Connexin46 mutations in autosomal dominant congenital cataract
Connexin46 mutations in autosomal dominant congenital cataract
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DOI：
10.1086/302383
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发表时间：
1999-05-01
影响因子：
9.8
通讯作者：
Bhattacharya, S
中科院分区：
文献类型：
--
作者：
Mackay, D;Ionides, A;Bhattacharya, S
常染色体显性“带状粉状”白内障的基因座已定位于染色体1q（CZP1）和13q （CZP3）。在这里，我们报告了CZP3位点的遗传改良，并确定了间隙连接蛋白α -3 （GJA3）或连接蛋白46 （Cx46）基因的潜在突变。连锁分析显示，D13S175位点的两点LOD评分(Z)呈显著正相关(最大Z [Z(max)] = > 7.0；最大重组频率[theta(max)] = 0)。单倍型分析表明，CZP3可能位于遗传区间D1381236-D13S175-D13S1316-cen-13pter，接近GJA3。对从CZP3候选区域分离的基因组克隆进行测序，发现一个开放阅读框编码435个氨基酸（47,435 D）的蛋白，与大鼠Cx46具有相似的88%同源性。对两个患有CZP3的家庭的GJA3突变分析发现了明显的序列变化，而这些变化在105个正常、不相关的个体中不存在。在家族B中，A- >G的转变导致密码子63 （N63S）上的天冬酰胺到丝氨酸的替换，并引入了一个新的MwoI限制位点。在E家族中，在核苷酸1137 （1137insC）插入一个C引入了一个新的BstXI位点，导致密码子380处发生移码。限制性分析证实，新的MwoI位点和BstXI位点分别在B和E家族中与疾病共分离。本研究确定GJA3是连接蛋白家族中与人类疾病有关的第六个成员，并强调了缝隙连接通讯在透明晶状体发育中的生理重要性。
Loci for autosomal dominant "zonular pulverulent" cataract have been mapped to chromosomes 1q(CZP1) and 13q (CZP3). Here we report genetic refinement of the CZP3 locus and identify underlying mutations in the gene for gap-junction protein alpha-3 (GJA3), or connexin46 (Cx46). Linkage analysis gave a significantly positive two-point LOD score (Z) at marker D13S175 (maximum Z [Z(max)] = > 7.0; maximum recombination frequency [theta(max)] = 0). Haplotyping indicated that CZP3 probably lies in the genetic interval D1381236-D13S175-D13S1316-cen-13pter, close to GJA3. Sequencing of a genomic clone isolated from the CZP3 candidate region identified an open reading frame coding for a protein of 435 amino acids (47,435 D) that shared similar to 88% homology with rat Cx46. Mutation analysis of GJA3 in two families with CZP3 detected distinct sequence changes that were not present in a panel of 105 normal, unrelated individuals. In family B, an A-->G transition resulted in an asparagine-to-serine substitution at codon 63 (N63S) and introduced a novel MwoI restriction site. In family E, insertion of a C at nucleotide 1137 (1137insC) introduced a novel BstXI site, causing a frameshift at codon 380. Restriction analysis confirmed that the novel MwoI and BstXI sites cosegregated with the disease in families B and E, respectively. This study identities GJA3 as the sixth member of the connexin gene family to be implicated in human disease, and it highlights the physiological importance of gap-junction communication in the development of a transparent eye lens.