Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Kim, Yoon-Jeon; Kim, You-Na; Yoon, Young-Hee; Seo, Eul‐Ju; Seo, Go-Hun; Keum, Changwon; Lee, Beom-Hee; Lee, Joo‐Yong

doi:10.3390/genes12050675

Cited by 15 publications

(7 citation statements)

References 37 publications

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“…Our approach implemented specific enrichment for this region, allowing us to unambiguously identify 5 out of 7 RPGR mutations located at ORF15, which might have been undetected otherwise. On the other hand, genetic studies in populations of different geographic origins identified other major genes, e.g., EYS is the main RP gene (up to 20-30% of cases) in some East Asian populations [24,25], likely indicating different genetic structures in these cohorts.…”

Section: Discussionmentioning

confidence: 99%

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Villanueva‐Mendoza

Tuson

Apam‐Garduño

et al. 2021

Genes

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In this work, we aimed to provide the genetic diagnosis of a large cohort of patients affected with inherited retinal dystrophies (IRDs) from Mexico. Our data add valuable information to the genetic portrait in rare ocular diseases of Mesoamerican populations, which are mostly under-represented in genetic studies. A cohort of 144 unrelated probands with a clinical diagnosis of IRD were analyzed by next-generation sequencing using target gene panels (overall including 346 genes and 65 intronic sequences). Four unsolved cases were analyzed by whole-exome sequencing (WES). The pathogenicity of new variants was assessed by in silico prediction algorithms and classified following the American College of Medical Genetics and Genomics (ACMG) guidelines. Pathogenic or likely pathogenic variants were identified in 105 probands, with a final diagnostic yield of 72.9%; 17 cases (11.8%) were partially solved. Eighteen patients were clinically reclassified after a genetic diagnostic test (17.1%). In our Mexican cohort, mutations in 48 genes were found, with ABCA4, CRB1, RPGR and USH2A as the major contributors. Notably, over 50 new putatively pathogenic variants were identified. Our data highlight cases with relevant clinical and genetic features due to mutations in the RAB28 and CWC27 genes, enrich the novel mutation repertoire and expand the IRD landscape of the Mexican population.

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Section: Discussionmentioning

confidence: 99%

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Villanueva‐Mendoza

Tuson

Apam‐Garduño

et al. 2021

Genes

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“…Existing rat RD models, such as the s334ter and P23H rat, accurately reproduce the degenerative process seen in human RP as shown by electrophysiologic data and ultrastructural histology ( 23 – 25 ). Although P23H and s334ter mutation of opsin gene is common in US, according to our NGS study, Pde6b is the most frequently affected gene in patients with RP in Asian population ( 26 – 28 ). Also, s334ter and P23H are RP models inherited in an autosomal dominant pattern, whereas our Pde6b KO model is an autosomal recessive pattern, showing differences in inheritance patterns.…”

Section: Discussionmentioning

confidence: 72%

Development of a novel knockout model of retinitis pigmentosa using Pde6b-knockout Long–Evans rats

et al. 2022

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Although rats with melanin-pigmentated retinal pigment epithelial (RPE) cells are physiologically more appropriate models for human eye research than their albino counterparts, reliable models from the former strain are not available to study retinal degeneration. Here, we describe the development of a novel Pde6b-knockout Long–Evans (LE Pde6b KO) rat model that recapitulates key features of human retinitis pigmentosa (RP). After the generation of the Pde6b-knockout Sprague–Dawley rats with the CRISPR-Cpf1 system, the LE rat was back-crossed over 5 generations to develop the pigmented LE Pde6b KO strain. Interestingly, LE Pde6b KO displayed well-developed bone-spicule pigmentation; a hallmark of fundus in patients with RP which cannot be observed in non-pigmented albino rats. Moreover, the rat model showed progressive thinning of the retina, which was evident by intravital imaging with optical coherence tomography. Histologically, significant atrophy was observed in the outer nuclear layer. Functionally, LE Pde6b KO presented a marked decrease of amplitude level during electroretinogram testing, demonstrating significant loss of visual function. Therefore, these findings suggest that the LE Pde6b KO model robustly recapitulates the hallmark phenotype of RP. We believe that the LE Pde6b KO model may be used effectively for preclinical translational research to further study retinal degeneration.

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“…Despite the rapid pace of RP pathogenic gene discovery in the last decade, research into the specific pathogenesis and precise gene therapy remain as major challenges for RP due to its high genetic heterogenicity [ 31 ]. In this study, a disease model of the RPE cells derived from an adRP patient with the PRPF6 missense variant of c.2699G > A (p.Arg900His) was successfully established, while this variant has not been previously reported in other laboratories.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem Cells of a Retinitis Pigmentosa Patient with the PRPF6 Mutation

Liang

Tan

Sun

et al. 2022

IJMS

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Pre-mRNA processing factors (PRPFs) are vital components of the spliceosome and are involved in the physiological process necessary for pre-mRNA splicing to mature mRNA. As an important member, PRPF6 mutation resulting in autosomal dominant retinitis pigmentosa (adRP) is not common. Recently, we reported the establishment of an induced pluripotent stem cells (iPSCs; CSUASOi004-A) model by reprogramming the peripheral blood mononuclear cells of a PRPF6-related adRP patient, which could recapitulate a consistent disease-specific genotype. In this study, a disease model of retinal pigment epithelial (RPE) cells was generated from the iPSCs of this patient to further investigate the underlying molecular and pathological mechanisms. The results showed the irregular morphology, disorganized apical microvilli and reduced expressions of RPE-specific genes in the patient’s iPSC-derived RPE cells. In addition, RPE cells carrying the PRPF6 mutation displayed a decrease in the phagocytosis of fluorescein isothiocyanate-labeled photoreceptor outer segments and exhibited impaired cell polarity and barrier function. This study will benefit the understanding of PRPF6-related RPE cells and future cell therapy.

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Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Cited by 15 publications

References 37 publications

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

The Genetic Landscape of Inherited Retinal Diseases in a Mexican Cohort: Genes, Mutations and Phenotypes

Development of a novel knockout model of retinitis pigmentosa using Pde6b-knockout Long–Evans rats

Aberrant Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem Cells of a Retinitis Pigmentosa Patient with the PRPF6 Mutation

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