[en] Leber congenital amaurosis (LCA) is a heterogeneous, early-onset inherited retinal dystrophy, which is associated with severe visual impairment. We aimed to determine the disease-causing variants in Iranian LCA and evaluate the clinical implications. Clinically, a possible LCA disease was found through diagnostic imaging, such as fundus photography, autofluorescence and optical coherence tomography. All affected patients showed typical eye symptoms associated with LCA including narrow arterioles, blindness, pigmentary changes and nystagmus. Target exome sequencing was performed to analyse the proband DNA. A homozygous novel c. 2889delT (p.P963 fs) mutation in the RPGRIP1 gene was identified, which was likely the deleterious and pathogenic mutation in the proband. Structurally, this mutation lost a retinitis pigmentosa GTPase regulator (RPGR)-interacting domain at the C-terminus which most likely impaired stability in the RPGRIP1 with the distribution of polarised proteins in the cilium connecting process. Sanger sequencing showed complete co-segregation in this pedigree. This study provides compelling evidence that the c. 2889delT (p.P963 fs) mutation in the RPGRIP1 gene works as a pathogenic mutation that contributes to the progression of LCA.
Disciplines :
Ophthalmology
Author, co-author :
Imani, Saber; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China ; Hunan Normal University Medical College, Changsha, Hunan, China ; Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Cheng, Jingliang; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Mobasher-Jannat, Abdolkarim; Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran ; Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
Wei, Chunli; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Fu, Shangyi; The Honors College, University of Houston, Houston, TX, USA ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Yang, Lisha; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
Jadidi, Khosrow; Department of Ophthalmology, Baqiyatallah University of Medical Sciences, Tehran, Iran
Khosravi, Mohammad Hossein ; Université de Liège - ULiège ; Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
Mohazzab-Torabi, Saman; Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
Shasaltaneh, Marzieh Dehghan; Laboratory of Neuro-organic Chemistry, Institute of Biochemistry and Biophysics (IBB), University of Tehran, Tehran, Iran ; Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
Li, Yumei; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Chen, Rui; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
Fu, Junjiang ; Key Laboratory of Epigenetics and Oncology, Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China ; Hunan Normal University Medical College, Changsha, Hunan, China
NSCF - National Natural Science Foundation of China
Funding text :
This work was supported in part by the National Natural Science Foundation of China (30371493, 81172049, 81672887), Science and Technology Innovation Team of Colleges and Universities of Sichuan Province in China (13TD0032), the Research Foundation of the Science and Technology Department of Sichuan Province in China (2015JY0038), the Research Foundation of the Education Department of Sichuan Province in China (17ZA0427, 17ZB0467), the Research Foundation of the Science and Technology Department of Liuzhou city in China (2013LZLY-J10, 2015-S-42(3/4)).
Koenekoop RK. An overview of Leber congenital amaurosis: a model to understand human retinal development. Surv Ophthalmol. 2004; 49: 379–98.
Schappert-Kimmijser J, Henkes HE, Van Den Bosch J. Amaurosis congenita (Leber). AMA Arch Ophthalmol. 1959; 61: 211–8.
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.
Berger W, Kloeckener-Gruissem B, Neidhardt J. The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res. 2010; 29: 335–75.
Chacon-Camacho OF, Zenteno JC. Review and update on the molecular basis of Leber congenital amaurosis. World J Clin Cases. 2015; 3: 112–24.
Dharmaraj S, Leroy BP, Sohocki MM, et al. The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations. Arch Ophthalmol. 2004; 122: 1029–37.
Heher KL, Traboulsi EI, Maumenee IH. The natural history of Leber's congenital amaurosis. Age-related findings in 35 patients. Ophthalmology. 1992; 99: 241–5.
Li T. Leber congenital amaurosis caused by mutations in RPGRIP1. Cold Spring Harb Perspect Med. 2014; 5: pii: a017384.
Ahmed E, Loewenstein J. Leber congenital amaurosis: disease, genetics and therapy. Semin Ophthalmol. 2008; 23: 39–43.
Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009; 13: 587–92.
Brecelj J, Stirn-Kranjc B. ERG and VEP follow-up study in children with Leber's congenital amaurosis. Eye. 1999; 13: 47–54.
Koenekoop RK. RPGRIP1 is mutated in Leber congenital amaurosis: a mini-review. Ophthalmic Genet. 2005; 26: 175–9.
Tiwari A, Lemke J, Altmueller J, et al. Identification of novel and recurrent disease-causing mutations in retinal dystrophies using whole exome sequencing (WES): benefits and limitations. PLoS One. 2016; 11: e0158692.
Chiang JP, Lamey T, McLaren T, et al. Progress and prospects of next-generation sequencing testing for inherited retinal dystrophy. Expert Rev Mol Diagn. 2015; 15: 1269–75.
Hu P, Wu S, Yuan L, et al. Compound heterozygous POMT1 mutations in a Chinese family with autosomal recessive muscular dystrophy-dystroglycanopathy C1. J Cell Mol Med. 2017; 21: 1388–93.
Davies WI, Downes SM, Fu JK, et al. Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin. Genet Med. 2012; 14: 891–9.
Xia H, Huang X, Guo Y, et al. Identification of a novel MYO15A mutation in a Chinese family with autosomal recessive nonsyndromic hearing loss. PLoS One. 2015; 10: e0136306.
Carrigan M, Duignan E, Malone CP, et al. Panel-based population next-generation sequencing for inherited retinal degenerations. Sci Rep. 2016; 6: 33248.
Wang F, Wang H, Tuan HF, et al. Next generation sequencing-based molecular diagnosis of retinitis pigmentosa: identification of a novel genotype-phenotype correlation and clinical refinements. Hum Genet. 2014; 133: 331–45.
