<i>PRPH2</i>
            mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease

Peeters, Manon H C A; Khan, Mubeen; Rooijakkers, Anoek A M B; Mulders, Timo; Haer‐Wigman, Lonneke; Boon, Camiel J F; Klaver, Caroline C W; Born, L. Ingeborgh van den; Hoyng, Carel B.; Cremers, Frans P.M.; Hollander, Anneke I. den; Dhaenens, Claire‐Marie; Collin, Rob W.J.

doi:10.1002/humu.24275

Cited by 25 publications

(22 citation statements)

References 204 publications

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“…The prevalence of founder variants was found to be different. In Caucasians, c.424C>T (p.Arg142Trp [13,43,46,49]. Among these variants, c.514C>T was reported in a previous study in Japan [50] and was found in four patients from four families in our cohort.…”

Section: Discussionsupporting

confidence: 64%

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

Oishi

Fujinami

Mawatari

et al. 2021

Genes

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Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40’s; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

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Section: Discussionsupporting

confidence: 64%

“…Previous reports have suggested association between the location of the variant in PRPH2 and clinical phenotype. Specifically, variants are mostly found in the D2 loop [13,43,[46][47][48], which is critical for protein-protein interactions. Variants that cause autosomal dominant RP tend to accumulate between Lys193 and Glu226 [3].…”

Section: Discussionmentioning

confidence: 99%

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

Oishi

Fujinami

Mawatari

et al. 2021

Genes

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“…Its autosomal dominant inheritance in macular dystrophies has been reported in other studies [9,14]. Further studies reported on a more generalised rod than cone or cone than rod dysfunction [12,13,15].…”

Section: Discussionsupporting

confidence: 53%

“…Many studies, including this one, have attempted to determine genotype-phenotype correlations of PRPH2, demonstrating a high clinical variability, even within the same family [12,13]. We ana-lysed the genetic and clinical characteristics of two siblings.…”

Section: Discussionmentioning

confidence: 99%

Clinical Heterogeneity in Two Siblings Harbouring a Heterozygous PRPH2 Pathogenic Variant

Sanlialp

Escher

Schaller

et al. 2023

Klin Monbl Augenheilkd

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Purpose The aim of the study was to describe the clinical and genetic correlation of a c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 in two siblings of Italian origin. Patients and Methods Both patients underwent ophthalmic examination, electrophysiological testing, autofluorescence imaging, and optical coherence tomography (OCT). Screening for pathogenic variants of the obtained DNA from the family members was carried out. Results The 52-year-old (♀, index patient) and 50-year-old (♂) siblings had BCVA (OD and OS) of 20/20 and 20/16 (♀) and 20/25 and 20/40 (♂), respectively, and suffered increased sensitivity to glare. Yellow irregular macular deposits, numerous small irregular hypo- and hyperreflective spots at the posterior pole, a patchy loss of photoreceptors, and retinal pigment epithelium (RPE) in the perifoveal region were seen. Electrophysiology showed dysfunction of rods and cones, with more affected cone dysfunction in the index patient, contrary to the generalised rod dysfunction in the brother of the index patient. The clinical, electrophysiological, and multimodal imaging findings of both siblings pointed towards Stargardt retinopathy with heterogenic presentation. The DNA analysis identified an autosomal dominant c.469 G>A p.(Asp157Asn) heterozygous pathogenic variant in PRPH2 associated with autosomal dominant cone-rod dystrophy and rod-cone dystrophy. PRPH2 codes for peripherin-2, a membrane protein that consists of 346 amino acids. Conclusions Our findings confirm a heterogeneity in clinical presentation associated with pathogenic variants in PRPH2. It may follow either an autosomal dominant or an autosomal recessive mode of inheritance and show a very heterogeneous clinical manifestation of retinal degeneration, e.g., autosomal dominant retinitis pigmentosa (♂ sibling; II-3) and autosomal dominant cone-rod dystrophy (index ♀ sibling; II-2), autosomal dominant macular dystrophy, and also autosomal recessive retinitis pigmentosa.

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“…To examine whether our workflow for HITI-mediated gene construction can be applied to other genes, we targeted mouse Prph2, the second leading cause of AdRP 40,41 . In the grID database in silico finder, three gRNA target sequences with grID scores ranging from 800 to 900 were selected around the 100 bp region of the proximal sequence from the Prph2 5'-UTR (Fig.…”

Section: Prph2 Locusmentioning

confidence: 99%

Efficient workflow for validating homology-independent targeted integration-mediated gene insertion in rod photoreceptor cells to treat dominant-negative mutations causing retinitis pigmentosa

Onishi,

Tsunekawa,

Mandai

et al. 2023

Preprint

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Among the genome-editing methods for repairing disease-causing mutations resulting in dominant inhibition, homology-independent targeted integration (HITI)-mediated gene insertion of the normal form of the causative gene is useful because it allows the development of mutation-agnostic therapeutic products. For the rapid optimization and validation of highly effective HITI-treatment gene constructs against dominant-negative inheritance of inherited retinal dystrophy, we improved the gene constructs available in both plasmid and adeno-associated virus (AAV) vectors, and established a workflow that uses in vivo electroporation to verify the in vivo efficacy. By targeting the mouse Rhodopsin gene, we derived a construct in which HITI-mediated gene insertion occurs in 80%-90% of transduced mouse rod photoreceptor cells. This construct suppressed degeneration and induced visual restoration in the mutant mice. The HITI-treatment constructs for the rhodopsin gene were shown to be effective in AAV vectors, and this construction is available for the mouse Peripherin 2 gene. These findings suggest that the workflow reported here may be useful for the generation of HITI-treatment constructs for various target genes and for the development of gene therapy products.

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PRPH2 mutation update: In silico assessment of 245 reported and 7 novel variants in patients with retinal disease

Cited by 25 publications

References 204 publications

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

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

Clinical Heterogeneity in Two Siblings Harbouring a Heterozygous PRPH2 Pathogenic Variant

Efficient workflow for validating homology-independent targeted integration-mediated gene insertion in rod photoreceptor cells to treat dominant-negative mutations causing retinitis pigmentosa

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