ArticleBiochimica et biophysica acta2016
Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells.
Article in Biochimica et biophysica acta, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Candidate Genes for Non-Syndromic Pediatric Cataracts.Clinical ophthalmology (Auckland, N.Z.) · 2026Review
- Through theGenes · 2024Review
- Whole Exome Sequencing of 20 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Cataracts.International journal of molecular sciences · 2023Article
- Endoplasmic Reticulum Stress and the Lysosomal Pathway Play Crucial Roles in the Progression of βB2-Crystallin Mutation-Induced Congenital Cataracts in Mice.Investigative ophthalmology & visual science · 2023Article
- Review
- Deficiency of Jamc Leads to Congenital Nuclear Cataract and Activates the Unfolded Protein Response in Mouse Lenses.Investigative ophthalmology & visual science · 2022Article
- αA and αB peptides from human cataractous lenses show antichaperone activity and enhance aggregation of lens proteins.Molecular vision · 2022Article
- LncRNA NEAT1 Recruits SFPQ to Regulate MITF Splicing and Control RPE Cell Proliferation.Investigative ophthalmology & visual science · 2021Article
- Inherited cataracts: Genetic mechanisms and pathways new and old.Experimental eye research · 2021Review
- Involvement of Anoikis in Dissociated Optic Nerve Fiber Layer Appearance.International journal of molecular sciences · 2021Review
- Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis.Translational vision science & technology · 2020Article
- Modulating EGFR-MTORC1-autophagy as a potential therapy for persistent fetal vasculature (PFV) disease.Autophagy · 2020Article
- GJA8 missense mutation disrupts hemichannels and induces cell apoptosis in human lens epithelial cells.Scientific reports · 2019Article
- Biology of Inherited Cataracts and Opportunities for Treatment.Annual review of vision science · 2019Review
- Two novel mutations identified in ADCC families impair crystallin protein distribution and induce apoptosis in human lens epithelial cells.Scientific reports · 2017Article
- Mutations and mechanisms in congenital and age-related cataracts.Experimental eye research · 2017Review
- Lens ER-stress response during cataract development in Mip-mutant mice.Biochimica et biophysica acta · 2016Article
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Authors and funding
6 authors at 2 institutions in 1 country.
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Abstract
βγ-Crystallins, having a uniquely stable two domain four Greek key structure, are crucial for transparency of the eye lens,. Mutations in lens crystallins have been proposed to cause cataract formation by a variety of mechanisms most of which involve destabilization of the protein fold. The underlying molecular mechanism for autosomal dominant zonular cataracts with sutural opacities in an Indian family caused by a c.215+1G>A splice mutation in the βA3/A1-crystallin gene CRYBA1 was elucidated using three transgenic mice models. This mutation causes a splice defect in which the mutant mRNA escapes nonsense mediated decay by skipping both exons 3 and 4. Skipping these exons results in an in-frame deletion of the mRNA and synthesis of an unstable p.Ile33_Ala119del mutant βA3/A1-crystallin protein. Transgenic expression of mutant βA3/A1-crystallin but not the wild type protein results in toxicity and abnormalities in the maturation and orientation of differentiating lens fibers in c.97_357del CRYBA1 transgenic mice, leading to a small spherical lens, cataract, and often lens capsule rupture. On a cellular level, the lenses accumulated p.Ile33_Ala119del βA3/A1-crystallin with resultant activation of the stress signaling pathway - unfolded protein response (UPR) and inhibition of normal protein synthesis, culminating in apoptosis. This highlights the mechanistic contrast between mild mutations that destabilize crystallins and other proteins, resulting in their being bound by the α-crystallins that buffer lens cells against damage by denatured proteins, and severely misfolded proteins that are not bound by α-crystallin but accumulate and have a direct toxic effect on lens cells, resulting in early onset cataracts.
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