1Farabi Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
2Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
3Department of Molecular Biology and Genetics, Islamic Azad University, Bushehr Branch, Bushehr, Iran
4Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
5Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
Objective(s): Childhood cataract is a genetically heterogeneous eye disorder that results in visual impairment. The aim of this study was to identify the genetic mutations of connexin 50 gene among Iranian families suffered from autosomal dominant congenital cataracts (ADCC). Materials and Methods: Families, having at least two members with bilateral familial congenital cataract, were selected for the study. Probands were evaluated by detailed ophthalmologist’s examination, and the pedigree analysis was performed. PCR amplifications were performed corresponding to coding region and intron-exon boundaries of GJA8, a candidate gene responsible for ADCC. PCR products were subjected to bidirectional sequencing, and the co-segregation of identified mutations was examined and finally, the impact of identified mutations on biological functions of GJA8 was predicted by in silico examination. Results: Three different genetic alterations, including c.130G>A (p.V44M), c.301G>T (p.R101L) and c.134G>T (p.W45L) in GJA8 gene were detected among three probands. Two identified mutations, W45L and V44M have been already reported, while the R101L is a novel mutation and its co-segregation was examined. This mutation was exclusively detected in the ADCC and could not be found among the healthy control group. The result of bioinformatic studies of R101L mutation predicted that this amino acid substitution within GJA8 could be a disease-afflicting mutation due to its potential effect on the protein structure and biological function. Conclusion: Our results suggest that mutations of lens connexin genes such as GJA8 gene could be one of the major mechanisms of cataract development, at least in a significant proportion of Iranian patients with ADCC.
1.Yi J, Yun J, Li ZK, Xu CT, Pan BR. Epidemiology and molecular genetics of congenital cataracts. Int J Ophthalmol, 2011; 4:422-432.
2.Mohebi M, Akbari A, Babaei N, Sadeghi A, Heidari M. Identification of a De Novo 3bp Deletion in CRYBA1/A3 Gene in Autosomal Dominant Congenital Cataract. Acta Med Iran 2016;54(12):778-783.
3.Rong X, Ji Y, Fang Y, Jiang Y, Lu Y. Long-Term Visual Outcomes of Secondary Intraocular Lens Implantation in Children with Congenital Cataracts. PLoS One 2015; 10:e0134864.
4.Sukhija J, Kaur S, Ram J. Outcome of a new acrylic intraocular lens implantation in pediatric cataract. J Pediatr Ophthalmol Strabismus 2015; 52:371-376.
5.Umar MM, Abubakar A, Achi I, Alhassan MB, Hassan A. Pediatric cataract surgery in National Eye Centre Kaduna, Nigeria: outcome and challenges. Middle East Afr J Ophthalmol 2015; 22:92-96.
6.Wang M, Xiao W. Congenital cataract: progress in surgical treatment and postoperative recovery of visual function. Eye Sci 2015; 30:38-47.
7.Hejtmancik JF, Smaoui N. Molecular genetics of cataract. Dev Ophthalmol 2003; 37:67-82.
8.Huang B, He W. Molecular characteristics of inherited congenital cataracts. Eur J Med Genet 2010; 53:347-57.
9.Deng H, Yuan L. Molecular genetics of congenital nuclear cataract. Eur J Med Genet 2014; 57:113-122.
10.Garnai SJ, Huyghe JR, Reed DM, Scott KM, Liebmann JM, Boehnke M, et al. Congenital cataracts: de novo gene conversion event in CRYBB2. Mol Vis 2014; 20:1579-1593.
11.He W, Li S. Congenital cataracts: gene mapping. Hum Genet 2000; 106:1-13.
12.Reddy MA, Francis PJ, Berry V, Bhattacharya SS, Moore AT. Molecular genetic basis of inherited cataract and associated phenotypes. Surv Ophthalmol 2004; 49:300-315.
13.Mobini G, Ghahremani M, Amanpour S, Dehpour A, Akbari A, Hoseiniharouni S, et al. Transforming growth factor beta-induced factor 2-linked X (TGIF2LX) regulates two morphogenesis genes, Nir1 and Nir2 in human colorectal. Acta Med Iran 2016; 54:302-307.
