ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions
ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions
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DOI：
10.1016/j.ajhg.2011.08.008
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发表时间：
2011-09-09
影响因子：
9.8
通讯作者：
Kuss, Andreas W.
中科院分区：
文献类型：
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作者：
Hu, Hao;Eggers, Katinka;Kuss, Andreas W.
导致智力表现受损的遗传变异非常多样化，而且人们仍然知之甚少。ST 3GAL 3编码高尔基体酶β-半乳糖苷-α 2，3-唾液酸转移酶-III，其在人类中主要形成蛋白质上的唾液酸刘易斯表位。ST 3GAL 3位于1号染色体MRT 4基因座内，以前被鉴定为与非综合征性常染色体隐性智力残疾相关。我们使用染色体分选和下一代测序相结合的方法，在MRT 4家族和第二个独立的伊朗血缘家族中寻找致病突变。两个不同的错义变化ST 3GAL 3共分离的疾病，但不存在于1000多个控制染色体。在细胞和生物化学测试系统中，这些突变被证明会导致高尔基体酶的ER滞留，并严重损害ST 3Gal-III功能。我们的数据提供了决定性的证据，即由ST 3Gal-III形成的糖表位是获得和/或维持更高认知功能的先决条件。
The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme beta-galactoside-alpha 2,3-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.