Molecular genetics of congenital cataracts

Li, Jinyu; Chen, Xiangjun; Yan, Yong-Bin; Yao, Ke

doi:10.1016/j.exer.2019.107872

Cited by 76 publications

(72 citation statements)

References 211 publications

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“…Cataracts, which are the leading cause of blindness worldwide, are produced by protein misfolding and aggregation ( Lee et al, 2017 ). Genetic mutation and environmental stress can affect the protein-folding process, resulting in protein misfolding and, in turn, disruption of lens protein stability, solubility, and interactions ( Fu et al, 2021 ; Li et al, 2020 ; Xu et al, 2021 ; Yang et al, 2020b ). Crystallins are the most important structural proteins in the lens and contain two superfamilies: i.e., α-crystallins and β/γ-crystallins.…”

Section: Introductionmentioning

confidence: 99%

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

Jia

Wang

et al. 2021

Zoological Research

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As small heat shock proteins, α-crystallins function as molecular chaperones and inhibit the misfolding and aggregation of β/γ-crystallins. Genetic mutations of CRYAA are associated with protein aggregation and cataract occurrence. One possible process underlying cataract formation is that endoplasmic reticulum stress (ERS) induces the unfolded protein response (UPR), leading to apoptosis. However, the pathogenic mechanism related to this remains unexplored. Here, we successfully constructed a cataract-causing CRYAA (Y118D) mutant mouse model, in which the lenses of the CRYAA-Y118D mutant mice showed severe posterior rupture, abnormal morphological changes, and aberrant arrangement of crystallin fibers. Histological analysis was consistent with the clinical pathological characteristics. We also explored the pathogenic factors involved in cataract development through transcriptome analysis. In addition, based on key pathway analysis, up-regulated genes in CRYAA-Y118D mutant mice were implicated in the ERS-UPR pathway. This study showed that prolonged activation of the UPR pathway and severe stress response can cause proteotoxic and ERS-induced cell death in CRYAA-Y118D mutant mice.

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Section: Introductionmentioning

confidence: 99%

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

Jia

Wang

et al. 2021

Zoological Research

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“…Opacity of the lens prevents light from entering the eye, thereby stunting the retinas and optic nerves and leading to amblyopia or blindness. About a quarter of CC cases are caused by genetic factors [ 1 , 2 ], and other pathogenic mechanisms include infection and trauma [ 3 ]. Congenital heart disease (CHD) is one of the most common congenital malformations in humans [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

“…The aetiology involves both environmental and genetic factors [ 5 ]. The lens and heart belong to different systems and develop from different germ layers; the lens develops from the ectoderm [ 3 ] and the heart develops from the mesoderm [ 6 ]. Despite these differences, some clinicians have made key observations suggesting that they may be linked.…”

Section: Introductionmentioning

confidence: 99%

“…Some aetiological bases, including genetic mutations, underlying CC and CHD have been revealed respectively. More than 100 genes and nearly 200 loci have been identified in monogenic forms of CC [ 3 ]. Copy number variation (CNV), leading to the deletion or duplication of functional DNA fragments, is one of the main genetic mechanisms underlying CHD.…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genetic findings in patients with congenital cataract and heart diseases

