Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed. Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. The proband, in addition to optic atrophy, had neurological symptoms consistent with relapsing remitting multiple sclerosis. Clinical exome analysis detected a novel mutation in the AFG3L2 gene (NM_006796.2:c.1010G > A; p.G337E), which segregated with optic atrophy in family members. AFG3L2 is a metalloprotease of the AAA subfamily which exerts quality control in the inner mitochondrial membrane. Interestingly, the identified mutation localizes close to the AAA domain of AFG3L2, while those localized in the proteolytic domain cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5). Functional studies in patient fibroblasts demonstrate that the p.G337E AFG3L2 mutation strongly destabilizes the long isoforms of OPA1 via OMA hyper-activation and leads to mitochondrial fragmentation, thus explaining the family phenotype. This study widens the clinical spectrum of neurodegenerative diseases caused by AFG3L2 mutations, which shall be considered as genetic cause of ADOA.

中文翻译：

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接近AAA域的新型AFG3L2突变会导致视神经萎缩症患者的OMA1和OPA1异常加工。

常染色体显性遗传性视神经萎缩（ADOA）是一种以神经性双侧视神经变性为特征的神经性眼科疾病。尽管OPA1中的杂合突变是ADOA的最常见遗传原因，但仍有大量病例仍未诊断。在这里，我们描述了一个家族，具有很强的ADOA历史，大多数家族成员跨越三代，从小就出现视觉症状。先证者，除了视神经萎缩外，还具有与复发缓解型多发性硬化症一致的神经系统症状。临床外显子组分析检测到AFG3L2基因的新突变（NM_006796.2：c.1010G> A; p.G337E），该突变与家族成员的视神经萎缩隔离。AFG3L2是AAA亚家族的金属蛋白酶，可控制线粒体内膜。有趣的是 确定的突变位于AFG3L2的AAA结构域附近，而位于蛋白水解结构域的突变导致显性28型脊髓小脑共济失调（SCA28）或隐性痉挛性共济失调伴癫痫（SPAX5）。对患者成纤维细胞的功能研究表明，p.G337E AFG3L2突变会通过OMA过度活化强烈破坏OPA1的长同工型，并导致线粒体断裂，从而解释了家族表型。这项研究拓宽了由AFG3L2突变引起的神经退行性疾病的临床范围，这被认为是ADOA的遗传原因。对患者成纤维细胞的功能研究表明，p.G337E AFG3L2突变会通过OMA过度活化强烈破坏OPA1的长同工型，并导致线粒体断裂，从而解释了家族表型。这项研究拓宽了由AFG3L2突变引起的神经退行性疾病的临床范围，这被认为是ADOA的遗传原因。对患者成纤维细胞的功能研究表明，p.G337E AFG3L2突变会通过OMA过度活化强烈破坏OPA1的长同工型，并导致线粒体断裂，从而解释了家族表型。这项研究拓宽了由AFG3L2突变引起的神经退行性疾病的临床范围，这被认为是ADOA的遗传原因。