J Clin Invest. 2021 Mar 15;131(6). doi: 10.1172/JCI147734.
Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disease and in most cases is caused by mutations in mitochondrial DNA-encoded (mtDNA-encoded) respiratory complex I subunit ND1, ND4, or ND6. In this issue of the JCI, Stenton et al. describe biallelic mutations in a nuclear DNA-encoded gene, DNAJC30, establishing recessively inherited LHON (arLHON). Functional studies suggest that DNAJC30 is a protein chaperone required for exchange of damaged complex I subunits. Hallmark mtDNA LHON features were also found in arLHON, including incomplete penetrance, male predominance, and positive response to idebenone therapy. These results extend complex I-deficient phenotypes to include recessively inherited optic neuropathy, with important clinical implications for genetic counseling and therapeutic considerations.
Leber 遗传性视神经病变（LHON）是最常见的线粒体疾病，在大多数情况下是由线粒体 DNA 编码（mtDNA 编码）呼吸复合物 I 亚基 ND1、ND4 或 ND6 的突变引起的。在本期 JCI 中，Stenton 等人描述了一种核 DNA 编码基因 DNAJC30 的双等位基因突变，确立了隐性遗传 LHON（arLHON）。功能研究表明，DNAJC30 是一种蛋白质伴侣，对于交换受损的复合物 I 亚基是必需的。arLHON 也发现了标志性的 mtDNA LHON 特征，包括不完全外显率、男性优势和对 idebenone 治疗的阳性反应。这些结果将复合物 I 缺陷表型扩展到包括隐性遗传性视神经病变，这对遗传咨询和治疗考虑具有重要的临床意义。
