Novel mutations of RPGRIP1 gene in a family with Leber congenital amaurosis_Chinese Journal of Ocular Fundus Diseases

Authors：

Tang He , Peng Haiying , Shi Pingling ,  Zhou Zhongqiang , Wei Yuanmeng , Li Miao , Liang Yingjuan , Nie Xiaodong , Huang Aiguo

Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan Eye Institute & Henan Eye Hospital, Henan Clinical Research Center for Ophthalmic Diseases, Zhengzhou 450003, China;

Corresponding author：

Zhou Zhongqiang, Email: zhouzhongqiang110@163.com

Keywords：

Leber congenital amaurosis/etiology; Genes; Mutation; RPGRIP1 gene

DOI：

10.3760/cma.j.cn511434-20191008-00315

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Objective To identify the pathogenic gene mutations in a family with Leber congenital amaurosis (LCA).Methods In October 2018, 1 patient and 3 normal family members from a LCA family was enrolled in this retrospective study. Detailed medical history of proband was obtained and fixation test, cycloplegic refraction, slit-lamp, fundus color photography and full-field ERG were performed. And other family members underwent BCVA, refraction slit-lamp, fundus biomicroscopy with the slit lamp, fundus color photography and full-field ERG. The family was investigated with a specific hereditary eye disease enrichment panel which contained 441 known pathogenic genes and based on targeted exome capture technology first to indentify the potential pathogenic genes and mutations. Then the potential pathogenic mutations were conformed by Sanger sequencing. Finally, the results were analyzed via bioinformatics analysis.Results The proband showed no trace object from childhood, but had obvious photophobia and nystagmus. No positive changes were found in the anterior segment, vitreous and retina in both eyes. Both cone and rod system function decreased significantly in full-field ERG in both eyes. Gene tests showed the proband carried both RPGRIP1 c.1635dupA and c.3565C＞T, which composited a heterozygous mutation. Bioinformatics analysis showed RPGRIP1 c.1635dupA was a pathogenic mutation, and RPGRIP1 c.3565C＞T which was a novel potential pathogenic mutation in LCA.Conclusion The compound heterozygous mutation, c.1635dupA and c.3565C＞T in RPGRIP1 may be responsible for the pathogenesis in this Chinese Han LCA pedigree.

Citation： Tang He, Peng Haiying, Shi Pingling, Zhou Zhongqiang, Wei Yuanmeng, Li Miao, Liang Yingjuan, Nie Xiaodong, Huang Aiguo. Novel mutations of RPGRIP1 gene in a family with Leber congenital amaurosis. Chinese Journal of Ocular Fundus Diseases, 2020, 36(3): 196-199. doi: 10.3760/cma.j.cn511434-20191008-00315 Copy

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10.	Hameed A, Abid A, Aziz A, et al. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy[J]. J Med Genet, 2003, 40(8): 616-619. DOI: 10.1136/jmg.40.8.616.
11.	Patel N, Aldahmesh MA, Alkuraya H, et al. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies[J]. Genet Med, 2016, 18(6): 554-562. DOI: 10.1038/gim.2015.127.
12.	Shu X, Fry A, Tulloch B, et al. RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin[J]. Hum Mol Genet, 2005, 14(9): 1183-1197. DOI: 10.1093/hmg/ddi129.
13.	Zhao D, Hong DH, Pawlyk B, et al. The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis[J]. Proc Natl Acad Sci USA, 2003, 100(7): 3965-3970. DOI: 10.1073/pnas.0637349100.
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15.	Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.

1. 文峰, 易长贤. 临床眼底病(内科卷). 北京: 人民卫生出版社, 2015: 537-538.Wen F, Yi CX. Clinical ophthalmic disease (internal medicine volume). Beijing: People's Medical Publishing House, 2015: 537-538.
2. Li T. Leber congenital amaurosis caused by mutations in RPGRIP1[J/OL]. Cold Spring Harb Perspect Med, 2014, 5(4): 017384[2014-11-20]. http://perspectivesinmedicine.cshlp.org/cgi/pmidlookup?view=long&pmid=25414380. DOI: 10.1101/cshperspect.a017384.
3. Koenekoop RK, Wang H, Majewski J, et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration[J]. Nat Genet, 2012, 44(9): 1035-1039. DOI: 10.1038/ng.2356.
4. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
5. Hanein S, Perrault I, Gerber S, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis[J]. Hum Mutat, 2004, 23(4): 306-317. DOI: 10.1002/humu.20010.
6. Ruiz A, Kuehn MH, Andorf JL, et al. Genomic organization and mutation analysis of the gene encoding lecithin retinol acyltransferase in human retinal pigment epithelium[J]. Invest Ophthalmol Vis Sci, 2001, 42(1): 31-37. DOI: 10.1007/PL00007900.
7. Kitiratschky VB, Wilke R, Renner AB, et al. Mutation analysis identifies GUCY2D as the major gene responsible for autosomal dominant progressive cone degeneration[J]. Invest Ophthalmol Vis Sci, 2008, 49(11): 5015-5023. DOI: 10.1167/iovs.08-1901.
8. den Hollander AI, Koenekoop RK, Yzer S, et al. Mutations in the CEP290(NPHP6) gene are a frequent cause of Leber congenital amaurosis[J]. Am J Hum Genet, 2006, 79(3): 556-561. DOI: 10.1086/507318.
9. Dryja TP, Adams SM, Grimsby JL, et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis[J]. Am J Hum Genet, 2001, 68(5): 1295-1298. DOI: 10.1086/320113.
10. Hameed A, Abid A, Aziz A, et al. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy[J]. J Med Genet, 2003, 40(8): 616-619. DOI: 10.1136/jmg.40.8.616.
11. Patel N, Aldahmesh MA, Alkuraya H, et al. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies[J]. Genet Med, 2016, 18(6): 554-562. DOI: 10.1038/gim.2015.127.
12. Shu X, Fry A, Tulloch B, et al. RPGR ORF15 isoform co-localizes with RPGRIP1 at centrioles and basal bodies and interacts with nucleophosmin[J]. Hum Mol Genet, 2005, 14(9): 1183-1197. DOI: 10.1093/hmg/ddi129.
13. Zhao D, Hong DH, Pawlyk B, et al. The retinitis pigmentosa GTPase regulator (RPGR)-interacting protein: subserving RPGR function and participating in disk morphogenesis[J]. Proc Natl Acad Sci USA, 2003, 100(7): 3965-3970. DOI: 10.1073/pnas.0637349100.
14. Patnaik SR, Raghupathy RK, Zhang X, et al. The role of RPGR and its interacting proteins in ciliopathies[J/OL]. J Ophthalmol, 2015, 2015: 414781[2015-06-01]. https://dx.doi.org/10.1155/2015/414781. DOI: 10.1155/2015/414781.
15. Le Meur G, Lebranchu P, Billaud F, et al. Safety and long-term efficacy of AAV4 gene therapy in patients with RPE65 Leber congenital amaurosis[J]. Mol Ther, 2018, 26(1): 256-268. DOI: 10.1016/j.ymthe.2017.09.014.

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