Abstract
Congenital cataract (CC) is a clinical and genetically heterogeneous eye disease that primarily causes lens disorder and even amblyopic blindness in children. As the mechanism underlying CC is genetically inherited, identification of CC-associated gene mutations and their role in protein distribution are topics of both pharmacological and biological research. Through physical and ophthalmic examinations, two Chinese pedigrees with autosomal dominant congenital cataract (ADCC) were recruited for this study. Mutation analyses of CC candidate genes by next-generation sequencing (NGS) and Sanger sequencing revealed a novel missense mutation in CRYBB2 (p.V146L) and a deletion mutation in CRYAA (p.116_118del). Both mutations fully co-segregated were not observed in unaffected family members or in 100 unrelated healthy controls. The CRYBB2 missense mutation disrupts the distribution of CRYBB2 in human lens epithelial cells (HLEpiCs), and the CRYAA deletion mutation causes hyperdispersion of CRYAA. Furthermore, these two crystallin mutations result in aberrant expression of unfolded protein response (UPR) marker genes as well as apoptosis in HLEpiCs. Collectively, these findings broaden the genetic spectrum of ADCC.
Highlights
Congenital cataract (CC) is a major cause of infant blindness and remains a significant health-care burden in children worldwide[1,2]
In keeping with these findings, the R49C missense mutation in αA-crystallin is related to upregulation of the PERK unfolded protein response (UPR) pathway in the mouse lens, leading to apoptosis[16], and variable activation of UPR is observed with the Cx50 mutant (S50P, G22R) in mice[27]
Our results demonstrate that the CRYBB2 and CRYAA mutations lead to apoptosis in human lens epithelial cells due to UPR
Summary
Congenital cataract (CC) is a major cause of infant blindness and remains a significant health-care burden in children worldwide[1,2]. Ma et al found that splicing mutations in the human βA3/A1-crystallin gene CRYBA1 result in severe misfolding of the protein and activate the UPR stress pathway and eventually apoptosis[26] In keeping with these findings, the R49C missense mutation in αA-crystallin is related to upregulation of the PERK UPR pathway in the mouse lens, leading to apoptosis[16], and variable activation of UPR is observed with the Cx50 mutant (S50P, G22R) in mice[27]. Functional analysis showed that the CRYBB2 mutation appears to abolish βB2-crystallin solubility and stabilization, leading to protein aggregation in human lens epithelial cells, whereas the CRYAA deletion mutation causes abnormal protein distribution. Our results demonstrate that the CRYBB2 and CRYAA mutations lead to apoptosis in human lens epithelial cells due to UPR
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