakker, A., Kulumbetova, J., Moutaoukil, Y., Smeets, B., Verheij, J., et al. (2011). Simultaneous mutation detection in 90 retinal disease genes in multiple patients using a custom-designed 300-kb retinal resequencing chip. Ophthalmology 118, 160–167. doi: 10.1016/j.ophtha.2010.04.022
Bradshaw, K., Hansen, R., and Fulton, A. (2004). Comparison of ERGs recorded with skin and corneal-contact electrodes in normal children and adults. Doc. Ophthalmol. 109, 43–55. doi: 10.1007/s10633-004-1751-3
Bramall, A. N., Wright, A. F., Jacobson, S. G., and McInnes, R. R. (2010). The genomic, biochemical, and cellular responses of the retina in inherited photoreceptor degenerations and prospects for the treatment of these disorders. Ann. Rev. Neurosci. 33, 441–472. doi: 10.1146/annurev-neuro-060909-153227
Cideciyan, A. V. (2000). In vivo assessment of photoreceptor function in human diseases caused by photoreceptor-specific gene mutations. Methods Enzymol. 316, 611–626. doi: 10.1016/s0076-6879(00)16753-9
Cideciyan, A. V., and Jacobson, S. G. (1993). Negative electroretinograms in retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 34, 3253–3263.
Cideciyan, A. V., and Jacobson, S. G. (1996). An alternative phototransduction model for human rod and cone ERG a-waves: normal parameters and variation with age. Vision Res. 36, 2609–2621. doi: 10.1016/0042-6989(95)00327-4
DePristo, M. A., Banks, E., Poplin, R., Garimella, K. V., Maguire, J. R., Hartl, C., et al. (2011). A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498. doi: 10.1038/ng.806
Evans, R. J., Schwarz, N., Nagel-Wolfrum, K., Wolfrum, U., Hardcastle, A. J., and Cheetham, M. E. (2010). The retinitis pigmentosa protein RP2 links pericentriolar vesicle transport between the Golgi and the primary cilium. Hum. Mol. Genet. 19, 1358–1367. doi: 10.1093/hmg/ddq012
Fahim, A. T., Daiger, S. P., and Weleber, R. G. (2000). “Nonsyndromic retinitis pigmentosa overview,” in GeneReviews, eds M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, G. Mirzaa, et al. (Seattle, WA: University of Washington).
Frederick, J. M., Hanke-Gogokhia, C., Ying, G., and Baehr, W. (2020). Diffuse or hitch a ride: how photoreceptor lipidated proteins get from here to there. Biol. Chem. 401, 573–584. doi: 10.1515/hsz-2019-0375
Fu, L., Li, Y., Yao, S., Guo, Q., You, Y., Zhu, X., et al. (2021). Autosomal recessive rod-cone dystrophy associated with compound heterozygous variants in ARL3 gene. Front. Cell Dev. Biol. 9:635424. doi: 10.3389/fcell.2021.635424
Garafalo, A. V., Cideciyan, A. V., Héon, E., Sheplock, R., Pearson, A., WeiYang Yu, C., et al. (2020). Progress in treating inherited retinal diseases: early subretinal gene therapy clinical trials and candidates for future initiatives. Prog. Retin. Eye Res. 77:100827. doi: 10.1016/j.preteyeres.2019.100827
Gotthardt, K., Lokaj, M., Koerner, C., Falk, N., Gießl, A., and Wittinghofer, A. (2015). A G-protein activation cascade from Arl13B to Arl3 and implications for ciliary targeting of lipidated proteins. Elife 4:e11859. doi: 10.7554/eLife.11859
Grayson, C., Bartolini, F., Chapple, J. P., Willison, K. R., Bhamidipati, A., Lewis, S. A., et al. (2002). Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3. Hum. Mol. Genet. 11, 3065–3074. doi: 10.1093/hmg/11.24.3065
