Screening the pathogenic causes of congenital cataract via whole exome sequencing technology in three families: <br />Molecular genetics of congenital cataract

Qi,Chenyang; He,Yunxuan; Jiang,Chun; Zhang,Xiaoxue; Zhu,Peiran; Li,Weiwei; Zhou,Hongjian; Xue,Chunyan; Xia,Xinyi

doi:10.3892/mmr.2023.13008

Screening the pathogenic causes of congenital cataract via whole exome sequencing technology in three families:
Molecular genetics of congenital cataract

Authors:
- Chenyang Qi
- Yunxuan He
- Chun Jiang
- Xiaoxue Zhang
- Peiran Zhu
- Weiwei Li
- Hongjian Zhou
- Chunyan Xue
- Xinyi Xia
View Affiliations

Affiliations: College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu 210002, P.R. China, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China, Department of Ophthalmology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, P.R. China
Published online on: May 10, 2023 https://doi.org/10.3892/mmr.2023.13008
Article Number: 121
Copyright: © Qi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Congenital cataract is the commonest cause of visual impairment and blindness in children worldwide. Among congenital cataract cases, ~25% are caused by genetic defects, while several genetic mutations have been identified in hereditary cataract. In the present study, a patient with cataract underwent clinical ophthalmic examination and pedigree analysis. Whole exome sequencing and Sanger sequencing were performed to identify and verify gene mutations. The frequency, conservation, pathogenicity and hydrophobicity of the mutated amino acids were analyzed by bioinformatics analysis. The clinical examination and investigation verified that the probands of family A and C suffered from nuclear cataracts. In addition, the proband of family B was diagnosed with white punctate opacity. The pattern of inheritance was autosomal dominant. The sequencing analysis results revealed a mutation c.592-c593insG (p.W198Wfs*22) in exon 6 of CRYBA1/A3, a known mutation c.463C > T (p.Q155X) in exon 6 of CRYBB2 and a third mutation c.865‑c.866insC (p.T289Tfs*91) in exon 2 of GJA8. Each variant was co‑segregated with disease in family And the mutation frequency in the database was <0.01. It has been reported that the mutation sites are highly conserved among different species, thus greatly affecting the sequence and structure of a protein, while exhibiting high pathogenicity in theory. The two crystallin gene mutations could notably enhance the local hydrophobicity of the protein, eventually resulting in its reduced solubility and destruction of lens transparency. The current study identified pathogenic genes in three families with congenital cataract and analyzed the association between mutation sites and different cataract phenotypes. Overall, the results could expand the genotype spectrum of congenital cataract and provide evidence for its clinical diagnosis.

