A Novel Mutation in the RPE65 Gene Causing Leber Congenital Amaurosis and Its Transcriptional Expression in Vitro

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Nov 11

PMID 25383945

Citations 8

Authors

Guoyan Mo

Qin Ding

Zhongshan Chen

Yunbo Li

Ming Yan

Lijing Bu

Yanping Song

Guohua Yin

Affiliations

Soon will be listed here.

Abstract

The retinal pigment epithelium-specific 65 kDa protein is an isomerase encoded by the RPE65 gene (MIM 180069) that is responsible for an essential enzymatic step required for the function of the visual cycle. Mutations in the RPE65 gene cause not only subtype II of Leber congenital amaurosis (LCA) but also early-onset severe retinal dystrophy (EOSRD). This study aims to investigate a Chinese case diagnosed as EOSRD and to characterize the polymorphisms of the RPE65 gene. A seven-year-old girl with clinical symptoms of EOSRD and her parents were recruited into this study. Ophthalmologic examinations, including best-corrected visual acuity, slit-lamp, Optical coherence tomography (OCT), and fundus examination with dilated pupils, were performed to determine the clinical characteristics of the whole family. We amplified and sequenced the entire coding region and adjacent intronic sequences of the coding regions of the RPE65 gene for the whole family to explore the possible mutation. Our results demonstrate that the patient exhibited the typical clinically features of EOSRD. Her bilateral decimal visual acuity was 0.3 and 0.4 in the left and right eyes, respectively. Spectral-domain optical coherence tomography (SD-OCT) was used to assess the retinal stratification for the whole family. All together, we identified four mutations within the RPE65 gene (c.1056G>A, c.1243+2T>A, c.1338+20A>C and c.1590C>A) in the patient. Among the four mutations, c.1056G>A and c.1338+20A>C had been reported previously and another two were found for the first time in this study. Her mother also carried the novel mutation (c.1243+2T>A). Either a single or a compound heterozygous or a homozygous one mutation is expected to cause EOSRD because mutations of RPE65 gene usually cause an autosomal recessive disease. Therefore, we speculate that the c.1590C>A mutation together with the c.1243+2T>A mutation may cause the patient's phenotype.

Citing Articles

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PMID: 37980693 DOI: 10.1007/s12033-023-00907-8.

c.393T>A, p.(Asn131Lys): Novel Sequence Variant Detected.

Bjelos M, Busic M, Curic A, Bosnar D, Saric B, Markovic L Case Rep Ophthalmol Med. 2022; 2022:5710080.

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Clinical Features and Natural History in a Cohort of Chinese Patients with RPE65-Associated Inherited Retinal Dystrophy.

Shi J, Xu K, Hu J, Xie Y, Zhang X, Zhang X J Clin Med. 2021; 10(22).

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Frequency and phenotypic characteristics of RPE65 mutations in the Chinese population.

Gao F, Wang D, Li J, Hu F, Xu P, Chen F Orphanet J Rare Dis. 2021; 16(1):174.

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Clinical Perspective: Treating RPE65-Associated Retinal Dystrophy.

Maguire A, Bennett J, Aleman E, Leroy B, Aleman T Mol Ther. 2020; 29(2):442-463.

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References

Hood D, Lin C, Lazow M, Locke K, Zhang X, Birch D . Thickness of receptor and post-receptor retinal layers in patients with retinitis pigmentosa measured with frequency-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2008; 50(5):2328-36. PMC: 2835526. DOI: 10.1167/iovs.08-2936. View

Ehnes A, Wenner Y, Friedburg C, Preising M, Bowl W, Sekundo W . Optical Coherence Tomography (OCT) Device Independent Intraretinal Layer Segmentation. Transl Vis Sci Technol. 2014; 3(1):1. PMC: 3922027. DOI: 10.1167/tvst.3.1.1. View

Morimura H, Fishman G, Grover S, Fulton A, Berson E, Dryja T . Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998; 95(6):3088-93. PMC: 19699. DOI: 10.1073/pnas.95.6.3088. View

Moiseyev G, Chen Y, Takahashi Y, Wu B, Ma J . RPE65 is the isomerohydrolase in the retinoid visual cycle. Proc Natl Acad Sci U S A. 2005; 102(35):12413-8. PMC: 1194921. DOI: 10.1073/pnas.0503460102. View

