Guleria Kamlesh, Sperling Karl, Singh Daljit, Varon Raymonda, Singh Jai Rup, Vanita Vanita
Centre for Genetic Disorders, Guru Nanak Dev University, Amritsar, India.
Mol Vis. 2007 Sep 11;13:1657-65.
To identify the genetic defect in an autosomal dominant congenital cataract family (ADCC), having 18 individuals in four generations affected with embryonal cataract.
A genome wide scan using the GeneChip Human Mapping 10K Array, version 2 was performed on DNA samples from eight affected and two unaffected members of an ADCC family having 18 members in four generations affected with embryonal cataract. The region of potential linkage delimited by single nucleotide polymorphic (SNP) markers was analyzed using fluorescently labeled microsatellite markers. Mutation screening was performed in the candidate gene by bidirectional sequencing of amplified products.
By whole genome screening linkage in this family, the genetic defect was located to a region of chromosome 13q11 which contains the candidate gene connexin 46 (GJA3) for ADCC. Sequencing of the coding region of GJA3 showed a novel heterozygous 98G>T change resulting in the substitution of highly conserved arginine by leucine at codon 33 (R33L), located in the first transmembrane domain of GJA3. This nucleotide change was not seen in any unaffected members of this family nor in 50 unrelated control subjects.
The present study describes a novel mutation (R33L) in the GJA3 associated with finely granular embryonal cataract. These findings expand the mutation spectrum of GJA3 in association with congenital cataract.
在一个常染色体显性遗传性先天性白内障家系（ADCC）中鉴定遗传缺陷，该家系四代中有18人患有胚胎性白内障。
使用GeneChip Human Mapping 10K Array 2版本对一个ADCC家系的DNA样本进行全基因组扫描，该家系四代中有18人患有胚胎性白内障，其中8名患者和2名未患病成员参与检测。使用荧光标记的微卫星标记分析由单核苷酸多态性（SNP）标记界定的潜在连锁区域。通过对扩增产物进行双向测序，在候选基因中进行突变筛查。
通过对该家系进行全基因组筛查连锁分析，遗传缺陷定位于13号染色体q11区域，该区域包含ADCC的候选基因连接蛋白46（GJA3）。GJA3编码区测序显示一个新的杂合98G>T变化，导致位于GJA3第一个跨膜结构域的第33位密码子处高度保守的精氨酸被亮氨酸取代（R33L）。该家系任何未患病成员以及50名无关对照受试者中均未发现这种核苷酸变化。
本研究描述了一个与细颗粒状胚胎性白内障相关的GJA3新突变（R33L）。这些发现扩展了与先天性白内障相关的GJA3突变谱。
