Ezer Shlomit, Daana Muhannad, Park Julien H, Yanovsky-Dagan Shira, Nordström Ulrika, Basal Adily, Edvardson Simon, Saada Ann, Otto Markus, Meiner Vardiella, Marklund Stefan L, Andersen Peter Munch, Harel Tamar
Department of Genetics, Hadassah Medical Organization, Jerusalem 9112001, Israel.
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Brain. 2022 Apr 29;145(3):872-878. doi: 10.1093/brain/awab416.
Pathogenic variants in SOD1, encoding superoxide dismutase 1, are responsible for about 20% of all familial amyotrophic lateral sclerosis cases, through a gain-of-function mechanism. Recently, two reports showed that a specific homozygous SOD1 loss-of-function variant is associated with an infantile progressive motor-neurological syndrome. Exome sequencing followed by molecular studies, including cDNA analysis, SOD1 protein levels and enzymatic activity, and plasma neurofilament light chain levels, were undertaken in an infant with severe global developmental delay, axial hypotonia and limb spasticity. We identified a homozygous 3-bp in-frame deletion in SOD1. cDNA analysis predicted the loss of a single valine residue from a tandem pair (p.Val119/Val120) in the wild-type protein, yet expression levels and splicing were preserved. Analysis of SOD1 activity and protein levels in erythrocyte lysates showed essentially no enzymatic activity and undetectable SOD1 protein in the child, whereas the parents had ∼50% protein expression and activity relative to controls. Neurofilament light chain levels in plasma were elevated, implying ongoing axonal injury and neurodegeneration. Thus, we provide confirmatory evidence of a second biallelic variant in an infant with a severe neurological syndrome and suggest that the in-frame deletion causes instability and subsequent degeneration of SOD1. We highlight the importance of the valine residues at positions V119-120, and suggest possible implications for future therapeutics research.
编码超氧化物歧化酶1的SOD1基因的致病性变异，通过功能获得机制，导致了约20%的家族性肌萎缩侧索硬化病例。最近，两项报告显示，一种特定的纯合SOD1功能丧失变异与一种婴儿进行性运动神经综合征有关。对一名患有严重全面发育迟缓、轴性肌张力减退和肢体痉挛的婴儿进行了外显子组测序，随后进行了分子研究，包括cDNA分析、SOD1蛋白水平和酶活性以及血浆神经丝轻链水平。我们在SOD1中鉴定出一个纯合的3个碱基对的框内缺失。cDNA分析预测野生型蛋白中一对串联的缬氨酸残基（p.Val119/Val120）会缺失一个，但表达水平和剪接得以保留。对红细胞裂解物中的SOD1活性和蛋白水平进行分析显示，该患儿基本没有酶活性且检测不到SOD1蛋白，而其父母的蛋白表达和活性相对于对照组约为50%。血浆中的神经丝轻链水平升高，这意味着存在持续的轴突损伤和神经变性。因此，我们为一名患有严重神经综合征的婴儿中存在的第二个双等位基因变异提供了确证，并表明框内缺失导致了SOD1的不稳定性及随后的变性。我们强调了V119 - 120位缬氨酸残基的重要性，并提出了对未来治疗研究可能的影响。