Bereta G, Kiser P, Golczak M, Sun W, Heon E, Saperstein D . Impact of retinal disease-associated RPE65 mutations on retinoid isomerization. Biochemistry. 2008; 47(37):9856-65. PMC: 2610467. DOI: 10.1021/bi800905v. View

Jacobson S, Aleman T, Cideciyan A, Roman A, Sumaroka A, Windsor E . Defining the residual vision in leber congenital amaurosis caused by RPE65 mutations. Invest Ophthalmol Vis Sci. 2009; 50(5):2368-75. PMC: 2731629. DOI: 10.1167/iovs.08-2696. View

Verma A, Perumalsamy V, Shetty S, Kulm M, Sundaresan P . Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients. PLoS One. 2013; 8(9):e73172. PMC: 3774716. DOI: 10.1371/journal.pone.0073172. View

Mamatha G, Srilekha S, Meenakshi S, Kumaramanickavel G . Screening of the RPE65 gene in the Asian Indian patients with leber congenital amaurosis. Ophthalmic Genet. 2008; 29(2):73-8. DOI: 10.1080/13816810802008259. View

den Hollander A, Lopez I, Yzer S, Zonneveld M, Janssen I, Strom T . Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. Invest Ophthalmol Vis Sci. 2007; 48(12):5690-8. DOI: 10.1167/iovs.07-0610. View

10.

Sitorus R, Lorenz B, Preising M . Analysis of three genes in Leber congenital amaurosis in Indonesian patients. Vision Res. 2003; 43(28):3087-93. DOI: 10.1016/j.visres.2003.08.008. View

11.

McKibbin M, Ali M, Mohamed M, Booth A, Bishop F, Pal B . Genotype-phenotype correlation for leber congenital amaurosis in Northern Pakistan. Arch Ophthalmol. 2010; 128(1):107-13. DOI: 10.1001/archophthalmol.2010.309. View

12.

Simovich M, Miller B, Ezzeldin H, Kirkland B, McLeod G, Fulmer C . Four novel mutations in the RPE65 gene in patients with Leber congenital amaurosis. Hum Mutat. 2001; 18(2):164. DOI: 10.1002/humu.1168. View

13.

Lorenz B, Gyurus P, Preising M, Bremser D, Gu S, Andrassi M . Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci. 2000; 41(9):2735-42. View

14.

Simonelli F, Ziviello C, Testa F, Rossi S, Fazzi E, Bianchi P . Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci. 2007; 48(9):4284-90. DOI: 10.1167/iovs.07-0068. View

15.

Xu F, Dong Q, Liu L, Li H, Liang X, Jiang R . Novel RPE65 mutations associated with Leber congenital amaurosis in Chinese patients. Mol Vis. 2012; 18:744-50. PMC: 3324356. View

16.

Perrault I, Rozet J, Ghazi I, Leowski C, Bonnemaison M, Gerber S . Different functional outcome of RetGC1 and RPE65 gene mutations in Leber congenital amaurosis. Am J Hum Genet. 1999; 64(4):1225-8. PMC: 1377849. DOI: 10.1086/302335. View

17.

Marlhens F, Bareil C, Griffoin J, Zrenner E, AMALRIC P, Eliaou C . Mutations in RPE65 cause Leber's congenital amaurosis. Nat Genet. 1997; 17(2):139-41. DOI: 10.1038/ng1097-139. View

18.

Hamel C, Jenkins N, Gilbert D, Copeland N, Redmond T . The gene for the retinal pigment epithelium-specific protein RPE65 is localized to human 1p31 and mouse 3. Genomics. 1994; 20(3):509-12. DOI: 10.1006/geno.1994.1212. View

19.

Lotery A, Namperumalsamy P, Jacobson S, Weleber R, Fishman G, Musarella M . Mutation analysis of 3 genes in patients with Leber congenital amaurosis. Arch Ophthalmol. 2000; 118(4):538-43. DOI: 10.1001/archopht.118.4.538. View

20.

Galvin J, Fishman G, Stone E, Koenekoop R . Evaluation of genotype-phenotype associations in leber congenital amaurosis. Retina. 2005; 25(7):919-29. DOI: 10.1097/00006982-200510000-00016. View