A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family
A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family
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CX46 中一种新的移码突变与中国家族遗传性显性白内障相关
DOI：
10.18240/ijo.2017.05.04
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发表时间：
2017-05-18
影响因子：
1.4
通讯作者：
Hu, Yan-Zhong
中科院分区：
文献类型：
--
作者：
Cui, Xiu-Kun;Zhu, Ke-Ke;Hu, Yan-Zhong
目的：目的：研究一个中国人遗传性常染色体显性白内障家系的基因突变情况，方法：对一个5代共20例白内障患者（男9例，女11例）和2例正常对照者进行遗传学分析，确定为一个典型的常染色体显性白内障家系。基因组DNA样本是从该家系参与者的外周血细胞中提取的。外显子测序用于基因突变筛查。利用计算机模拟技术研究了连接蛋白46（CX46）突变体的结构特征。结果：选择11个已知的白内障相关基因（cryaa、cryab、crybb 1、crybb 2、crygc、crygd、Gja 3、Gja 8、Hsf 4、Mip和Pitx 3），采用外显子测序法进行基因突变检测。CX46 cDNA第1195位的一个新的胞嘧啶插入（c. 1194_1195 insC），但在2例正常白内障患者和正常对照组中均未发现，这导致CX46的C端（cx46 fs 400）比野生型CX46多延伸30个氨基酸。计算机蛋白结构分析表明，与野生型CX 46相比，突变体显示出独特的疏水性和蛋白质二级结构。免疫印迹结果显示，在老化白内障透镜组织中表达的CX 46蛋白在先证者透镜中缺失。相比之下，CX 50、α A-晶状体蛋白和α B-晶状体蛋白在先证者和老化性白内障组织中表达相等。结论：CX46 cDNA第1195位胞嘧啶插入突变是一个新的突变位点，与该家系的常染色体显性遗传性白内障有关。C端移码突变参与调控CX46蛋白表达。
AIM: To investigate the genetic mutations that are associated the hereditary autosomal dominant cataract in a Chinese family.METHODS: A Chinese family consisting of 20 cataract patients (including 9 male and 11 female) and 2 unaffected individuals from 5 generations were diagnosed to be a typical autosomal dominant cataract pedigree. Genomic DNA samples were extracted from the peripheral blood cells of the participants in this pedigree. Exon sequence was used for genetic mutation screening. In silico analysis was used to study the structure characteristics of connexin 46 (CX46) mutant. Immunoblotting was conduceted for testing the expression of CX46.RESULTS: To determine the involved genetic mutations, 11 well-known cataract-associated genes (cryaa, cryab, crybb1, crybb2, crygc, crygd, Gja3, Gja8, Hsf4, Mip and Pitx3) were chosen for genetic mutation test by using exon sequencing. A novel cytosine insertion at position 1195 of CX46 cDNA (c. 1194_ 1195ins C) was found in the samples of 5 tested cataract patients but not in the unaffected 2 individuals nor in normal controls, which resulted in 30 amino acids more extension in CX46C-terminus (cx46fs400) compared with the wild-type CX46. In silico protein structure analysis indicated that the mutant showed distinctive hydrophobicity and protein secondary structure compared with the wild-type CX46. The immunoblot results revealed that CX46 protein, which expressed in the aging cataract lens tissues, was absence in the proband lens. In contrast, CX50, alpha A-crystallin and alphaB-crystallin expressed equally in both proband and aging cataract tissues. Those results revealed that the cx46fs400 mutation could impair CX46 protein expression.CONCLUSION: The insertion of cytosine at position 1195 of CX46 cDNA is a novel mutation site that is associated with the autosomal dominant cataracts in this Chinese family. The C-terminal frameshift mutation is involved in regulating CX46 protein expression.