View Figures

View References

1	Sun W, Xiao X, Li S, Guo X and Zhang Q: Exome sequencing of 18 Chinese families with congenital cataracts: A new sight of the NHS gene. PLoS One. 9:e1004552014. View Article : Google Scholar : PubMed/NCBI
2	Li J, Chen X, Yan Y and Yao K: Molecular genetics of congenital cataracts. Exp Eye Res. 191:1078722020. View Article : Google Scholar : PubMed/NCBI
3	Jiao X, Khan SY, Irum B, Khan AO, Wang Q, Kabir F, Khan AA, Husnain T, Akram J, Riazuddin S, et al: Correction: missense mutations in CRYAB are liable for recessive congenital cataracts. PLoS One. 12:e01714032017. View Article : Google Scholar : PubMed/NCBI
4	Kumar M, Agarwal T, Kaur P, Kumar M, Khokhar S and Dada R: Molecular and structural analysis of genetic variations in congenital cataract. Mol Vision. 19:2436–2450. 2013.PubMed/NCBI
5	Khan I, Chandani S and Balasubramanian D: Structural study of the G57W mutant of human gamma-S-crystallin, associated with congenital cataract. Mol Vis. 22:771–782. 2016.PubMed/NCBI
6	Yue B, Haddad BG, Khan U, Chen H, Atalla M, Zhang Z, Zuckerman DM, Reichow SL and Bai D: Connexin 46 and connexin 50 gap junction channel properties are shaped by structural and dynamic features of their N-terminal domains. J Physiol. 599:3313–3335. 2021. View Article : Google Scholar : PubMed/NCBI
7	Valiunas V, Brink PR and White TW: Lens connexin channels have differential permeability to the second messenger cAMP. Invest Ophthalmol Vis Sci. 60:3821–3829. 2019. View Article : Google Scholar : PubMed/NCBI
8	Brink PR, Valiunas V and White TW: Lens connexin channels show differential permeability to signaling molecules. Int J Mol Sci. 21:69432020. View Article : Google Scholar : PubMed/NCBI
9	Berry V, Ionides A, Pontikos N, Georgiou M, Yu J, Ocaka LA, Moore AT, Quinlan RA and Michaelides M: The genetic landscape of crystallins in congenital cataract. Orphanet J Rare Dis. 15:3332020. View Article : Google Scholar : PubMed/NCBI
10	Mothobi ME, Guo S, Liu Y, Chen Q, Yussuf AS, Zhu X and Fang Z: Mutation analysis of congenital cataract in a Basotho family identified a new missense allele in CRYBB2. Mol Vis. 15:1470–1475. 2009.PubMed/NCBI
11	Pauli S, Söker T, Klopp N, Illig T, Engel W and Graw J: Mutation analysis in a German family identified a new cataract-causing allele in the CRYBB2 gene. Mol Vis. 13:962–967. 2007.PubMed/NCBI
12	Micheal S, Niewold ITG, Siddiqui SN, Zafar SN, Khan MI and Bergen AAB: Delineation of novel autosomal recessive mutation in GJA3 and autosomal dominant mutations in GJA8 in Pakistani congenital cataract families. Genes (Basel). 9:1122018. View Article : Google Scholar : PubMed/NCBI
13	Li H and Homer N: A survey of sequence alignment algorithms for next-generation sequencing. Brief Bioinform. 11:473–483. 2010. View Article : Google Scholar : PubMed/NCBI
14	Li H and Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 25:1754–1760. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ghoneim DH, Myers JR, Tuttle E and Paciorkowski AR: Comparison of insertion/deletion calling algorithms on human next-generation sequencing data. BMC Res Notes. 7:8642014. View Article : Google Scholar : PubMed/NCBI
16	Bateman JB, von-Bischhoffshaunsen FR, Richter L, Flodman P, Burch D and Spence MA: Gene conversion mutation in crystallin, beta-B2 (CRYBB2) in a Chilean family with autosomal dominant cataract. Ophthalmology. 114:425–432. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hegde S, Kesterson RA and Srivastava OP: CRYβA3/A1-crystallin knockout develops nuclear cataract and causes impaired lysosomal cargo clearance and calpain activation. PLoS One. 11:e01490272016. View Article : Google Scholar : PubMed/NCBI
18	Hejtmancik JF: Congenital cataracts and their molecular genetics. Semin Cell Dev Biol. 19:134–149. 2008. View Article : Google Scholar : PubMed/NCBI
