m.3290T >c变异体可能是抵抗致病性m.3243的保护因子bbbbg变体：一个案例研究

The m.3290T > C variant might be a protective factor against the pathogenic m.3243 A > G variant: a case study

m.3290T >c变异体可能是抵抗致病性m.3243的保护因子bbbbg变体：一个案例研究

Authors: Ning Zhang, Zhikang Zhang, Ying Zhang, Xun Su, Yuzhou Gao, Jing Yang, Weiwei Zou, Dongmei Ji, Yunxia Cao

Source: Orphanet Journal of Rare Diseases

PMID:  40514671

DOI:  10.1186/s13023-025-03774-5

Abstract

The mitochondrial m.3243 A > G variant is a prevalent mitochondrial disease mutation that causes multisystem maternal inheritance disorders. While clinical severity typically correlates with mutation load, symptom manifestation may be influenced by other variants and environmental factors. Notably, the m.3290T > C variant has been hypothesized as a potential protective variant for m.3243 A > G pathogenicity, though clinical evidence remains limited. Here we reported a six-generation Chinese pedigree carrying both m.3243 A > G and homoplasmic m.3290T > C variants. Clinical and genetic analyses revealed that carriers with extremely high m.3243 A > G heteroplasmy (> 95%) exhibited severe symptoms, whereas those with moderate or high levels showed limited or no clinical symptoms. Our findings provide novel evidence for the protective role of m.3290T > C in mitigating m.3243 A > G pathogenicity, highlighting its potential clinical significance.

Keywords: MELAS; Mitochondrial DNA; Mitochondrial disease; m.3243A > G; m.3290T > C.

摘要：

线粒体中的 m.3243 A > G 变异是一种常见的线粒体疾病突变，会导致多系统母系遗传疾病。虽然临床严重程度通常与突变负荷相关，但症状表现可能受到其他变异和环境因素的影响。值得注意的是，m.3290T > C 变异曾被推测为 m.3243 A > G 致病性的一个潜在保护性变异，但临床证据仍有限。在此，我们报道了一个携带 m.3243 A > G 和同质性 m.3290T > C 变异的六代中国人家系。临床和遗传分析表明，具有极高 m.3243 A > G 异质性（>95%）的携带者表现出严重的症状，而那些具有中等或较高水平的则表现出有限或没有临床症状。我们的发现为 m.3290T > C 在减轻 m.3243 A > G 致病性方面所起的保护作用提供了新的证据，突显了其潜在的临床意义。

关键词：MELAS；线粒体 DNA；线粒体疾病；m.3243A > G；m.3290T > C。