Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay.,Journal of Human Genetics

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Mutations in TOMM70 lead to multi-OXPHOS deficiencies and cause severe anemia, lactic acidosis, and developmental delay.
Journal of Human Genetics ( IF 2.6 ) Pub Date : 2020-01-06 , DOI: 10.1038/s10038-019-0714-1
Xiujuan Wei ₁ , Miaomiao Du ₁ , Jie Xie ₁ , Ting Luo ₁ , Yan Zhou ₁ , Kun Zhang ₁ , Jin Li ₁ , Deyu Chen ₁ , Pu Xu ₁ , Manli Jia ₁ , Huaibin Zhou ₁ , Hezhi Fang ₁ , Jianxin Lyu _{1,

2} , Yanling Yang ₃

Affiliation

TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. Here, we identified two compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)] from a patient with severe anemia, lactic acidosis, and developmental delay. Patient-derived immortalized lymphocytes showed decreased TOM70 expression, oligomerized TOM70 complex, and TOM 20/22/40 complex compared with expression in control lymphocytes. Functional analysis revealed that patient-derived cells exhibited multi-oxidative phosphorylation system (OXPHOS) complex defects, with complex IV being primarily affected. As a result, patient-derived cells grew slower in galactose medium and generated less ATP and more extracellular lactic acid than did control cells. In vitro cell model compensatory experiments confirmed the pathogenicity of TOMM70 variants since only wild-type TOM70, but not mutant TOM70, could restore the complex IV defect and TOM70 expression in TOM70 knockdown U2OS cells. Altogether, we report the first case of mitochondrial disease-causing mutations in TOMM70 and demonstrate that TOM70 is essential for multi-OXPHOS assembly. Mutational screening of TOMM70 should be employed to identify mitochondrial disease-causing gene mutations in the future.

中文翻译：

TOMM70 的突变导致多种 OXPHOS 缺乏并导致严重的贫血、乳酸酸中毒和发育迟缓。

TOM70 是 TOM 复合体的成员，可将胞质蛋白转运至线粒体。在这里，我们从一名患有严重贫血、乳酸酸中毒和发育迟缓的患者身上发现了 TOMM70 中的两个复合杂合变体 [c.794C>T (p.T265M) 和 c.1745C>T (p.A582V)]。与对照淋巴细胞中的表达相比，患者来源的永生化淋巴细胞的 TOM70 表达、寡聚化的 TOM70 复合物和 TOM 20/22/40 复合物的表达降低。功能分析显示，患者来源的细胞表现出多氧化磷酸化系统 (OXPHOS) 复合物缺陷，其中复合物 IV 主要受到影响。结果，与对照细胞相比，患者来源的细胞在半乳糖培养基中生长较慢，产生的 ATP 和细胞外乳酸更多。体外细胞模型补偿实验证实了 TOMM70 变体的致病性，因为只有野生型 TOM70 而不是突变型 TOM70 可以恢复 TOM70 敲低 U2OS 细胞中的复杂 IV 缺陷和 TOM70 表达。总之，我们报告了第一例 TOMM70 中引起线粒体疾病的突变，并证明 TOM70 对于多 OXPHOS 组装至关重要。未来应采用 TOMM70 的突变筛选来鉴定线粒体致病基因突变。

更新日期：2020-01-06

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