Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, 20 Chazhong Road, Fuzhou, 350005, China.
Fujian Key Laboratory of Molecular Neurology, Fuzhou, China.
BMC Neurol. 2018 Apr 5;18(1):35. doi: 10.1186/s12883-018-1028-1.
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China.
Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients.
Two TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 ± 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 ± 41.8 months (n = 8).
We found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival.
肌萎缩侧索硬化症（ALS）是一种破坏性的运动神经元疾病，具有显著的临床和遗传异质性。迄今为止，中国仅报道了少数 TARDBP-ALS 家系，而在东南地区尚未报道其突变分析。
通过 Sanger 测序对 SOD1 和 FUS 突变阴性的 7 个 ALS 家系的索引病例进行 TARDBP 基因外显子 2-6 的筛选。在 215 例散发性 ALS 患者中分析 TARDBP 外显子 6。
在 5 个无关家系中发现了 TARDBP 外显子 6 中的 2 个突变（p.M337V 和 p.G348C）。这 5 个家系中有 4 个携带相同的 p.M337V 突变（家系 1II3、家系 2II6、家系 3II4 和家系 4II4），而 p.G348C 突变则在家系 5（II5）中发现。在 215 例散发性患者中，仅在 5 例患者中检测到单个核苷酸多态性（p.A366A），未发现责任突变。在 TARDBP 相关家族性 ALS 患者中，发病年龄的平均值为 57.0±4.7 岁，延髓（50.0%，6/12）和上肢（41.7%，5/12）起病率较高，而肢体起病率较低（8.3%，1/12）。此外，TARDBP 突变的 ALS 患者表现出良性的疾病进程，平均生存时间为 106.5±41.8 个月（n=8）。
我们在东南地区的家族性 ALS 中发现了 TARDBP p.M337V 突变的高频率。TARDBP 相关 ALS 患者的疾病过程呈良性，生存时间延长。
