Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

Dias, Marina França; Joo, Kwangsic; Kemp, Jessica A.; Fialho, Sílvia Ligório; Silva-Cunha, Armando; Woo, Se Joon; Kwon, Young Jik

doi:10.1016/j.preteyeres.2017.10.004

Cited by 316 publications

(271 citation statements)

References 247 publications

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“…Several studies have shown a rather high diagnostic yield (50%-79%) of multigene panels in patients with RD. [1][2][3][4] However, those cohorts were not selected on the basis of a particular mode of inheritance. Thus, the magnitude of autosomal recessive (AR) RD that is accounted for by known disease genes remains unknown.…”

Section: Funding Informationmentioning

confidence: 99%

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Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Patel

Alkuraya²,

Alzahrani

et al. 2018

Clinical Genetics

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Retinal dystrophies (RDs) are hereditary blinding eye conditions that are highly variable in their clinical presentation. The remarkable genetic heterogeneity that characterizes RD was a major challenge in establishing the molecular diagnosis in these patients until the recent advent of next-generation sequencing. It remains unclear, however, what percentage of autosomal recessive RD remain undiagnosed when all established RD genes are sequenced. We enrolled 75 families in which RD segregates in an apparently autosomal recessive manner. We show that the yield of a multigene panel that contains known RD genes is 67.5%. The higher yield (82.3%) when whole exome sequencing was implemented instead was often due to hits in genes that were not included in the original design of the panel. We also show the value of homozygosity mapping even during the era of exome sequencing in uncovering cryptic mutations. In total, we describe 45 unique likely deleterious variants (of which 18 are novel including one deep intronic and one genomic deletion mutation). Our study suggests that the genetic heterogeneity of autosomal recessive RD is approaching saturation and that any new RD genes will probably account for only a minor role in the mutation burden.

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Section: Funding Informationmentioning

confidence: 99%

“…There are currently 261 genes listed with established links to RDs (http://www.sph.uth.tmc.edu/RetNet/). Several studies have shown a rather high diagnostic yield (50%‐79%) of multigene panels in patients with RD . However, those cohorts were not selected on the basis of a particular mode of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Patel

Alkuraya²,

Alzahrani

et al. 2018

Clinical Genetics

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show abstract

“…Each of these disorders is influenced, to various degrees, by mutations in a number of distinct genes. RP, for instance, has been associated with mutations in~80 genes and can be inherited as an autosomal-dominant, autosomal-recessive, or X-linked trait (4). It is characterized initially by degeneration of rod photoreceptors, followed by a loss of cone photoreceptors and of the photoreceptor-trophic retinal pigment epithelium (RPE).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, patients suffer from progressive night blindness, tunnel vision and rarely may become totally blind (4,5).…”

Section: Introductionmentioning

confidence: 99%

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

Lian

Liu

et al. 2019

Preprint

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AbstractPhotoreceptor cell degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become commercially available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

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“…This basic work was first carried out in the laboratory in 1984 [6-9] in primary cells/animal models [13-19], and AAV is now one of the top clinical gene therapy vectors in use today [20-22]. While wt AAV will replicate in differentiating keratinocytes [23, 24] and certain cell lines (often with genotoxic stress) [25-28] in the laboratory, in tissue culture, most cell types AAV require co-infection by a helper virus, such as adenovirus (Ad), herpes simplex virus (HSV), or human papillomavirus (HPV), to allow productive AAV infection to occur [24, 29-31].…”

Section: Introductionmentioning

confidence: 99%

The HPV16 E1 Carboxyl Domain Provides a Helper Function for Adeno-Associated Virus Replication

et al. 2018

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Background/Aims: Recombinant adeno-associated virus (rAAV) is now in the clinic, yet production of rAAV remains problematic. We previously determined that human papillomavirus type 16 (HPV16) E1 protein boosts rAAV yields and E1 enhances AAV Rep78’s replication-related biochemistries. Here, we deletion-mapped the helper domain within E1 to help glean its mechanism of action. Methods: Rep78-E1 interaction was analyzed by Gal4-based yeast two-hybrid (Y2H)-cDNA assay. rAAV DNA replication was studied by AAV/helper plasmid transfection into HEK293 cells and Southern blot. Gene expression analysis was made of AAV and E1 plasmid transfection, cDNA generation, and then quantitative polymerase chain reaction. NCBI protein BLAST was used for the homology analysis. Results: Gal4-Y2H- cDNA assay found in vivo Rep78-E1-binding activity across E1, but the carboxyl-third (amino acids [aa] 421–649) of E1 contained the predominant DNA replication helper domain. The amino-half of E1 (aa 1–337) inhibited transcription of rep (p5 promoter) and cap (p40, trending lower) from non-replicating helper plasmid by quantitative (q)RT-PCR. Conclusions: The aa 421–649 helper domain of HPV16 E1 includes the ATP-binding/helicase region of E1 which boosts rAAV production and has homology with the analogous region of parvovirus NS-1/Rep78 by NCBI protein BLAST, suggesting these biochemistries are responsible for the mechanism of action in E1 helper function.

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Molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspectives

Cited by 316 publications

References 247 publications

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

Mutations in known disease genes account for the majority of autosomal recessive retinal dystrophies

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

The HPV16 E1 Carboxyl Domain Provides a Helper Function for Adeno-Associated Virus Replication

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