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Genotype–Phenotype of RPE65 Mutations: A Reference Guide for Gene Testing and Its Clinical Application

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Advances in Vision Research, Volume III

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

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Abstract

The RPE65 gene encodes a retinal pigment epithelium-specific isomerase that catalyzes the conversion of all-trans retinyl esters to 11-cis retinol, the activity of which affects the formation of visual pigment in photoreceptors. Mutations in RPE65 in inherited retinal dystrophies have been studied widely worldwide, especially now that gene therapy for patients with RPE65 mutations is available in the clinic. The aim of this study is to reveal the RPE65 mutation spectrum and frequency, the associated phenotypic characteristics, and potential genotype–phenotype correlations. In total, 201 mutations in RPE65 were identified in 479 patients from 353 families based on data reported in the literature. Mutations in 349 families caused autosomal recessive retinal degeneration, while a c.1430A>G (p.Asp477Gly) mutation in four families resulted in autosomal dominant retinal degeneration resembling retinitis pigmentosa, choroideremia, or vitelliform macular dystrophy with incomplete penetrance. Mutations identified in families with biallelic RPE65 mutations included missense (113/200 [56.5%]), frameshift indel (39/200 [19.5%]), splicing defect (24/200 [12.0%]), nonsense (19/200 [9.5%]), inframe indel (4/200 [2.0%]), and start loss (1/200 [0.5%]). A significant reduction in visual acuity was noticeable at 15 years of age and at 35 years of age, suggesting a critical window for treatment including gene therapy. Two major types of fundus changes were observed: (1) mild or obvious tapetoretinal degeneration, generalized or located mainly in the mid-peripheral retina; and (2) fundus albipunctatus-like retinopathy. Typical bone-spicule pigmentation was rarely seen in early childhood but may be observed after 35 years of age. A severe phenotype (Leber congenital amaurosis) is frequently associated with biallelic loss-of-function mutations, while milder phenotypes are more likely to be associated with one or two missense mutations. The overall information presented here should be useful as a reference guide in clinical practice, especially for clinical gene testing and enrollment in gene therapy.

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Acknowledgments

This work was supported by grants from the Science and Technology Planning Projects of Guangdong (2015A030401032), National Natural Science Foundation of China (81371058), the Key Projects of Guangzhou (201607020013), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology.

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Authors and Affiliations

  1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

    Zhen Yi & Qingjiong Zhang

  2. Sorbonne Université, INSERM, CNRS, Paris, France

    Christina Zeitz

  3. Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan

    Takeshi Iwata

  4. Global Eye Genetics Consortium (GEGC), Tokyo, Japan

    Takeshi Iwata, J. Fielding Hejtmancik & Qingjiong Zhang

  5. Ophthalmic Genetics and Visual Function Branch, National Eye Institute , National Institutes of Health, Bethesda, MD, USA

    J. Fielding Hejtmancik

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  1. Zhen Yi
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  5. Qingjiong Zhang
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Correspondence to Qingjiong Zhang .

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  1. National Eye Institute, National Institutes of Health, Bethesda, MD, USA

    Gyan Prakash

  2. National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

    Takeshi Iwata

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Yi, Z., Zeitz, C., Iwata, T., Hejtmancik, J.F., Zhang, Q. (2021). Genotype–Phenotype of RPE65 Mutations: A Reference Guide for Gene Testing and Its Clinical Application. In: Prakash, G., Iwata, T. (eds) Advances in Vision Research, Volume III. Essentials in Ophthalmology. Springer, Singapore. https://doi.org/10.1007/978-981-15-9184-6_14

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