Zhong Shanshan, Wen Shumeng, Qiu Yusen, Yu Yanyan, Xin Ling, He Yang, Gao Xuguang, Fang Hezhi, Hong Daojun, Zhang Jun
Department of Neurology, Peking University People's Hospital, Beijing, China.
Key Laboratory of Laboratory Medicine, College of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China.
Mol Genet Genomic Med. 2019 Mar;7(3):e541. doi: 10.1002/mgg3.541. Epub 2019 Jan 8.
Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients.
The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis.
The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified.
Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.
异质性线粒体3697G>A突变与Leber遗传性视神经病变（LHON）、线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）以及LHON/MELAS重叠综合征相关。然而，纯质性m.3697G>A突变仅在一个患有Leigh综合征的家族中被发现，该纯质性突变的表型和致病性仍需在新患者中进行研究。
对一个多代遗传家族的12名个体进行了临床访谈。通过外显子组下一代测序筛选突变，随后通过聚合酶链反应-限制性片段长度多态性进行确认。通过生化分析测量线粒体复合物活性和ATP产生率。
患有双侧纹状体坏死（BSN）的男性后代表现为严重的痉挛性肌张力障碍且完全显性，而女性后代症状较轻且显性率较低。所有后代均携带NC_012920.1的纯质性突变：m.3697G>A，p.(Gly131Ser)。生化分析显示复合体I存在孤立缺陷，但男性患者的缺陷程度高于女性患者。ATP产生率也呈现类似模式。然而，未在X染色体上鉴定出可能的修饰基因。
纯质性m.3697G>A突变可能与BSN相关，这扩展了m.3697G>A的临床谱。我们的初步研究未发现支持双重打击假说的潜在修饰因子，而女性患者体内高水平的雌激素可能对突变细胞代谢发挥潜在的补偿作用。
