The Translocase of Outer Mitochondrial Membrane (TOMM) complex is the entry gate for virtually all mitochondrial proteins and is essential to build the mitochondrial proteome. TOMM70 is a receptor that assists mainly in mitochondrial protein import. Here, we report two individuals with de novo variants in the C-terminal region of TOMM70. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset. Both individuals were undiagnosed despite extensive genetics workups. Individual 1, was found to have a p.Thr607Ile variant while individual 2 was found to have a p.Ile554Phe variant in TOMM70. To functionally assess both TOMM70 variants, we replaced the Drosophila Tom70 coding region with a Kozak-mini-GAL4 transgene using CRISPR-Cas9. Homozygous mutant animals die as pupae, but lethality is rescued by the mini-GAL4 driven expression of human UAS-TOMM70 cDNA. Both modeled variants lead to significantly less rescue indicating that they are loss-of-function alleles. Similarly, RNAi-mediated knock-down of Tom70 in the developing eye causes roughening and synaptic transmission defect, common findings in neurodegenerative and mitochondrial disorders. These phenotypes were rescued by the reference, but not the variants, of TOMM70. Altogether, our data indicate that de novo loss-of-function variants in TOMM70 result in variable white matter disease and neurological phenotypes in affected individuals.

中文翻译：

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TOMM70（线粒体输入转位酶的受体）的从头突变会导致神经损伤。


线粒体外膜转位酶 (TOMM) 复合体是几乎所有线粒体蛋白的入口，对于构建线粒体蛋白质组至关重要。 TOMM70 是一种主要协助线粒体蛋白质输入的受体。在这里，我们报告了两个在 TOMM70 C 末端区域具有新生变异的个体。虽然两个人都表现出共同的症状，包括肌张力减退、反射亢进、共济失调、肌张力障碍和明显的白质异常，但两个人之间也存在差异，最突出的是症状出现的年龄。尽管进行了广泛的遗传学检查，这两个人仍未得到诊断。在 TOMM70 中，个体 1 被发现具有 p.Thr607Ile 变异，而个体 2 被发现具有 p.Ile554Phe 变异。为了对这两种 TOMM70 变体进行功能评估，我们使用 CRISPR-Cas9 将果蝇 Tom70 编码区替换为 Kozak-mini-GAL4 转基因。纯合突变动物在蛹时死亡，但通过人类 UAS-TOMM70 cDNA 的 mini-GAL4 驱动表达来挽救致死性。两种建模变体都导致救援显着减少，表明它们是功能丧失的等位基因。同样，在发育中的眼睛中，RNAi 介导的 Tom70 敲低会导致眼睛粗糙和突触传递缺陷，这是神经退行性疾病和线粒体疾病中的常见现象。这些表型是由 TOMM70 的参考而非变体拯救的。总而言之，我们的数据表明 TOMM70 的从头功能丧失变异会导致受影响个体的不同白质疾病和神经表型。