To demonstrate the causal role in disease of the MT-TP m.15992A>T mutation observed in patients from 5 independent families.

Lactate measurement, muscle histology, and mitochondrial activities in patients; PCR-based analyses of the size, amount, and sequence of muscle mitochondrial DNA (mtDNA) and proportion of the mutation; respiration, mitochondrial activities, proteins, translation, transfer RNA (tRNA) levels, and base modification state in skin fibroblasts and cybrids; and reactive oxygen species production, proliferation in the absence of glucose, and plasma membrane potential in cybrids.

All patients presented with severe exercise intolerance and hyperlactatemia. They were associated with prominent exercise-induced muscle swelling, conspicuous in masseter muscles (2 families), and/or with congenital cataract (2 families). MRI confirmed exercise-induced muscle edema. Muscle disclosed severe combined respiratory defect. Muscle mtDNA had normal size and amount. Its sequence was almost identical in all patients, defining the haplotype as J1c10, and sharing 31 variants, only 1 of which, MT-TP m.15992A>T, was likely pathogenic. The mutation was homoplasmic in all tissues and family members. Fibroblasts and cybrids with homoplasmic mutation had defective respiration, low complex III activity, and decreased tRNA^Pro amount. Their respiratory complexes amount and tRNA^Pro aminoacylation appeared normal. Low proliferation in the absence of glucose demonstrated the relevance of the defects on cybrid biology while abnormal loss of cell volume when faced to plasma membrane depolarization provided a link to the muscle edema observed in patients.

The homoplasmic MT-TP m.15992A>T mutation in the J1c10 haplotype causes exercise-induced muscle swelling and fatigue.

为了证明在来自 5 个独立家庭的患者中观察到的MT-TP m.15992A>T 突变在疾病中的因果作用。

患者的乳酸测量、肌肉组织学和线粒体活动；基于 PCR 的肌肉线粒体 DNA (mtDNA) 的大小、数量和序列以及突变比例的分析；皮肤成纤维细胞和胞质体的呼吸、线粒体活动、蛋白质、翻译、转移 RNA (tRNA) 水平和碱基修饰状态；和活性氧的产生，在没有葡萄糖的情况下增殖，以及胞质杂种的质膜电位。

所有患者都出现严重的运动不耐受和高乳酸血症。它们与明显的运动引起的肌肉肿胀有关，在咬肌中很明显（2 个家族），和/或与先天性白内障（2 个家族）有关。MRI证实运动引起的肌肉水肿。肌肉显示严重的联合呼吸缺陷。肌肉mtDNA具有正常大小和数量。它的序列在所有患者中几乎相同，将单倍型定义为 J1c10，共有 31 个变体，其中只有 1 个，MT-TP m.15992A>T，可能是致病的。该突变在所有组织和家庭成员中都是同质的。具有同质突变的成纤维细胞和胞质杂种具有呼吸功能障碍、复合物 III 活性低和 tRNA ^Pro量减少。它们的呼吸复合物数量和tRNA^前氨基酰化出现正常。在没有葡萄糖的情况下低增殖证明了细胞生物学缺陷的相关性，而当面临质膜去极化时细胞体积的异常损失提供了与患者中观察到的肌肉水肿的联系。

J1c10 单倍型中的同质MT-TP m.15992A>T 突变导致运动引起的肌肉肿胀和疲劳。