There is increasing evidence of mitochondrial dysfunction in autism spectrum disorders (ASD), but the causal relationships are unclear. In an ASD patient whose identical twin was unaffected, we identified a postzygotic mosaic mutation p.Q639* in the TRAP1 gene, which encodes a mitochondrial chaperone of the HSP90 family. Additional screening of 176 unrelated ASD probands revealed an identical TRAP1 variant in a male patient who had inherited it from a healthy mother. Notably, newly generated knock-in Trap1 p.Q641* mice display ASD-related behavioral abnormalities that are more pronounced in males than in females. Accordingly, Trap1 p.Q641* mutation also resulted in sex-specific changes in synaptic plasticity, the number of presynaptic mitochondria, and mitochondrial respiration. Thus, the TRAP1 p.Q639* mutation is the first example of a monogenic ASD caused by impaired mitochondrial protein homeostasis.

中文翻译：

---

线粒体伴侣 TRAP1 的突变导致自闭症，男性症状更严重。


越来越多的证据表明自闭症谱系障碍 （ASD） 中存在线粒体功能障碍，但因果关系尚不清楚。在同卵双胞胎未受影响的 ASD 患者中，我们在 TRAP1 基因中鉴定出合子后嵌合突变 p.Q639*，该基因编码 HSP90 家族的线粒体伴侣。对 176 例无关的 ASD 先证者的额外筛查显示，在一名从健康母亲那里遗传的男性患者中，存在相同的 TRAP1 变异。值得注意的是，新生成的敲入 Trap1 p.Q641* 小鼠表现出与 ASD 相关的行为异常，这些异常在雄性中比在雌性中更明显。因此，Trap1 p.Q641* 突变也导致突触可塑性、突触前线粒体数量和线粒体呼吸的性别特异性变化。因此，TRAP1 p.Q639* 突变是由线粒体蛋白稳态受损引起的单基因 ASD 的第一个例子。