Autosomal dominant coralliform cataract related to a missense mutation of the γD-crystallin gene

Background Congenital cataract is a sight-threatening disease that affects about 1-6 cases per 10000 live births and causes 10%-30% of all blindness in children About 25% of all cases are due to genetic defects We identified autosomal dominant congenital coralliform cataracts-related genetic defect in a four-generation Chinese family Methods Complete ophthalmological examinations were performed prior to lens extraction Lens samples were then studied by electron microscopy Genomic DNA from family members were examined using whole-genomic linkage analysis, with two-point logarithm of odds (LOD) scores calculated using the Linkage program package (version 5 1) Mutation analysis of candidate genes was performed by direct sequencing Finally, a three-dimensional protein model was predicted using Swiss-Model (version 2 0) Results Eleven of the 23 examined individuals had congenital cataracts Ultrastructure studies revealed crystal deposits in the lens, and granules extensively dispersed in transformed lens fiber cells The maximum two-point LOD score, 3 5 at θ=0 1, was obtained for the marker D2S325 Mutation analysis of the γ-crystallin (CRYG) gene cluster identified a mutation (P23T) in exon 2 of γD-crystallin (CRYGD) Protein structure modeling demonstrated that the P23T mutation caused a subtle change on the surface of the γD protein Conclusions The results suggest that the coralliform cataract phenotype is due to a mutated CRYGD gene, and that this sequence change is identical to one reported by Santhiya to be related to another distinct clinical condition, lamellar cataract This study provides evidence that this same genetic defect may be associated with a different phenotype This is the first report identifying the genetic defect associated with an autosomal dominant congenital coralliform cataract

先天性白内障家系中γD晶体蛋白P23T突变意义的生物信息学分析

本研究前期工作发现在一个遗传性先天性白内障家系中,γD晶体蛋白发生了P23T突变.因此本研究对γD晶体蛋白及其突变体进行了氨基酸序列分析,结构域预测及立体结构模拟等生物信息学研究,以探讨P23T突变对γD晶体蛋白结构与功能的影响.研究结果表明:P23T突变可能影响人γD晶体蛋白与钙离子的结合,导致晶状体内钙离子动态失衡;可以使蛋白分子间形成氢键,降低晶体蛋白溶解度;并使蛋白质表面局部极性的改变,影响蛋白与其它分子的结合.

遗传性珊瑚状白内障突变晶状体蛋白分子构型及超微结构分析

目的:探讨珊瑚状遗传性白内障家系P23T突变的γD晶状体蛋白与病变晶状体结构的关系。方法:记录晶状体摘除术前的晶状体裂隙灯照片;应用SWISS-MODEL程序,建立人γD晶状体蛋白及其P23T突变体的计算机立体结构模型;透射和扫描电镜观测晶状体提取物。结果:蛋白立体结构模型分析发现,P23T的突变降低了蛋白最终分子总势能,使蛋白表面结构发生改变。电镜检查发现,白内障晶状体内有大小不等的结晶片和异常的卵圆形结构,晶状体上皮细胞出现裂解。结论:γD晶状体蛋白P23T突变体可能与晶状体内异常结晶片和晶状体上皮细胞的病理改变有关,其发生机制还有待分子动力学的研究。

特殊表型先天性白内障小鼠晶状体中细胞缝隙连接蛋白的表达

目的观察γD-晶状体蛋白点突变导致的小鼠先天性白内障表型,检测该特殊表型先天性白内障小鼠晶状体中细胞缝隙连接蛋白(Cx)的表达。方法观察突变小鼠出生后不同时间晶状体的形态学变化;应用免疫荧光染色法分析晶状体内Cx46和Cx50的表达和分布。结果突变小鼠模型呈稳定一致的显性遗传,出生后7 d即表现为明显的核性白内障,出生后21 d纯合子小鼠晶状体混浊严重,后囊膜自然破裂;免疫荧光染色分析发现突变小鼠晶状体内Cx46和Cx50的表达均出现下降,越靠近晶状体中心部下降越明显。结论γD-晶状体蛋白点突变可导致晶状体后囊膜破裂这种特殊表型的先天性白内障,白内障的形成和后囊膜破裂的产生与晶状体内Cx46和Cx50的表达下降有关。