Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia; Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia; Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia.
Neurology Department, LR18SP03, Razi Universitary Hospital, Tunis, Tunisia; Clinical Investigation Center (CIC) "Neurosciences and Mental Health", Razi Universitary Hospital, Tunis, Tunisia.
Neurobiol Aging. 2022 Dec;120:27-33. doi: 10.1016/j.neurobiolaging.2022.08.002. Epub 2022 Aug 14.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. To date, mutations in more than 30 genes have been linked to familial ALS forms. However, no mutational screenings have been reported in African populations so far. We aimed to investigate the presence of rare genetic variants in the 4 most common ALS causative genes among a Tunisian cohort. Patients were screened for mutations in SOD1 (exons 1-5), TARDBP (exon 6), FUS (exons 5, 6, 13/14, and 15). Juvenile ALS (JALS) patients were screened also for ALS2 (exons 3, 10, 28). Analysis of C9ORF72 was conducted by fluorescent amplicon-length analysis and repeat-primed PCR. We analyzed 197 Tunisian ALS patients, including 11 familial forms (fALS) with 17 ALS cases, 167 sporadic (sALS) and 13 JALS cases. The pathogenic variant TARDBP p.G294A mutation was reported among 18 patients. Repeat expansion in C9orf72 was recorded in 9 patients. Interestingly, 2 unrelated patients carried a double mutation in both C9orf72 and TARDBP genes. Finally, the p.Asp91Val mutation in SOD1 was identified among 4 cases in homozygous state including 3 sALS and 1 familial JALS with recessive inheritance. No pathogenic variants in FUS were identified, nor ALS2 variants in JALS cases. In our Tunisian cohort the most frequently mutated gene is TARDBP (9.4%), followed by C9orf72 (3.9%) and SOD1 (2.1%). Our study broadens the mutational spectrum in patients with ALS and defines for the first time the mutational frequency of the main ALS genes in patients of African ethnicity.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病。迄今为止，已有 30 多个基因的突变与家族性 ALS 形式有关。然而，迄今为止尚未在非洲人群中报告进行突变筛查。我们旨在调查突尼斯队列中最常见的 4 个 ALS 致病基因中罕见遗传变异的存在。对 SOD1（外显子 1-5）、TARDBP（外显子 6）、FUS（外显子 5、6、13/14 和 15）进行了突变筛选。还对青少年肌萎缩侧索硬化症（JALS）患者进行了 ALS2（外显子 3、10、28）的突变筛选。通过荧光扩增子长度分析和重复引物 PCR 对 C9ORF72 进行了分析。我们分析了 197 名突尼斯 ALS 患者，包括 11 例家族性 ALS（fALS），其中 17 例为 ALS 病例，167 例散发性（sALS）和 13 例 JALS 病例。报告了 18 例患者携带 TARDBP p.G294A 致病性变异。在 9 例患者中记录了 C9orf72 重复扩展。有趣的是，2 例无关联的患者在 C9orf72 和 TARDBP 基因中均携带双突变。最后，在 4 例以纯合状态存在的病例中发现了 SOD1 的 p.Asp91Val 突变，包括 3 例 sALS 和 1 例具有隐性遗传的家族性 JALS。未发现 FUS 的致病性变异，也未发现 JALS 病例的 ALS2 变异。在我们的突尼斯队列中，最常突变的基因是 TARDBP（9.4%），其次是 C9orf72（3.9%）和 SOD1（2.1%）。我们的研究拓宽了 ALS 患者的突变谱，并首次定义了非洲裔患者主要 ALS 基因的突变频率。
