V76D mutation in a conserved γD-crystallin region leads to dominant cataracts in mice
V76D mutation in a conserved γD-crystallin region leads to dominant cataracts in mice
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DOI：
10.1007/s00335-002-3021-6
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发表时间：
2002-08-01
期刊：
影响因子：
2.5
通讯作者：
de Angelis, MH
中科院分区：
文献类型：
--
作者：
Graw, J;Löster, J;de Angelis, MH
在大规模的ENU突变筛选中，检测到一个具有显性白内障的小鼠突变体，并将其命名为Aey4。本研究的目的是对该突变体进行形态描述。突变的图谱。以及潜在分子损伤的特征。裂隙灯检查显示出强烈的核性白内障，内皮质有均匀的乳白色混浊。组织学分析显示，整个晶状体中都有残留的细胞核。该突变通过全基因组连锁将6个伽马晶状体蛋白编码基因和紧密连锁的βA2晶状体蛋白编码基因与相关候选基因定位在1号染色体上。最后，GAMMA D-晶状体蛋白编码基因外显子2(符号：Crygd)的T->；A交换被证明是导致白内障表型的原因：这种特殊的突变是。因此，参考Crygo(Aey4)。密码子76的改变导致Val--&Gt；Asp的氨基酸交换。这个位置的Val是高度保守的：它存在于所有小鼠和大鼠的GammaD/E/F-晶状体蛋白中，也存在于人类的GammaA-和GammaD-晶状体蛋白中。它可能会被Ile单独取代。它存在于所有牛的伽马晶体蛋白中，存在于大鼠和小鼠的伽马A/B/C晶体蛋白中，以及存在于人的伽马B/C晶体蛋白中。预测疏水侧链由极性侧链和酸性侧链交换可能通过76位周围10个氨基酸的等电点急剧下降1.5pH单位而影响微环境。Crygd(Aey4)进一步证明了Cryg基因簇的完整性对于晶状体透明性的重要性。
During a large-scale ENU mutagenesis screen, a mouse mutant with a dominant cataract was detected and referred to as Aey4. Aim of this studs was the morphological description of the mutant. the mapping of the mutation. and the characterization of the underlying molecular lesion. The slit-lamp examination revealed a strong nuclear cataract surrounded by a homogeneous milky opacity in the inner cortex. The histological analysis demonstrated remnants of cell nuclei throughout the entire lens. The mutation was mapped to Chromosome 1 by a genome-wide linkage making the six gamma-crystallin encoding genes and the closely linked betaA2-crystallin encoding gene to relevant candidate genes. Finally, a T-->A exchange in exon 2 of the gammaD-crystallin encoding gene (symbol: Crygd) was demonstrated to be causative for the cataract phenotype: this particular mutation is. therefore, referred to Crygo(Aey4) . The alteration in codon 76 leads to an amino acid exchange of Val-->Asp. Val at this position is highly conserved: it is found in all mouse and rat gammaD/E/F-crystallins as well as in the human gammaA- and gammaD-crystallins. It may, be replaced solely by Ile. which is present in all bovine gamma-crystallins, in the rat and mouse gammaA/B/C-crystallins, as well as in the human gammaB/C-crystallins. It is predicted that the exchange of a hydrophobic side chain by a polar and acidic one might influence the microenvironment by a dramatic decrease of the isoelectric point by 1.5 pH units in the 10 amino acids surrounding position 76. The Crygd(Aey4) additionally demonstrates the importance of the integrity of the Cryg gene cluster for lens transparency.