Human βA3/A1-crystallin splicing mutation causes cataracts by activating the unfolded protein response and inducing apoptosis in differentiating lens fiber cells

摘要: 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 variety mechanisms most which involve destabilization protein fold. The underlying molecular mechanism autosomal dominant zonular cataracts with sutural opacities an Indian family caused c.215+1G>A splice mutation βA3/A1-crystallin gene CRYBA1 was elucidated using three transgenic mice models. This causes defect mutant mRNA escapes nonsense mediated decay skipping both exons 3 and 4. Skipping these results in-frame deletion synthesis unstable p.Ile33_Ala119del protein. Transgenic expression but not wild type toxicity abnormalities maturation orientation differentiating fibers c.97_357del mice, leading small spherical lens, cataract, often capsule rupture. On cellular level, lenses accumulated resultant activation stress signaling pathway - unfolded response (UPR) inhibition normal synthesis, culminating apoptosis. highlights mechanistic contrast between mild mutations that destabilize other proteins, resulting their being bound α-crystallins buffer cells against damage denatured severely misfolded proteins α-crystallin accumulate direct toxic effect on cells, early onset cataracts.