14.Akbari A, Ghahremani MH, Mobini GR, Abastabar M, Akhtari J, Bolhassani M, et al. Down-regulation of miR-135b in colon adenocarcinoma induced by a TGF-β receptor I kinase inhibitor (SD-208). Iran J Basic Med Sci 2015; 18:856-861.
15.Yazdi MK, Akbari A, Soltan Dallal MM. Multiplex polymerase chain reaction (PCR) assay for simultaneous detection of shiga-like toxin (stx1 and stx2), intimin (eae) and invasive plasmid antigen H (ipaH) genes in diarrheagenic Escherichia coli. Afr J Biotechnol 2011; 109:1522-1526.
16.Akbari A, Mobini GR, Maghsoudi R, Akhtari J, Faghihloo E, Farahnejad Z. Modulation of transforming growth factor-β signaling transducers in colon adenocarcinoma cells induced by staphylococcal enterotoxin B. Mol Med Rep 2016; 13:909-991.
17.Akbari A, Farahnejad Z, Akhtari J, Abastabar M, Mobini GR, Mehbod AS. Staphylococcus aureus Enterotoxin B Down-Regulates the Expression of Transforming Growth Factor-Beta (TGF-β) Signaling Transducers in Human Glioblastoma. Jundishapur J Microbiol 2016; 9:e27297.
18.Akbari A, Amanpour S, Muhammadnejad S, Ghahremani MH, Gaffari SH, Dehpour AR, et al. Evaluation of antitumor activity of a TGF-beta receptor I inhibitor (SD-208) on human colon adenocarcinoma. Daru J Pharm Sci. 2014;22:47–54.
19.Beyer EC, Berthoud VM. Connexin hemichannels in the lens. Front Physiol 2014; 5:20.
20.Chen C, Sun Q, Gu M, Liu K, Sun Y, Xu X. A novel Cx50 (GJA8) p.H277Y mutation associated with autosomal dominant congenital cataract identified with targeted next-generation sequencing. Graefes Arch Clin Exp Ophthalmol 2015; 253:915-924.
21.Jiang JX. Gap junctions or hemichannel-dependent and independent roles of connexins in cataractogenesis
and lens development. Curr Mol Med 2010; 10:851-863.
22.Li J, Wang Q, Fu Q, Zhu Y, Zhai Y, Yu Y, Zhang K, Yao K. A novel connexin 50 gene (gap junction protein, alpha 8) mutation associated with congenital nuclear and zonular pulverulent cataract. Mol Vis 2013; 19:767-774.
23.Minogue PJ, Tong JJ, Arora A, Russell-Eggitt I, Hunt DM, Moore AT, et al. A mutant connexin50 with enhanced hemichannel function leads to cell death. Invest Ophthalmol Vis Sci 2009; 50:5837-5845.
24.Pfenniger A, Wohlwend A, Kwak BR. Mutations in connexin genes and disease. Eur J Clin Invest 2011; 41:103-116.
25.Rubinos C, Villone K, Mhaske PV, White TW, Srinivas M. Functional effects of Cx50 mutations associated with congenital cataracts. Am J Physiol Cell Physiol 2014; 306:C212-220.
26.Zhu Y, Yu H, Wang W, Gong X, Yao K. Correction: A Novel GJA8 Mutation (p.V44A) Causing Autosomal Dominant Congenital Cataract. PLoS One 2015; 10:e0125949.
27.Zhu Y, Yu H, Wang W, Gong X, Yao K. A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract. PLoS One 2014; 9:e115406.
28.Wang L, Luo Y, Wen W, Zhang S, Lu Y. Another evidence for a D47N mutation in GJA8 associated with autosomal dominant congenital cataract. Mol Vis 2011; 17:2380-2385.
29.Mackay DS, Bennett TM, Culican SM, Shiels A. Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with
inherited cataract. Hum Genomics 2014; 8:19.
30.Ren Q, Riquelme MA, Xu J, Yan X, Nicholson BJ, Gu S, et al. Cataract-causing mutation of human connexin 46 impairs gap junction, but increases hemichannel function and cell death. PLoS One 2013; 8:e74732.
31.Sarkar D, Ray K, Sengupta M. Structure-function correlation analysis of connexin50 missense mutations causing congenital cataract: electrostatic potential alteration could determine intracellular trafficking fate of mutants. Biomed Res Int 2014; 2014:673895.