Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.
Neurol Sci. 2022 Oct;43(10):6087-6090. doi: 10.1007/s10072-022-06229-y. Epub 2022 Jun 22.
ALS symptoms have been previously described only in the context of ATXN2 CAG expansions, whereas missense mutations of the gene have never been described in ALS patients.
We identified a novel missense mutation (c.2860C > T) of ATXN2, for which in silico analysis showed a possible pathogenic effect on protein expression, in a patient presenting an aggressive disease phenotype.
Our findings raise the possibility for unknown genetic factors interacting with ATXN2 mutations, or for an autonomous pathogenic role for this specific point mutation in ATXN2 gene in driving the clinical phenotype toward ALS. We also found that stress granules in the fibroblasts from the patient entrapped higher amounts of defective ribosomal products compared to fibroblasts from three healthy subjects, suggesting that ATXN2 mutation-related toxicity may have implication in protein quality control.
先前仅在 ATXN2 CAG 扩展的背景下描述了 ALS 症状，而该基因的错义突变从未在 ALS 患者中描述过。
我们在一位表现出侵袭性疾病表型的患者中发现了 ATXN2 的一种新的错义突变（c.2860C>T），该突变的计算机分析显示可能对蛋白质表达产生致病性影响。
我们的发现提出了一种可能性，即未知的遗传因素与 ATXN2 突变相互作用，或者该特定点突变在 ATXN2 基因中具有自主的致病性作用，导致临床表型向 ALS 发展。我们还发现，与三名健康受试者的成纤维细胞相比，患者的成纤维细胞中的应激颗粒困住了更多的有缺陷的核糖体产物，这表明 ATXN2 突变相关的毒性可能对蛋白质质量控制有影响。
