Dense nuclear cataract caused by the gammaB-crystallin S11R point mutation.
Dense nuclear cataract caused by the gammaB-crystallin S11R point mutation.
复制标题
由 gammaB-晶状体蛋白 S11R 点突变引起的致密核白内障。
DOI：
10.1167/iovs.07-0942
复制
发表时间：
2008
影响因子：
4.4
通讯作者：
Gong,Xiaohua
中科院分区：
文献类型：
--
作者：
Li,Lin;Chang,Bo;Cheng,Catherine;Chang,Da;Hawes,NormanL;Xia,Chun-hong;Gong,Xiaohua
目的。鉴定小鼠新显性白内障的致病基因突变，并研究突变基因如何导致致密核性白内障的分子基础。全基因组连锁分析和DNA测序用于确定基因突变。使用组织学、免疫组织化学和蛋白质印迹来表征晶状体表型。通过电感耦合等离子体发射光谱仪 (ICP-OES) 测量离子浓度。结果。在该白内障小鼠品系中发现了 γB-晶状体蛋白基因的点突变（A 到 C），该突变导致 γB-S11R 突变蛋白。纯合突变小鼠出现了与内部晶状体纤维细胞破坏相关的致密核白内障。免疫组织化学数据显示，γ-晶状体蛋白聚集在失去肌动蛋白丝的内部成熟纤维的细胞边界处。蛋白质印迹显示与核性白内障相关的晶状体蛋白降解增加。 ICP-OES 证实突变晶状体中钙浓度显着升高。结论。这种显性白内障是由 γB-S11R 突变引起的。突变的 γB-S11R 蛋白触发了 γ-晶状体蛋白聚集，可能破坏了内部纤维细胞的膜细胞骨架结构，导致钙流入增加。随后激活钙依赖性蛋白质降解和内部成熟纤维细胞的变性导致致密核白内障。
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 γB-crystallin gene, which results in the γB-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 γ-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 γB-S11R mutation. Mutant γB-S11R proteins triggered the γ-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.