Beth Israel Deaconess Medical Center, Departments of Pathology and Neurology, Harvard Medical School, Boston, MA 02215, USA.
Sci Transl Med. 2011 Oct 5;3(103):103ra97. doi: 10.1126/scitranslmed.3002627.
People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism--maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)--affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.
患有自闭症谱系障碍的人表现为社交互动受损、沟通减少以及重复性行为增加。该疾病具有重要的遗传成分，最近的研究表明，一些个体中经常出现基因组拷贝数变异（CNVs）。在自闭症患者中，1%至 3%的人会出现一种常见的 CNV——母源 15q11-13 重复（dup15）和三重复制（等臂染色体额外染色体，idic15）——该 CNV 会影响几个被认为是自闭症行为特征基础的基因。为了验证这一点，我们使其中一个基因——仅在成熟神经元中从母源等位基因表达的泛素蛋白连接酶 Ube3a——的剂量增加三倍，并在小鼠中重新构建了三个核心自闭症特征：社交互动受损、沟通障碍和重复性刻板行为增加。这些自闭症特征的出现率取决于 Ube3a 基因的拷贝数。在 Ube3a 基因剂量增加的动物中，由于突触前释放概率、突触谷氨酸浓度和突触后动作电位耦合减少，谷氨酸能而非 GABA 能突触传递受到抑制。这些结果表明，Ube3a 基因剂量可能导致患有母源 15q11-13 重复的个体的自闭症特征，并支持增加 E3A 泛素连接酶基因剂量会导致兴奋性突触传递减少的观点。