Imani S, Cheng J, Shasaltaneh MD, et al. Genetic identification and molecular modeling characterization reveal a novel PROM1 mutation in stargardt4-like macular dystrophy. Oncotarget. 2017; In press.
Zhang L, Yang M, Gan L, et al. DLX4 upregulates TWIST and enhances tumor migration, invasion and metastasis. Int J Biol Sci. 2012; 8: 1178–87.
Fu S, Cheng J, Wei C, et al. Development of diagnostic SCAR markers for genomic DNA amplifications in breast carcinoma by DNA cloning of high-GC RAMP-PCR fragments. Oncotarget. 2017; 8: 43866–77.
Fu J, Li L, Lu G. Relationship between microdeletion on Y chromosome and patients with idiopathic azoospermia and severe oligozoospermia in the Chinese. Chin Med J. 2002; 115: 72–5.
Zhou Q, Cheng J, Yang W, et al. Identification of a novel heterozygous missense mutation in the CACNA1F gene in a chinese family with retinitis pigmentosa by next generation sequencing. Biomed Res Int. 2015; 2015: 907827.
Zhu L, Cheng J, Zhou B, et al. Diagnosis for choroideremia in a large Chinese pedigree by next-generation sequencing (NGS) and noninvasive prenatal testing (NIPT). Mol Med Rep. 2017; 53: 1157–64.
Deng H, Deng S, Xu H, et al. Exome sequencing of a pedigree reveals S339L mutation in the TLN2 Gene as a cause of fifth finger camptodactyly. PLoS One. 2016; 11: e0155180.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25: 1754–60.
Challis D, Yu J, Evani US, et al. An integrative variant analysis suite for whole exome next-generation sequencing data. BMC Bioinformatics. 2012; 13: 8.
Psaty BM, O'Donnell CJ, Gudnason V, et al. Cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium: design of prospective meta-analyses of genome-wide association studies from 5 cohorts. Circ Cardiovasc Genet. 2009; 2: 73–80.
Genomes Project C, Abecasis GR, Altshuler D, et al. A map of human genome variation from population-scale sequencing. Nature. 2010; 467: 1061–73.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38: e164.
Tennessen JA, Bigham AW, O'Connor TD, et al. Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012; 337: 64–9.
Xiu X, Yuan J, Deng X, et al. A novel COL4A5 mutation identified in a Chinese Han family using exome sequencing. Biomed Res Int. 2014; 2014: 186048.
Rozen S, Skaletsky H. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol. 2000; 132: 365–86.
Zhang Q, Xu M, Verriotto JD, et al. Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands. Sci Rep. 2016; 6: 32792.
Deng H, Lu Q, Xu H, et al. Identification of a novel Missense FBN2 Mutation in a Chinese family with congenital contractural arachnodactyly using exome sequencing. PLoS One. 2016; 11: e0155908.
Beheshtian M, Saee Rad S, Babanejad M, et al. Impact of whole exome sequencing among Iranian patients with autosomal recessive retinitis pigmentosa. Arch Iran Med. 2015; 18: 776–85.
Koenekoop RK, Wang H, Majewski J, et al. Mutations in NMNAT1 cause Leber congenital amaurosis and identify a new disease pathway for retinal degeneration. Nat Genet. 2012; 44: 1035–9.
Coene KL, Mans DA, Boldt K, et al. The ciliopathy-associated protein homologs RPGRIP1 and RPGRIP1L are linked to cilium integrity through interaction with Nek4 serine/threonine kinase. Hum Mol Genet. 2011; 20: 3592–605.
Dryja TP, Adams SM, Grimsby JL, et al. Null RPGRIP1 alleles in patients with Leber congenital amaurosis. Am J Hum Genet. 2001; 68: 1295–8.
Arts HH, Cremers FP, Knoers NV, Roepman R. Focus on molecules: RPGRIP1. Exp Eye Res. 2009; 88: 332–3.
Khan AO, Al-Mesfer S, Al-Turkmani S, et al. Genetic analysis of strictly defined Leber congenital amaurosis with (and without) neurodevelopmental delay. Br J Ophthalmol. 2014; 98: 1724–8.
Bin Dahman HA, Bin Mubaireek AH, Alhaddad ZH. Joubert syndrome in a neonate: case report with literature review. Sudan J Paediatr. 2016; 16: 53–7.
Lyseng-Williamson KA. Idebenone: a review in Leber's hereditary optic neuropathy. Drugs. 2016; 76: 805–13.
Itchimouh S, Khabtou K, Mahdaoui S, et al. Meckel Gruber syndrome: about a rare case. Pan Afr Med J. 2016; 25: 43.
Li L, Xiao X, Li S, et al. Detection of variants in 15 genes in 87 unrelated Chinese patients with Leber congenital amaurosis. PLoS One. 2011; 6: e19458.
Srilekha S, Arokiasamy T, Srikrupa NN, et al. Homozygosity mapping in Leber congenital amaurosis and autosomal recessive retinitis pigmentosa in South Indian families. PLoS One. 2015; 10: e0131679.
Ozgul RK, Bozkurt B, Kiratli H, Ogus A. Exclusion of LCA5 locus in a consanguineous Turkish family with macular coloboma-type LCA. Eye. 2006; 20: 817–9.
Ahmad A, Daud S, Kakar N, et al. Identification of a novel LCA5 mutation in a Pakistani family with Leber congenital amaurosis and cataracts. Mol Vis. 2011; 17: 1940–5.
Gerber S, Perrault I, Hanein S, 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.
