Zhang Lu, Qu Xin, Su Sheng, Guan Linan, Liu Ping
Eye Hospital, the First Affiliated Hospital, Harbin Medical University, Harbin, China.
Mol Vis. 2012;18:2114-8. Epub 2012 Jul 26.
To identify the potential pathogenic mutation over five generations of a Chinese family with congenital Coppock-like cataracts (CCL).
We investigated five generations of a Chinese family affected with CCL. The family resides in a relatively isolated region of northern China. Peripheral blood samples were collected from all of the family members, and genomic DNA was then extracted from the blood samples. A genome-wide linkage scan was performed using about 400 microsatellite markers. Two-point LOD (linkage odd disequilibrium) scores (Z) were calculated using the LINKAGE programs (ver. 5.1). Cyrillic software processed the resulting haplotypes. Mutation detection was performed in the candidate gene by direct sequencing.
The maximum LOD score was obtained at marker D13S175 (lod score [Z(max)]=5.90; recombination fraction [θ]=0.0). Haplotype analysis traced the disease gene to a 6.99-cM interval bounded by D13S1316 and D13S1275 on chromosome 13q12.11. Direct sequencing of the candidate gene GJA3 (gap junction protein alpha-3) revealed a c.427G>A transition in exon 2 of GJA3 that co-segregated with the cataract in the family members and was not observed in 100 control patients. This single-nucleotide change resulted in the substitution of a highly conserved glycine by arginine (G143R).
The present study identified a novel mutation in GJA3 that causes CCL. As the first report to relate p.G143R mutation in GJA3, it expands the mutation spectrum of GJA3. Our report is the first in identification of the mutation of GJA3 in the cytoplasmic-loop domain. This mutation is associated with multiple members of a five-generation family with congenital CCL.
鉴定一个患有先天性类科波克氏白内障（CCL）的中国家系五代人中的潜在致病突变。
我们调查了一个患有CCL的中国家系的五代人。该家系居住在中国北方一个相对隔离的地区。从所有家庭成员采集外周血样本，然后从血样中提取基因组DNA。使用约400个微卫星标记进行全基因组连锁扫描。使用LINKAGE程序（版本5.1）计算两点LOD（连锁不平衡）分数（Z）。西里尔软件处理所得单倍型。通过直接测序在候选基因中进行突变检测。
在标记D13S175处获得最大LOD分数（LOD分数[Z（最大值）]=5.90；重组分数[θ]=0.0）。单倍型分析将疾病基因定位到13q12.11染色体上由D13S1316和D13S1275界定的6.99厘摩区间。候选基因GJA3（间隙连接蛋白α-3）的直接测序显示GJA3外显子2中有一个c.427G>A转换，该转换与家庭成员中的白内障共分离，在100名对照患者中未观察到。这个单核苷酸变化导致一个高度保守的甘氨酸被精氨酸取代（G143R）。
本研究鉴定出GJA3中的一个新突变，该突变导致CCL。作为首次报道GJA3中p.G143R突变，它扩展了GJA3的突变谱。我们的报告是首次鉴定出GJA3在细胞质环结构域的突变。该突变与一个患有先天性CCL的五代家系的多个成员相关。
