Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Oishi, Akio; Fujinami, Kaoru; Mawatari, Go; Nao‐i, Nobuhisa; Ikeda, Yasuhiro; Ueno, Shinji; Kuniyoshi, Kazuki; Hayashi, Takaaki; Kondo, Hiroyuki; Mizota, Atsushi; Shinoda, Kei; Kusuhara, Sentaro; Nakamura, Makoto; Iwata, Takeshi; Tsujikawa, Akitaka; Tsunoda, Kazushige

doi:10.3390/genes12111817

Cited by 13 publications

(13 citation statements)

References 59 publications

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“…Our cohort included 14 females and 14 males. The age of the patients ranged from 37 to 79 years with a mean (±SD) of 58 ± 1235 and the mean age of onset of symptoms was 41 ± 1283 years old, similar to data already reported in previous studies [ 7 , 9 , 20 ]. BCVA of the patients ranged from light perception to 20/20 Snellen.…”

Section: Resultssupporting

confidence: 86%

“…An unusual feature already discussed and reported in the literature [ 20 , 30 , 31 ] was the presence of monocular CNV in five affected patients (17%) in our group presenting with different phenotypes (PD, CACD, ECA).…”

Section: Resultssupporting

confidence: 64%

“…[ 3 , 7 ] Therefore, without consistent genotype–phenotype correlations, the accepted view is that a single mutation in PRPH2 may cause a spectrum of phenotypes, impacting on both the central photopic system and peripheral scotopic cellular elements. In other reports it is evidenced that many genetic variants are mostly found in the D2 loop [ 11 , 20 ], which is critical for protein–protein interactions. In agreement, we found that most of our patients have a mutation in this domain, except for family 2 (Trp97*), family 6 (Arg46*), and family 10 (Ser301A).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the prevalence of PRPH2 disease is reported differently among countries, 10.3% in France, 9% in America, 9% in Italy, 5% in Japan, and 3.5% in North America [ 2 , 18 , 19 , 20 , 21 ]. Moreover, because of the reduced frequency out of Europe, a European ancestry has been suggested [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

et al. 2022

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PRPH2 gene mutations are frequently found in inherited retinal dystrophies (IRD) and are associated with a wide spectrum of clinical phenotypes. We studied 28 subjects affected by IRD carrying pathogenic PRPH2 mutations, belonging to 11 unrelated families. Functional tests (best-corrected visual acuity measurement, chromatic test, visual field, full-field, 30 Hz flicker, and multifocal electroretinogram), morphological retino-choroidal imaging (optical coherence tomography, optical coherence tomography angiography, and fundus autofluorescence), and clinical data were collected and analyzed. Common primary complaints, with onset in their 40s, were visual acuity reduction and abnormal dark adaptation. Visual acuity ranged from light perception to 20/20 Snellen. Visual field peripheral constriction and central scotoma were found. Chromatic sense was reduced in one third of patients. Electrophysiological tests were abnormal in most of the patients. Choroidal neovascular lesions were detected in five patients. Three novel PRPH2 variants were found in four different families. Based on the present multimodal study, we identified seven distinct PRPH2 phenotypes in 11 unrelated families carrying either different mutations or the same mutation, both within the same family or among them. Fundus autofluorescence modality turned out to be the most adequate imaging method for early recognition of this dystrophy, and the optical coherence tomography angiography was highly informative to promptly detect choroidal neovascularization, even in the presence of the extensive chorioretinal atrophy phenotype.

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Section: Resultssupporting

confidence: 86%

Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

et al. 2022

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“…Here, we have demonstrated the clinical features associated with eleven patients who harbor the P210R mutation in PRPH2 . Recently, Oishi et al 39 reported that the missense mutation P210R causes autosomal dominant RP. 15 This clinical diagnosis was likely based on the observation of pigment clumping that occasionally occurs in these patients (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2

