The Identification and Characterization of the P.G91 Deletion in CRYBA1 in a Chinese Family with Congenital Cataracts

Overview

Journal BMC Med Genet

Publisher Biomed Central

Specialty Genetics

Date 2019 Sep 7

PMID 31488069

Citations 4

Authors

Dan Li

Qinghe Jing

Yongxiang Jiang

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in more than 52 genes have been identified in isolated congenital cataracts, the majority of which are located in crystalline and connexin (gap junction) genes. An in-frame one amino acid deletion in the beta-crystalline gene CRYBA1 has been reported in several different Chinese, Caucasian and Iranian families of congenital cataracts. Further functional studies are needed to confirm the variant pathogenicity.

Methods: The purpose of this study is to identify the genetic causes that contribute to congenital cataracts with esotropia and nystagmus in a Chinese family. Whole-exome sequencing was performed on samples from all five family members. The two brothers of the father and their daughters were then enrolled in the study, and 40 suspected variants were sequenced among the 9 subjects using Sanger sequencing. The mRNA and protein levels of CRYBA1 in the lens epithelium from cataract patients and normal controls were compared using quantitative polymerase chain reaction (qPCR) and Western blot analyses. The wild-type and mutated forms (p.G91del) of CRYBA1 cDNA were transfected into two types of cell lines, and the expression level of exogenous CRYBA1 was measured by Western blot analysis. The exogenous CRYBA1 proteins were visualized by immunofluorescence staining.

Results: In this two-generation family, all three descendants inherited congenital cataracts with esotropia and nystagmus from the father, while the mother's lens was normal. After two rounds of sequencing, CRYBA1 (c. 269-271 del, p.G91del) was identified as the mutation responsible for the autosomal dominant congenital cataract in the Chinese family. CRYBA1 showed lower expression in cataract lenses than in control lenses. The deleted form (p.G91del) of CRYBA1 showed lower expression and was more aggregate to the cell membrane than the wild-type CRYBA1.

Conclusions: We performed molecular experiments to confirm that the p.G91del mutation in CRYBA1 results in abnormal expression and distribution of CRYBA1 protein, and this study could serve as an example of the pathogenicity of an in-frame small deletion in an inherited eye disorder.

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References

Qi Y, Jia H, Huang S, Lin H, Gu J, Su H . A deletion mutation in the betaA1/A3 crystallin gene ( CRYBA1/A3) is associated with autosomal dominant congenital nuclear cataract in a Chinese family. Hum Genet. 2003; 114(2):192-7. DOI: 10.1007/s00439-003-1049-7. View

Lu S, Zhao C, Jiao H, Kere J, Tang X, Zhao F . Two Chinese families with pulverulent congenital cataracts and deltaG91 CRYBA1 mutations. Mol Vis. 2007; 13:1154-60. View

Sun W, Xiao X, Li S, Guo X, Zhang Q . Mutation analysis of 12 genes in Chinese families with congenital cataracts. Mol Vis. 2011; 17:2197-206. PMC: 3159683. View

Zhu Y, Shentu X, Wang W, Li J, Jin C, Yao K . A Chinese family with progressive childhood cataracts and IVS3+1G>A CRYBA3/A1 mutations. Mol Vis. 2010; 16:2347-53. PMC: 2994768. View

Burdon K, Wirth M, Mackey D, Russell-Eggitt I, Craig J, Elder J . Investigation of crystallin genes in familial cataract, and report of two disease associated mutations. Br J Ophthalmol. 2003; 88(1):79-83. PMC: 1771940. DOI: 10.1136/bjo.88.1.79. View

Schwarz J, Cooper D, Schuelke M, Seelow D . MutationTaster2: mutation prediction for the deep-sequencing age. Nat Methods. 2014; 11(4):361-2. DOI: 10.1038/nmeth.2890. View

Gillespie R, OSullivan J, Ashworth J, Bhaskar S, Williams S, Biswas S . Personalized diagnosis and management of congenital cataract by next-generation sequencing. Ophthalmology. 2014; 121(11):2124-37.e1-2. DOI: 10.1016/j.ophtha.2014.06.006. View

Salomon D, Sacco P, Roy S, Simcha I, Johnson K, Wheelock M . Regulation of beta-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin-proteasome system. J Cell Biol. 1998; 139(5):1325-35. PMC: 2140206. DOI: 10.1083/jcb.139.5.1325. View

Yang Z, Li Q, Ma Z, Guo Y, Zhu S, Ma X . A G→T splice site mutation of CRYBA1/A3 associated with autosomal dominant suture cataracts in a Chinese family. Mol Vis. 2011; 17:2065-71. PMC: 3156781. View

10.

Yang G, Zhai X, Zhao J . A recurrent mutation in CRYBA1 is associated with an autosomal dominant congenital nuclear cataract disease in a Chinese family. Mol Vis. 2011; 17:1559-63. PMC: 3115749. View

11.

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. 2017; 54(12):778-783. View

12.

Lovestone S, McLoughlin D . Protein aggregates and dementia: is there a common toxicity?. J Neurol Neurosurg Psychiatry. 2002; 72(2):152-61. PMC: 1737746. DOI: 10.1136/jnnp.72.2.152. View

13.

Gu Z, Ji B, Wan C, He G, Zhang J, Zhang M . A splice site mutation in CRYBA1/A3 causing autosomal dominant posterior polar cataract in a Chinese pedigree. Mol Vis. 2010; 16:154-60. PMC: 2817011. View

14.

Ferrini W, Schorderet D, Othenin-Girard P, Uffer S, Heon E, Munier F . CRYBA3/A1 gene mutation associated with suture-sparing autosomal dominant congenital nuclear cataract: a novel phenotype. Invest Ophthalmol Vis Sci. 2004; 45(5):1436-41. DOI: 10.1167/iovs.03-0760. View

15.

Yang Z, Su D, Li Q, Yang F, Ma Z, Zhu S . A novel T→G splice site mutation of CRYBA1/A3 associated with autosomal dominant nuclear cataracts in a Chinese family. Mol Vis. 2012; 18:1283-8. PMC: 3365137. View

16.

Wang J, Shen Y . When a "disease-causing mutation" is not a pathogenic variant. Clin Chem. 2013; 60(5):711-3. DOI: 10.1373/clinchem.2013.215947. View

17.

Li D, Wang S, Ye H, Tang Y, Qiu X, Fan Q . Distribution of gene mutations in sporadic congenital cataract in a Han Chinese population. Mol Vis. 2016; 22:589-98. PMC: 4896834. View

18.

Thomas M, Maconachie G, Sheth V, McLean R, Gottlob I . Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. Eur J Hum Genet. 2017; 25(6):725-734. PMC: 5477371. DOI: 10.1038/ejhg.2017.44. View

19.

Sergouniotis P, Barton S, Waller S, Perveen R, Ellingford J, Campbell C . The role of small in-frame insertions/deletions in inherited eye disorders and how structural modelling can help estimate their pathogenicity. Orphanet J Rare Dis. 2016; 11(1):125. PMC: 5024463. DOI: 10.1186/s13023-016-0505-0. View

20.

Zhang G, Kang L, Chen J, Xue Y, Yang M, Qin B . CtBP2 Regulates TGFβ2-Induced Epithelial-Mesenchymal Transition Through Notch Signaling Pathway in Lens Epithelial Cells. Curr Eye Res. 2015; 41(8):1057-1063. DOI: 10.3109/02713683.2015.1092554. View