A novel exon 17 deletion mutation of RPGRIP1 gene in two siblings with Leber congenital amaurosis
Tóm tắt
To investigate mutations of causal genes in two affected male siblings of a Japanese family with suspected Leber congenital amaurosis (LCA) and to characterize the related clinical features. After obtaining informed consent, genomic DNA was extracted from peripheral blood of the proband and his family members. Mutation screening was initially performed with microarrays. The PCR and direct sequencing were successively done for confirmation of mutation detected by microarray, and the two patients who are the subjects of this study were also clinically examined.
Results of the microarray suggested deletion of exon 17 of RPGRIP1. Confirmation by PCR and direct sequencing following microarray analysis revealed that both siblings had homozygous deletion of exon 17 of the RPGRIP1 gene, while their unaffected parents were heterozygous carriers. Length of the deletion was 1339 bp including exon 17 at the position of c.2710+372_2895+76del1339. Clinical features of the two siblings showed nystagmus, poor visual acuity, hyperopia, and photophobia since early childhood; but there was no oculo-digital sign, vessel attenuation or RPE mottling from the mid-retina to the periphery. Full-field single flash ERG was recordable but 30 Hz flicker ERG was not detectable. Although the present patients did not show sufficient clinical findings as LCA, PCR findings and direct sequencing following microarray analysis confirmed that they were LCA. Genetic analyses are helpful for confirmation of clinical diagnosis.
Tài liệu tham khảo
von Leber TKG. Ueber retinitis pigmentosa und angeborene amaurose. Archiv für Ophthalmol. 1869;15:1–25.
Stone EM. Leber congenital amaurosis—a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2007;144:791–811.
Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004;49:379–98.
Cremers FP, van den Hurk JA, den Hollander AI. Molecular genetics of Leber congenital amaurosis. Hum Mol Genet. 2002;11:1169–76.
RetNet. https://sph.uth.edu/retnet/. Accessed 20 Sep 2013.
Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, et al. Effect of gene therapy on visual function in Leberʼs congenital amaurosis. N Engl J Med. 2008;358:2231–9.
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, et al. Safety and efficacy of gene transfer for Leberʼs congenital amaurosis. N Engl J Med. 2008;358:2240–8.
Hauswirth WW, Aleman TS, Kaushal S, Cideciyan AV, Schwartz SB, Wang L, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19:979–90.
Li Y, Wang H, Peng J, Gibbs RA, Lewis RA, Lupski JR, et al. Mutation survey of known LCA genes and loci in the Saudi Arabian population. Invest Ophthalmol Vis Sci. 2009;50:1336–43.
Booij JC, Bakker A, Kulumbetova J, Moutaoukil Y, Smeets B, Verheij J, et al. Simultaneous mutation detection in 90 retinal disease genes in multiple patients using a custom-designed 300-kb retinal resequencing chip. Ophthalmol. 2011;118:160–7.
Li L, Xiao X, Li S, Jia X, Wang P, Guo X, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PLoS ONE. 2011;. doi:10.1371/journal.pone.0019458.
Chen Y, Zhang Q, Shen T, Xiao X, Li S, Guan L, et al. Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2013;54:4351–7.
Corton M, Nishiguchi KM, Avila-Fernández A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, et al. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS ONE. 2013;. doi:10.1371/journal.pone.0065574.
Huang L, Zhang Q, Li S, Guan L, Xiao X, Zhang J, et al. Exome sequencing of 47 chinese families with cone-rod dystrophy: mutations in 25 known causative genes. PLoS ONE. 2013;. doi:10.1371/journal.pone.0065546.
Wang X, Wang H, Sun V, Tuan HF, Keser V, Wang K, et al. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. J Med Genet. 2013;50:674–88.
Murakami A. Gene information analysis for ophthalmic gene diagnosis and therapy. Nippon Ganka Gakkai Zasshi. 2014;118:283–98 (in Japanese).
Hameed A, Abid A, Aziz A, Ismail M, Mehdi SQ, Khaliq S. Evidence of RPGRIP1 gene mutations associated with recessive cone-rod dystrophy. J Med Genet. 2003;40:616–9.
Khan AO, Abu-Safieh L, Eisenberger T, Bolz HJ, Alkuraya FS. The RPGRIP1-related retinal phenotype in children. Br J Ophthalmol. 2013;97:760–4.
Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, et al. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–47.
Damji KF, Sohocki MM, Khan R, Gupta SK, Rahim M, Loyer M, et al. Leber’s congenital amaurosis with anterior keratoconus in Pakistani families is caused by the Trp278X mutation in the AIPL1 gene on 17p. Can J Ophthalmol. 2001;36:252–9.
Dryja TP, Adams SM, Grimsby JL, McGee TL, Hong DH, Li T, et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet. 2001;68:1295–8.
Gerber S, Perrault I, Hanein S, Barbet F, Ducroq D, Ghazi I, et al. Complete exon–intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis. Eur J Hum Genet. 2001;9:561–71.
Hanein S, Perrault I, Gerber S, Tanguy G, Barbet F, Ducroq D, 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. Hum Mutat. 2004;23:306–17.
Yousef YA, Finger PT. Optical coherence tomography of radiation optic neuropathy. Ophthalmic Surg Lasers Imaging. 2012;43:6–12.
Jacobson SG, Cideciyan AV, Aleman TS, Sumaroka A, Schwartz SB, Roman AJ, et al. Leber congenital amaurosis caused by an RPGRIP1 mutation shows treatment potential. Ophthalmol. 2007;114:895–8.
Pawlyk BS, Smith AJ, Buch PK, Adamian M, Hong DH, Sandberg MA, et al. Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci. 2005;46:3039–45.
Pawlyk BS, Bulgakov OV, Liu X, Xu X, Adamian M, Sun X, et al. Replacement gene therapy with a human RPGRIP1 sequence slows photoreceptor degeneration in a murine model of Leber congenital amaurosis. Hum Gene Ther. 2010;21:993–1004.
Kuznetsova T, Iwabe S, Boesze-Battaglia K, Pearce-Kelling S, Chang-Min Y, McDaid K, et al. Exclusion of RPGRIP1 ins44 from primary causal association with early-onset cone-rod dystrophy in dogs. Invest Ophthalmol Vis Sci. 2012;53:5486–501.
Human Gene Mutation Database. http://www.hgmd.cf.ac.uk/ac/gene.php?gene=RPGRIP1. Accessed 25 Oct 2013.
Batzer MA, Deininger PL. Alu repeats and human genomic diversity. Nat Rev Genet. 2002;3:370–9.
Zhao Y, Hong DH, Pawlyk B, Yue G, Adamian M, Grynberg M, et al. The retinitis pigmentosa GTPase regulator (RPGR)- interacting protein: subserving RPGR function and participating in disk morphogenesis. Proc Natl Acad Sci USA. 2003;100:3965–70.
Koenekoop RK. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet. 2005;26:175–9.
Miyadera K, Kato K, Aguirre-Hernández J, Tokuriki T, Morimoto K, Busse C, et al. Phenotypic variation and genotype–phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis. 2009;15:2287–305.
Narfström K, Jeong M, Hyman J, Madsen RW, Bergström TF. Assessment of hereditary retinal degeneration in the English springer spaniel dog and disease relationship to an RPGRIP1 mutation. Stem Cells Int. 2012;. doi:10.1155/2012/685901.