Conley

McClard

Mwoyosvi

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose More than 200 different mutations in peripherin-2 ( PRPH2 ) are associated with multiple subtypes of inherited retinal diseases (IRDs), including retinitis pigmentosa and cone or macular diseases. Our goal was to understand how the poorly characterized PRPH2 mutation p.Pro210Arg (P210R) affects visual function and retinal structure as well as gain insight into the mechanism driving the clinical pathology. Methods Eleven patients had clinical assessments including best-corrected visual acuity (BCVA), full field and multifocal electroretinography (ERG), static (spot size V) and kinetic perimetry (Octopus 900), and dark-adapted chromatic (DAC; Medmont; spot size V) perimetry. Images were acquired with the Optos ultra-wide field camera and spectral-domain optical coherence tomography (SD-OCT). Molecular characteristics of the P210R mutant protein were evaluated in vitro. Results Patients with the P210R mutation had BCVA (Snellen) ranging from 20/15 to 20/80. Perimetry showed a reduction in sensitivity, while ERG findings suggested that cone function was more impaired than rod function. Scotomas were identified corresponding to atrophic retinal lesions. Imaging revealed heterogeneous outer retinal changes such as hyperfluorescent flecks, hypo-autofluorescence (AF) regions of atrophy, and thinning of the photoreceptor layer on SD-OCT. In vitro findings suggested that P210R-Prph2 retains the ability to interact with binding partner Rom1 but abnormally accumulates in the endoplasmic reticulum (ER), suggesting the protein does not fold properly. Conclusions Rod and cone sensitivities were decreased in subjects with the P210R mutation in PRPH2 . There was scotomatous vision loss that occurred within the macula, likely due to atrophy that occurs after drusen have formed and have begun to resolve. This suggests that although rod and cone photoreceptors are dependent on PRPH2, preventing blindness in this specific subgroup of patients could involve therapeutics that impede the formation or lifecycle of drusen.

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Specification of variant interpretation guidelines for inherited retinal dystrophy in Japan

Fujinami,

Nishiguchi,

Oishi

et al. 2024

Jpn J Ophthalmol

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Accurate interpretation of sequence variants in inherited retinal dystrophy (IRD) is vital given the significant genetic heterogeneity observed in this disorder. To achieve consistent and accurate diagnoses, establishment of standardized guidelines for variant interpretation is essential. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation serve as the global "cross-disease" standard for classifying variants in Mendelian hereditary disorders. These guidelines propose a systematic approach for categorizing variants into 5 classes based on various types of evidence, such as population data, computational data, functional data, and segregation data. However, for clinical genetic diagnosis and to ensure standardized diagnosis and treatment criteria, additional specifications based on features associated with each disorder are necessary. In this context, we present a comprehensive framework outlining the newly specified ACMG/AMP rules tailored explicitly to IRD in the Japanese population on behalf of the Research Group on Rare and Intractable Diseases (Ministry of Health, Labour and Welfare of Japan). These guidelines consider disease frequencies, allele frequencies, and both the phenotypic and the genotypic characteristics unique to IRD in the Japanese population. Adjustments and modifications have been incorporated to reflect the specific requirements of the population. By incorporating these IRD-specific factors and refining the existing ACMG/AMP guidelines, we aim to enhance the accuracy and consistency of variant interpretation in IRD cases, particularly in the Japanese population. These guidelines serve as a valuable resource for ophthalmologists and clinical geneticists involved in the diagnosis and treatment of IRD, providing them with a standardized framework to assess and classify genetic variants. Keywords ACMG/AMP guidelines • Genetic diagnosis • Inherited retinal dystrophy • Japanese • Variant interpretationThe advent of gene therapy as a potential treatment for inherited retinal dystrophy (IRD), aimed at targeting the underlying causative gene or disease variant, has sparked global

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Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Cited by 13 publications

References 59 publications

Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2

Specification of variant interpretation guidelines for inherited retinal dystrophy in Japan

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Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan

Cited by 13 publications

References 59 publications

Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

Multimodal Study of PRPH2 Gene-Related Retinal Phenotypes

Delineating the Clinical Phenotype of Patients With the c.629C&gt;G, p.Pro210Arg Mutation in Peripherin-2

Specification of variant interpretation guidelines for inherited retinal dystrophy in Japan

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Delineating the Clinical Phenotype of Patients With the c.629C>G, p.Pro210Arg Mutation in Peripherin-2