Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

Abstract

Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype-phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

The genetic landscape of crystallins in congenital cataract

“…To date, 308 disease-causing variants have been found in total in the crystallins, accounting for nearly 23.0% of all inherited cataract variants ( Fig. 1) [5,17]. In this study, we have undertaken whole-exome sequencing (WES) in order to identify pathogenic variants underlying autosomal dominant congenital cataract (ADCC) in five large families of British origin and five sporadic cases from our ADCC panel.…”

Variants in PAX6, PITX3 and HSF4 Causing Autosomal Dominant Congenital Cataract

“…Congenital cataract are clinically and genetically heterogeneous, displaying various phenotypes [1]. So far nearly 50 genes have been found causing mostly isolated congenital cataracts broadly including genes encoding lens soluble proteins -crystallins; membrane proteins-gap junctions, aquaporins, receptor tyrosine kinase gene EPH receptor A2, an endoplasmic reticulum membrane-embedded protein, Wolframin, chromatin modifying protein-4B, lens integral membrane protein; AQP0, Connexin 50 and LIM2 cytoskeletal proteins-filensin, phakinin, vimentin and genes encoding transcription or developmental factors EYA1, MAF, FOXE3, VSX2, PAX6, PITX3 and HSF4 (https :// cat-map.wustl.edu/) [2][3][4].…”

Mutations in PIKFYVE cause autosomal dominant congenital cataract

“…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).…”