To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

We identified 7 and 8 new heterozygous pathogenic variants in SPG7 and AFG3L2. Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in AFG3L2 that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the SPG7 variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Our results position SPG7 and AFG3L2 as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

改进最常见的遗传性视神经疾病显性视神经萎缩 (DOA) 的基因诊断，并推断基因型-表型相关性。

在接受眼科、神经病学和脑部 MRI 研究的 DOA 患者中，通过新一代测序筛选了 22 个基因的外显子序列。

我们在SPG7和AFG3L2中鉴定了 7 和 8 个新的杂合致病变异。这两个基因都编码线粒体基质 AAA (m-AAA) 蛋白酶，最初分别参与隐性遗传性痉挛性截瘫 7 型 (HSP7) 和显性脊髓小脑性共济失调 28 (SCA28)。值得注意的是，导致 DOA 的AFG3L2变异与 SCA28 中报告的变异位于不同的域，这可能解释了这两种表型表现之间缺乏临床重叠。相比之下，在 DOA 中鉴定的SPG7变体散布在那些负责 HSP7 的变体中，其中先前已报道视神经病变。

我们的结果将SPG7和AFG3L2定位为在 DOA 中筛选的候选基因，并表明 m-AAA 蛋白酶对线粒体蛋白质稳态和成熟的调节对于视神经生理学的维持至关重要。