A novel MAF missense mutation leads to congenital nuclear cataract by impacting the transactivation of crystallin and noncrystallin genes

doi:10.1016/j.gene.2019.01.011

Gene

Volume 692, 15 April 2019, Pages 113-118

https://doi.org/10.1016/j.gene.2019.01.011 Get rights and content

Highlights

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A novel MAF mutation was identified in a Chinese family with congenital non-syndromic bilateral nuclear cataracts.
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The mutation is in highly conserved EHR region of MAF and is predicted to be pathogenic by multiple algorithms.
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It significantly impairs the transcriptional activity of cataracts-associated crystallin and non-crystallin genes.

Abstract

The transcription factor v-maf avain musculoaponeurotic fibrosarcoma oncogene homolog (MAF) plays an important role in lens development. It contains a unique extended homology region (EHR) in the DNA binding domain. MAF mutations are associated with phenotypically distinct forms of congenital cataract and show different effects on the transactivation of target genes. Mutations in the MAF EHR region were rarely reported and their corresponding phenotype and impact on target genes' transactivation were not evaluated. A three- generation Chinese family with congenital cataract was recruited. The patients in the family present non-syndromic congenital nuclear and lamellar opacities. A novel MAF mutation (c.812 T > A, p.Val271Glu) was identified by targeted next-generation sequencing. The mutation is in highly conserved EHR region of MAF and co-segregates with the cataract in the family. It is predicted to be pathogenic by multiple algorithms and is absent in a control population. Dual luciferase activity assay shows the mutation significantly impair the transcriptional activity of four crystallin genes (CRYAA, CRYBA4, CRYBA1, and CRYGA) and two non-crystallin genes (HMOX1 and KDELR2). Herein, we report a novel missense mutation in the MAF EHR region of the DNA binding domain in a family with congenital cataract. The mutation is associated with non-syndromic bilateral nuclear cataract and impacts the transactivation of cataract associated genes involved in lens structure and stress response.

Introduction

Congenital cataract refers to the occurrence of lens opacities at birth or within a year due to the influence of various factors on the development of the lens during the embryonic stage. It is the leading cause of blindness in children and seriously impairs the visual health in newborns, with an estimated incidence 0.01%–0.06% in developed countries (Apple et al., 2000; Gilbert and Foster, 2001). About 1/3 of congenital cataracts are monogenic, and may present as syndromic form or non-syndromic form with prominent phenotypic and genetic heterogeneity (Shiels and Hejtmancik, 2013). To date, >30 genes have been identified as causative in non-syndromic congenital cataract, and at least 150 cataract-associated loci have been reported (Hejtmancik, 2008; Huang and He, 2010; Shiels et al., 2010). Lens development is a complicated process. At the initial stage, the optic vesicle induces nearby surface ectoderm to form the lens placode, and then, the lens placode invaginates and forms a lens vesicle. The cells at the posterior of the vesicle begin to differentiate and elongate to form the lens fiber cells. Eventually, the lens fiber cells lose their nuclei and become transcriptionally silent. Meanwhile, the cells at the anterior of the vesicle undergo limited differentiation and give rise to the lens epithelium. The entire process involves determination, embryonic induction, cellular differentiation, transdifferentiation and regeneration. It requires precise expression of lens structure genes, and other genes involved in response to membrane damage, proteolysis, protein aggregation, and oxidative stress. Transcription factors act as important regulators of the development and differentiation of many organs and tissues. MAF (v-maf avain musculoaponeurotic fibrosarcoma oncogene homolog) is one of the transcriptional factor genes that is responsible for congenital cataract. The Maf family is characterized by a typical basic leucine zipper (bZIP) structure, and is divided into two subgroups, large Maf (MAFA, MAFB, MAF, and NRL) and small Maf (MAFF, MAFG, MAFK). Both subgroups contain DNA binding domains, and large Mafs also have a transactivation domain in the N-terminal (Tsuchiya et al., 2015). Different from other bZIP transcription factors, Mafs contain a highly-conserved extended homology region (EHR) in the DNA binding domain that allows the recognition of longer DNA sequences. However, mutations in EHR associated with cataract were rarely reported, and consequences of target genes transactivation were not evaluated.

Here we identify a novel missense mutation in EHR within the C-terminal DNA binding domain of MAF in a family with congenital nuclear cataract, and show the mutation impairs the transactivation of four crystallin genes (the alpha-crystallin A chain gene, CRYAA; the beta-crystallin A4 gene, CRYBA4; the beta-crystallin A3 gene, CRYBA1; the gamma-crystallin A gene, CRYGA) and two non-crystallin genes (the heme oxygenase1 gene, HMOX1; the ER lumen protein-retaining receptor 2 gene, KDELR2) essential for lens development.

Section snippets

Subjects

This study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Chinese Academy of Medical Sciences. Written informed consent was obtained from all participating individuals or their guardians enrolled in our study. We collected peripheral blood samples from a three-generation Han Chinese family with autosomal dominant cataract for DNA analysis. Diagnosis of cataracts was done based on the medical history or the ocular examinations performed in

Clinical features

We identified a Chinese family with a clear diagnosis of autosomal dominant congenital cataract (ADCC) (Fig. 1A). The proband (III:1) was diagnosed at two years old with bilateral congenital cataract, showing nuclear and lamellar opacities in both eyes (Fig. 1B) with a complaint of decreased visual acuity. The girl underwent surgery shortly after diagnosis and reached a best-corrected visual acuity of 0.8 two years later. The 30-year-old mother (II:2) of the proband was diagnosed with bilateral

Discussion

MAF mutations are rarely reported although it has been >10 years after MAF was identified as the responsible gene for congenital cataract. In the present study, we identified a novel p.Val271Glu mutation in MAF, and provide the genetic and functional evidence to support its pathogenicity in congenital cataract. To date, there are 17 missense mutations reported in patients with congenital cataract and syndromes with cataract as one of the phenotypes (Fig. 1G) (Jamieson et al., 2002; Vanita et

Acknowledgments

We thank all the participants in the study. This work is financially supported by the National Key Research and Development Program of China (2016YFC0905100); the CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-002); the National Science Foundation of China (NSFC) (81741074) and the Science and Technology Funds from Liaoning Education Department (L:2015593).

Declaration of interest statement

The authors declared that they have no conflicts of interest to this work.

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¹: These authors contributed equally to this work.

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Short communicationA novel MAF missense mutation leads to congenital nuclear cataract by impacting the transactivation of crystallin and noncrystallin genes