Song

et al. 2021

Orphanet J Rare Dis

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Background Congenital cataract (CC) and congenital heart disease (CHD) are significant birth defects. In clinical practice, the concurrence of CC and CHD is frequently observed in patients. Additionally, some monogenic diseases, copy number variation (CNV) syndromes, and diseases associated with intrauterine infection involve both cataract and heart defects. However, little is known about the association between CC and CHD. Here, we characterised the demographic, clinical, and genetic features of patients with CC and heart defects. Methods Medical records for 334 hospitalised patients diagnosed with CC were reviewed. Demographic and clinical features of patients with CC with and without CHD were compared. Clinical and genomic information for patients with ‘cataract’ and ‘cardiac defects’ were reviewed from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). Microarray-based comparative genomic hybridisation and whole-exome sequencing were performed in 10 trio families with CC and CHD to detect de novo genomic alterations, including copy number variants and single nucleotide changes. Results In a retrospective analysis of 334 patients with CC over the past 10 years at our hospital, we observed a high proportion of patients (41.13%) with CHD (including innocent CHD, which reported as left-to-right shunt in echocardiography test). The CC with CHD group had higher incidences of preterm birth and Down’s syndrome than the CC without CHD group. Atrial septal defect was the most frequent heart defect. A total of 44 cases with cataracts and heart diseases were retrieved from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). In total, 52 genomic alterations were reported, 44% of which were de novo germline variants. In the 10 trio families with CC and CHD, we found de novo CNVs responsible for two well-known chromosomal disorders and identified a novel pathogenic mutation in GJA8 responsible for CC. Conclusions We observed significant associations between CHD and CC in our 10-year patient cohort. Based on the cohort and data from DECIPHER, developmental syndromes in some patients were due to genetic defects, thus explaining the concurrence of CC and CHD. Additionally, we detected de novo mutations as an independent cause of cataracts. Our findings suggest that developmental syndromes in patients with CC deserve more attention in clinical practice by ophthalmologists.

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“…A variety of factors, including gene mutations that affect lens metabolism are closely associated with cataract (J. Li, Chen, Yan, & Yao, 2020), and autosomal dominant congenital cataract is the most common mode of inheritance (Berry, Georgiou, et al, 2020). To date, mutations in at least 50 genes involved in lens structure and development have been linked to isolated congenital cataract (Berry, Ionides, et al, 2020;Shiels & Hejtmancik, 2017), including crystallin genes (CRYAA, CRYAB, CRYBB1, CRYBB2, CRYBB3, CRYBA1/A3, CRYBA2, CRYBA4, CRYGC, CRYGD and CRYGS) (Bhat, 2003;Zhuang et al, 2019), membrane protein genes (GJA3, GJA8, MIP and LIM2) (Berry, Francis, Kaushal, Moore, & Bhattacharya, 2000;Beyer, Ebihara, & Berthoud, 2013;Pei et al, 2020), growth and transcription factor genes (PITX3, MAF and HSF4) (Anand, Agrawal, Slavotinek, & Lachke, 2018), beaded filament structural protein genes (BFSP1 and BFSP2) (Song et al, 2009) and other genes (CHMP4B and EPHA2) (Dave et al, 2016;Shiels et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Mutations in PIKFYVE cause autosomal dominant congenital cataract

Wang

et al. 2021

Preprint

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Congenital cataract, an ocular disease predominantly occurring within the first decade of life, is one of the leading causes of blindness in children. Through whole exome sequencing of a Chinese family with congenital cataract, we identified a disease-causing mutation (p.G1943E) in PIKFYVE, which affecting the PIP kinase domain of the PIKfyve protein. We demonstrated that heterozygous/homozygous disruption of PIKfyve kinase domain, instead of overexpression of PIKFYVEG1943E in zebrafish mimicked the cataract defect in human patients, suggesting that haploinsufficiency, rather than dominant-negative inhibition of PIKfyve activity caused the disease. Phenotypical analysis of pikfyve zebrafish mutants revealed that loss of Pikfyve caused aberrant vacuolation (accumulation of Rab7+Lc3+ amphisomes) in lens cells, which was significantly alleviated by treatment with the V-ATPase inhibitor bafilomycin A1 (Baf-A1). Collectively, we identified PIKFYVE as a novel causative gene for congenital cataract and demonstrated the potential application of Baf-A1 in treatment of congenital cataract.

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Molecular genetics of congenital cataracts

Cited by 76 publications

References 211 publications

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

Cataract-causing allele in CRYAA (Y118D) proceeds through endoplasmic reticulum stress in mouse model

Clinical and genetic findings in patients with congenital cataract and heart diseases

Mutations in PIKFYVE cause autosomal dominant congenital cataract

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