Department of General Paediatrics, University of Münster, Münster, Germany.
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, USA.
Brain. 2019 Aug 1;142(8):2230-2237. doi: 10.1093/brain/awz182.
Superoxide dismutase 1 (SOD1) is the principal cytoplasmic superoxide dismutase in humans and plays a major role in redox potential regulation. It catalyses the transformation of the superoxide anion (O2•-) into hydrogen peroxide. Heterozygous variants in SOD1 are a common cause of familial amyotrophic lateral sclerosis. In this study we describe the homozygous truncating variant c.335dupG (p.C112Wfs*11) in SOD1 that leads to total absence of enzyme activity. The resulting phenotype is severe and marked by progressive loss of motor abilities, tetraspasticity with predominance in the lower extremities, mild cerebellar atrophy, and hyperekplexia-like symptoms. Heterozygous carriers have a markedly reduced enzyme activity when compared to wild-type controls but show no overt neurologic phenotype. These results are in contrast with the previously proposed theory that a loss of function is the underlying mechanism in SOD1-related motor neuron disease and should be considered before application of previously proposed SOD1 silencing as a treatment option for amyotrophic lateral sclerosis.
超氧化物歧化酶 1（SOD1）是人类细胞质中超氧化物歧化酶的主要成分，在氧化还原电势调节中起着重要作用。它催化超氧阴离子（O2•-）转化为过氧化氢。SOD1 的杂合变异是家族性肌萎缩侧索硬化症的常见原因。在这项研究中，我们描述了 SOD1 中导致酶活性完全缺失的纯合截短变体 c.335dupG（p.C112Wfs*11）。由此产生的表型严重，表现为运动能力逐渐丧失、下肢为主的四肢痉挛、轻度小脑萎缩和类肌阵挛样症状。与野生型对照相比，杂合携带者的酶活性明显降低，但没有明显的神经表型。这些结果与先前提出的理论相反，即功能丧失是 SOD1 相关运动神经元疾病的潜在机制，在考虑以前提出的 SOD1 沉默作为肌萎缩侧索硬化症的治疗选择之前，应加以考虑。