19	Yang Z, Li Q, Ma Z, Guo Y, Zhu S and Ma X: A G→T splice site mutation of CRYBA1/A3 associated with autosomal dominant suture cataracts in a Chinese family. Mol Vis. 17:2065–2071. 2011.PubMed/NCBI
20	Ni SH, Zhang JM and Zhao J: A novel missense mutation of CRYBA1 in a northern Chinese family with inherited coronary cataract with blue punctate opacities. Eur J Ophthalmol. 32:193–199. 2022. View Article : Google Scholar : PubMed/NCBI
21	Weisschuh N, Aisenbrey S, Wissinger B and Riess A: Identification of a novel CRYBB2 missense mutation causing congenital autosomal dominant cataract. Mol Vis. 18:174–180. 2012.PubMed/NCBI
22	Litt M, Carrero-Valenzuela R, LaMorticella DM, Schultz DW, Mitchell TN, Kramer P and Maumenee IH: Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human β-crystallin gene CRYBB2. Hum Mol Genet. 6:665–668. 1997. View Article : Google Scholar : PubMed/NCBI
23	Gill D, Klose R, Munier FL, McFadden M, Priston M, Billingsley G, Ducrey N, Schorderet DF and Héon E: Genetic heterogeneity of the Coppock-like cataract: A mutation in CRYBB2 on chromosome 22q11.2. Invest Ophthalmol Vis Sci. 41:159–165. 2000.PubMed/NCBI
24	Vanita, Sarhadi V, Reis A, Jung M, Singh D, Sperling K, Singh JR and Bürger J: A unique form of autosomal dominant cataract explained by gene conversion between beta-crystallin B2 and its pseudogene. J Med Genet. 38:392–396. 2001. View Article : Google Scholar : PubMed/NCBI
25	Valiunas V and White TW: Connexin43 and connexin50 channels exhibit different permeability to the second messenger inositol triphosphate. Sci Rep. 10:87442020. View Article : Google Scholar : PubMed/NCBI
26	Xin L and Bai D: Functional roles of the amino terminal domain in determining biophysical properties of Cx50 gap junction channels. Front Physiol. 4:3732013. View Article : Google Scholar : PubMed/NCBI
27	Meşe G, Richard G and White TW: Gap junctions: Basic structure and function. J Invest Dermatol. 127:2516–2524. 2007. View Article : Google Scholar : PubMed/NCBI
28	Zheng JQ, Ma ZW and Sun HM: A heterozygous transversion of connexin 50 in a family with congenital nuclear cataract in the northeast of China. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 22:76–78. 2005.PubMed/NCBI
29	Berry V, Mackay D, Khaliq S, Francis PJ, Hameed A, Anwar K, Mehdi SQ, Newbold RJ, Ionides A, Shiels A, et al: Connexin 50 mutation in a family with congenital ‘zonular nuclear’ pulverulent cataract of Pakistani origin. Hum Genet. 105:168–170. 1999. View Article : Google Scholar : PubMed/NCBI
30	Berry V, Ionides A, Pontikos N, Moghul I, Moore AT, Quinlan RA and Michaelides M: Whole exome sequencing reveals novel and recurrent disease-causing variants in lens specific gap junctional protein encoding genes causing congenital cataract. Genes. 11:5122020. View Article : Google Scholar : PubMed/NCBI
31	Li L, Fan DB, Zhao YT, Li Y, Yang ZB and Zheng GY: GJA8 missense mutation disrupts hemichannels and induces cell apoptosis in human lens epithelial cells. Sci Rep. 9:191572019. View Article : Google Scholar : PubMed/NCBI
32	Ponnam SP, Ramesha K, Tejwani S, Ramamurthy B and Kannabiran C: Mutation of the gap junction protein alpha 8 (GJA8) gene causes autosomal recessive cataract. J Med Genet. 44:e852007. View Article : Google Scholar : PubMed/NCBI
33	Hadrami M, Bonnet C, Veten F, Zeitz C, Condroyer C, Wang P, Biya M, Sidi Ahmed MA, Zhang Q, Cheikh S, et al: A novel missense mutation of GJA8 causes congenital cataract in a large Mauritanian family. Eur J Ophthalmol. 29:621–628. 2019. View Article : Google Scholar : PubMed/NCBI
34	Ceroni F, Aguilera-Garcia D, Chassaing N, Bax DA, Blanco-Kelly F, Ramos P, Tarilonte M, Villaverde C, da Silva LRJ, Ballesta-Martínez MJ, et al: New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies. Hum Genet. 138:1027–1042. 2019. View Article : Google Scholar : PubMed/NCBI
35	Devi RR and Vijayalakshmi P: Novel mutations in GJA8 associated with autosomal dominant congenital cataract and microcornea. Mol Vis. 12:190–195. 2006.PubMed/NCBI