Mutation of a Gene Essential for Ribosome Biogenesis, EMG1, Causes Bowen-Conradi Syndrome
Mutation of a Gene Essential for Ribosome Biogenesis, EMG1, Causes Bowen-Conradi Syndrome
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DOI：
10.1016/j.ajhg.2009.04.017
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发表时间：
2009-06-12
影响因子：
9.8
通讯作者：
Triggs-Raine, Barbara
中科院分区：
文献类型：
--
作者：
Armistead, Joy;Khatkar, Sunita;Triggs-Raine, Barbara
Bowen-Conradi综合征（BCS）是一种常染色体隐性遗传疾病，其特征是严重的产前和产后发育障碍、严重的精神发育迟滞和幼儿期死亡。几乎所有报告的BCS病例都发生在赫特人中，估计出生患病率为1/355。我们以前本地化BCS基因在人类染色体12p13.3上的1.9 Mbp的间隔。在这个区间内的59个基因被列为BCS的候选基因，其中35个，包括所有最好的候选基因，被测序。我们鉴定了18 S核糖体组装蛋白EMG 1中的变异体NM-006331.6：c.400A -> G，p.D86G作为BCS的可能原因。这种突变与疾病分离，在414个非Hutterite等位基因中未发现，并改变了高度保守的天冬氨酸（D）残基。人EMG 1的结构模型表明，D86残基与精氨酸84形成盐桥，该盐桥将被甘氨酸（G）取代破坏。EMG 1 mRNA在所有成人和胎儿组织中检测到。在BCS患者成纤维细胞中，EMG 1 mRNA水平与正常细胞没有差异，但与正常对照组相比，EMG 1蛋白显著降低。在哺乳动物细胞中，过表达携带D86 G突变的EMG 1降低了可溶性EMG 1蛋白的水平，在酵母双杂交分析中，D86 G取代增加了EMG 1亚基之间的相互作用。这些发现表明，D-to-G突变导致EMG 1聚集，从而降低蛋白水平并导致BCS。
Bowen-Conradi syndrome (BCS) is an autosomal-recessive disorder characterized by severely impaired prenatal and postnatal growth, profound psychomotor retardation, and death in early childhood. Nearly all reported BCS cases have been among Hutterites, with an estimated birth prevalence of 1/355. We previously localized the BCS gene to a 1.9 Mbp interval on human chromosome 12p13.3. The 59 genes in this interval were ranked as candidates for BCS, and 35 of these, including all of the best candidates, were sequenced. We identified variant NM-006331.6:c.400A -> G, p.D86G in the 18S ribosome assembly protein EMG1 as the probable cause of BCS. This mutation segregated with disease, was not found in 414 non-Hutterite alleles, and altered a highly conserved aspartic acid (D) residue. A structural model of human EMG1 suggested that the D86 residue formed a salt bridge with arginine 84 that would be disrupted by the glycine (G) substitution. EMG1 mRNA was detected in all human adult and fetal tissues tested. In BCS patient fibroblasts, EMG1 mRNA levels did not differ from those of normal cells, but EMG1 protein was dramatically reduced in comparison to that of normal controls. In mammalian cells, overexpression of EMG1 harboring the D86G mutation decreased the level of soluble EMG1 protein, and in yeast two-hybrid analysis, the D86G substitution increased interaction between EMG1 subunits. These findings suggested that the D-to-G mutation caused aggregation of EMG1, thereby reducing the level of the protein and causing BCS.