Pei Rui, Liang Peng-Fei, Ye Wei, Li Ji, Ma Ji-Yuan, Zhou Jian
Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, China.
Int J Ophthalmol. 2020 Oct 18;13(10):1512-1520. doi: 10.18240/ijo.2020.10.02. eCollection 2020.
To identify mutations in the genes of a four-generation Chinese family with congenital membranous cataracts and investigate the morphologic changes and possible functional damage underlying the role of the mutant gene.
Whole exome analysis of thirteen members of a four-generation pedigree affected with congenital membranous cataracts was performed; co-segregation analysis of identified variants was validated by Sanger sequencing. All members underwent detailed physical and complete eye examinations. The physical changes caused by the mutation were analyzed in silico through homology modeling. The lens fiber block from a patient was observed under a scanning electron microscope (SEM). Cell membrane proteins and cytoplasmic proteins from the human lenses donated by one patient with cataract in this family and from the dislocated lens resulted from the penetrating ocular trauma of a patient unrelated with this family were extracted, and the expression and localization of MP20 and Cx46 were detected by Western blot (WB) assay in these proteins.
A novel heterozygous mutation (c.388C>T, p.R130C) was identified with congenital membranous cataracts inherited by an autosomal dominant (AD) pattern. Nystagmus and amblyopia were observed in all patients of this family, and exotropia and long axial length were observed in most patients. A/B ultrasound scan and ultrasound biomicroscopy revealed obvious thin crystalline lenses from 1.7 to 2.7 mm in central thickness in all cataract eyes. The bioinformatic analysis showed that the mutation was deleterious to the physiological function of -encoded MP20. Furthermore, by SEM, ultrastructure of the cataract nucleus showed that lens fiber cells (LFCs) remained morphologic characteristics of immature fiber cells, including flap cell surface with straight edges and lacking normal ball-and-socket joint boundaries, which implied that the differentiation of LFCs might be inhibited. Accumulation of MP20 and Cx46 in the cytoplasm was observed in the cytoplasm of the LFCs in human cataract lens.
We identify a novel heterozygous (c.388C>T, p.R130C) mutation inherited by an AD pattern. This mutation causes the abnormal sub-localization of MP20 and Cx46 in LFCs resulting in membranous cataracts.
鉴定一个患有先天性膜性白内障的四代中国家系的基因突变，并研究突变基因作用下的形态学变化及可能的功能损害。
对一个患有先天性膜性白内障的四代家系的13名成员进行全外显子组分析；通过Sanger测序验证已鉴定变异的共分离分析。所有成员均接受详细的体格检查和全面的眼部检查。通过同源建模在计算机上分析由该突变引起的物理变化。在扫描电子显微镜（SEM）下观察一名患者的晶状体纤维块。提取该家系中一名白内障患者捐献的人晶状体以及一名与该家系无关的患者因穿透性眼外伤导致的脱位晶状体的细胞膜蛋白和细胞质蛋白，并通过蛋白质免疫印迹（WB）分析检测这些蛋白中MP20和Cx46的表达及定位。
鉴定出一种新的杂合突变（c.388C>T，p.R130C），其以常染色体显性（AD）模式遗传导致先天性膜性白内障。该家系所有患者均观察到眼球震颤和弱视，大多数患者观察到外斜视和眼轴长度过长。A/B超声扫描和超声生物显微镜检查显示，所有白内障眼的晶状体中央厚度明显变薄，为1.7至2.7毫米。生物信息学分析表明，该突变对编码的MP20的生理功能有害。此外，通过SEM观察，白内障核的超微结构显示晶状体纤维细胞（LFCs）保持未成熟纤维细胞的形态特征，包括细胞表面有直边的片状结构且缺乏正常的球窝关节边界，这表明LFCs的分化可能受到抑制。在人类白内障晶状体的LFCs细胞质中观察到MP20和Cx46在细胞质中积累。
我们鉴定出一种新的以AD模式遗传的杂合（c.388C>T，p.R130C）突变。这种突变导致MP20和Cx46在LFCs中异常亚定位，从而导致膜性白内障。
