Dense nuclear cataract caused by the gamma B-crystallin S11R point mutation

作者：Li Lin; Chang Bo; Cheng Catherine; Chang Da; Hawes Norman L; Xia Chun Hong; Gong Xiaohua^*

来源：Investigative Ophthalmology & Visual Science, 2008, 49(1): 304-309.

DOI：10.1167/iovs.07-0942

PURPOSE. To identify the causative gene mutation for a new dominant cataract in mice and to investigate the molecular basis for how the mutated gene leads to a dense nuclear cataract.
METHODS. Genomewide linkage analysis and DNA sequencing were used to determine the gene mutation. Histology, immunohistochemistry, and Western blotting were used to characterize lens phenotypes. Ion concentrations were measured by an inductively coupled plasma-optical emission spectrometer (ICP-OES).
RESULTS. A point mutation (A to C) of the gamma B-crystallin gene, which results in the gamma B-S11R mutant protein, was identified in this cataractous mouse line. Homozygous mutant mice developed dense nuclear cataracts associated with disrupted inner lens fiber cells. Immunohistochemistry data revealed gamma-crystallin aggregates at the cell boundaries of inner mature fibers that lose actin filaments. Western blotting showed an increased degradation of crystallin proteins correlated with the nuclear cataract. ICP-OES confirmed a substantial elevation of calcium concentration in mutant lenses.
CONCLUSIONS. This dominant cataract was caused by the gamma B-S11R mutation. Mutant gamma B-S11R proteins triggered the gamma-crystallin aggregation that probably disrupted membrane-cytoskeleton structures of inner fiber cells, causing increased calcium influxes. Subsequent activation of calcium-dependent protein degradation and degeneration of inner mature fiber cells led to the dense nuclear cataract.

• 出版日期2008-1