Hanke-Gogokhia, C., Wu, Z., Gerstner, C. D., Frederick, J. M., Zhang, H., and Baehr, W. (2016). Arf-like protein 3 (ARL3) regulates protein trafficking and ciliogenesis in mouse photoreceptors. J. Biol. Chem. 291, 7142–7155. doi: 10.1074/jbc.M115.710954
Hejtmancik, J. F., and Daiger, S. P. (2020). Understanding the genetic architecture of human retinal degenerations. Proc. Natl. Acad. Sci. U.S.A. 117, 3904–3906. doi: 10.1073/pnas.1922925117
Holtan, J. P., Teigen, K., Aukrust, I., Bragadóttir, R., and Houge, G. (2019). Dominant ARL3-related retinitis pigmentosa. Ophthalmic Genet. 40, 124–128. doi: 10.1080/13816810.2019.1586965
Ismail, S., Chen, Y.-X., Miertzschke, M., Vetter, I. R., Koerner, C., and Wittinghofer, A. (2012). Structural basis for Arl3-specific release of myristoylated ciliary cargo from UNC119. EMBO J. 31, 4085–4094. doi: 10.1038/emboj.2012.257
Jacobson, S. G., Cideciyan, A. V., Aleman, T. S., Pianta, M. J., Sumaroka, A., Schwartz, S. B., et al. (2003). Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. Hum. Mol. Genet. 12, 1073–1078. doi: 10.1093/hmg/ddg117
Jacobson, S. G., Voigt, W. J., Parel, J. M., Apáthy, P. P., Nghiem-Phu, L., Myers, S. W., et al. (1986). Automated light- and dark-adapted perimetry for evaluating retinitis pigmentosa. Ophthalmology 93, 1604–1611. doi: 10.1016/s0161-6420(86)33522-x
Jacobson, S. G., Yagasaki, K., Feuer, W. J., and Roman, A. J. (1989). Interocular asymmetry of visual function in heterozygotes of X-linked retinitis pigmentosa. Exp. Eye Res. 48, 679–691. doi: 10.1016/0014-4835(89)90009-2
Krill, A. E. (1977). Krill’s Hereditary Retinal and Choroidal Diseases, Vol. 2. Hagerstown, MD: Harper.
Kruczek, K., Qu, Z., Gentry, J., Fadl, B. R., Gieser, L., Hiriyanna, S., et al. (2021). Gene therapy of dominant CRX-Leber congenital amaurosis using patient stem cell-derived retinal organoids. Stem Cell Rep. 16, 252–263. doi: 10.1016/j.stemcr.2020.12.018
Kruczek, K., and Swaroop, A. (2020). Pluripotent stem cell-derived retinal organoids for disease modeling and development of therapies. Stem Cells 38, 1206–1215. doi: 10.1002/stem.3239
Marmor, M. F., Aguirre, G., Arden, G., Berson, E., Birch, D. G., Boughman, J. A., et al. (1983). Retinitis pigmentosa: a symposium on terminology and methods of examination. Ophthalmology 90, 126–131.
Michaelides, M., Chen, L. L., Brantley, M. A. Jr., Andorf, J. L., Isaak, E. M., Jenkins, S. A., et al. (2007). ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull’s-eye maculopathy. Br. J. Ophthalmol. 91, 1650–1655. doi: 10.1136/bjo.2007.118356
O’Sullivan, J., Mullaney, B. G., Bhaskar, S. S., Dickerson, J. E., Hall, G., O’Grady, A., et al. (2012). A paradigm shift in the delivery of services for diagnosis of inherited retinal disease. J. Med. Genet. 49, 322–326. doi: 10.1136/jmedgenet-2012-100847
Pagon, R. A. (1988). Retinitis pigmentosa. Surv. Ophthalmol. 33, 133–177.
Ratnapriya, R., and Swaroop, A. (2013). Genetic architecture of retinal and macular degenerative diseases: the promise and challenges of next-generation sequencing. Genome Med. 5:84.
Retinal Information Network (2021). RetNet, the Retinal Information Network. Available online at: https://sph.uth.edu/RetNet/ (Accessed July 1, 2020).
Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology. Genet. Med. 17, 405–424. doi: 10.1038/gim.2015.30
Roberts, L., Ratnapriya, R., du Plessis, M., Chaitankar, V., Ramesar, R. S., and Swaroop, A. (2016). Molecular diagnosis of inherited retinal diseases in indigenous African populations by whole-exome sequencing. Invest. Ophthalmol. Vis. Sci. 57, 6374–6381. doi: 10.1167/iovs.16-19785
Rodrigues, C. H. M., Myung, Y., Pires, D. E. V., and Ascher, D. B. (2019). MCSM-PPI2: predicting the effects of mutations on protein-protein interactions. Nucleic Acids Res. 47, W338–W344. doi: 10.1093/nar/gkz383
Roman, A. J., Schwartz, S. B., Aleman, T. S., Cideciyan, A. V., Chico, J. D., Windsor, E. A., et al. (2005). Quantifying rod photoreceptor-mediated vision in retinal degenerations: dark-adapted thresholds as outcome measures. Exp. Eye Res. 80, 259–272. doi: 10.1016/j.exer.2004.09.00
Sánchez-Bellver, L., Toulis, V., and Marfany, G. (2021). On the wrong track: alterations of ciliary transport in inherited retinal dystrophies. Front. Cell Dev. Biol. 9:623734. doi: 10.3389/fcell.2021.623734
Schrick, J. J., Vogel, P., Abuin, A., Hampton, B., and Rice, D. S. (2006). ADP-ribosylation factor-like 3 is involved in kidney and photoreceptor development. Am. J. Pathol. 168, 1288–1298. doi: 10.2353/ajpath.2006.050941
Schwarz, N., Hardcastle, A. J., and Cheetham, M. E. (2012). Arl3 and RP2 mediated assembly and traffic of membrane associated cilia proteins. Vision Res. 75, 2–4. doi: 10.1016/j.visres.2012.07.016
Sheikh, S. A., Sisk, R. A., Schiavon, C. R., Waryah, Y. M., Usmani, M. A., Steel, D. H., et al. (2019). Homozygous variant in ARL3 causes autosomal recessive cone rod dystrophy. Invest. Ophthalmol. Vis. Sci. 60, 4811–4819. doi: 10.1167/iovs.19-27263
Strom, S. P., Clark, M. J., Martinez, A., Garcia, S., Abelazeem, A. A., Matynia, A., et al. (2016). De novo occurrence of a variant in ARL3 and apparent autosomal dominant transmission of retinitis pigmentosa. PLoS One 11:e0150944. doi: 10.1371/journal.pone.0150944
Sudharsan, R., and Beltran, W. A. (2019). Progress in gene therapy for rhodopsin autosomal dominant retinitis pigmentosa. Adv. Exp. Med. Biol. 1185, 113–118. doi: 10.1007/978-3-030-27378-1_19
Sumaroka, A., Cideciyan, A. V., Charng, J., Wu, V., Powers, C. A., Iyer, B. S., et al. (2019). Autosomal dominant retinitis pigmentosa due to class B Rhodopsin mutations: an objective outcome for future treatment trials. Int. J. Mol. Sci. 20:5344. doi: 10.3390/ijms20215344
Thiadens, A. A., Phan, T. M., Zekveld-Vroon, R. C., Leroy, B. P., van den Born, L. I., Hoyng, C. B., et al. (2012). Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology 119, 819–826. doi: 10.1016/j.ophtha.2011.10.011
Veltel, S., Gasper, R., Eisenacher, E., and Wittinghofer, A. (2008). The retinitis pigmentosa 2 gene product is a GTPase-activating protein for arf-like 3. Nat. Struct. Mol. Biol. 15, 373–380. doi: 10.1038/nsmb.1396
Verbakel, S. K., van Huet, R., Boon, C., den Hollander, A. I., Collin, R., Klaver, C., et al. (2018). Non-syndromic retinitis pigmentosa. Prog. Retin. Eye Res. 66, 157–186. doi: 10.1016/j.preteyeres.2018.03.005
Wang, K., Li, M., and Hakonarson, H. (2010). ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38:e164. doi: 10.1093/nar/gkq603
Wright, A. F., Chakarova, C. F., Abd El-Aziz, M. M., and Bhattacharya, S. S. (2010). Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nat. Rev. Genet. 11, 273–284. doi: 10.1038/nrg2717
Wright, Z. C., Loskutov, Y., Murphy, D., Stoilov, P., Pugacheva, E., Goldberg, A. F. X., et al. (2018). ADP-ribosylation factor-like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons. Sci. Rep. 8:16967.
Wright, Z. C., Singh, R. K., Alpino, R., Goldberg, A. F., Sokolov, M., and Ramamurthy, V. (2016). ARL3 regulates trafficking of prenylated phototransduction proteins to the rod outer segment. Hum. Mol. Genet. 25, 2031–2044. doi: 10.1093/hmg/ddw077
Yagasaki, K., and Jacobson, S. G. (1989). Cone-rod dystrophy. phenotypic diversity by retinal function testing. Arch. Ophthalmol. 107, 701–708. doi: 10.1001/archopht.1989.01070010719034
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