Department for Human Molecular Genetics, Max-Planck Institute for Molecular Genetics, Berlin, Germany.
Am J Hum Genet. 2011 Sep 9;89(3):407-14. doi: 10.1016/j.ajhg.2011.08.008.
The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3-sialyltransferase-III that in humans predominantly forms the sialyl Lewis a epitope on proteins. ST3GAL3 resides on chromosome 1 within the MRT4 locus previously identified to associate with nonsyndromic autosomal recessive intellectual disability. We searched for the disease-causing mutations in the MRT4 family and a second independent consanguineous Iranian family by using a combination of chromosome sorting and next-generation sequencing. Two different missense changes in ST3GAL3 cosegregate with the disease but were absent in more than 1000 control chromosomes. In cellular and biochemical test systems, these mutations were shown to cause ER retention of the Golgi enzyme and drastically impair ST3Gal-III functionality. Our data provide conclusive evidence that glycotopes formed by ST3Gal-III are prerequisite for attaining and/or maintaining higher cognitive functions.
导致智力表现受损的遗传变异非常多样化，目前仍知之甚少。ST3GAL3 编码的高尔基体酶β-半乳糖苷-α2,3-唾液酸转移酶-III 在人类中主要在蛋白质上形成唾液酸化 Lewis a 表位。ST3GAL3 位于染色体 1 上的 MRT4 基因座内，该基因座先前被确定与非综合征常染色体隐性智力残疾相关。我们通过使用染色体分拣和下一代测序的组合，在 MRT4 家族和第二个独立的伊朗近亲家庭中寻找致病突变。ST3GAL3 中的两个不同的错义变化与疾病共分离，但在 1000 多个对照染色体中不存在。在细胞和生化测试系统中，这些突变导致高尔基体酶的 ER 滞留，并严重损害 ST3Gal-III 的功能。我们的数据提供了确凿的证据，表明 ST3Gal-III 形成的糖基化表位是获得和/或维持更高认知功能的先决条件。
