SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis,Neurology Genetics

当前位置： X-MOL 学术 › Neurol. Genet. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

SMN1 Duplications Are Associated With Progressive Muscular Atrophy, but Not With Multifocal Motor Neuropathy and Primary Lateral Sclerosis
Neurology Genetics ( IF 3.1 ) Pub Date : 2021-08-01 , DOI: 10.1212/nxg.0000000000000598
Jeroen W Bos ₁ , Ewout J N Groen ₁ , Renske I Wadman ₁ , Chantall A D Curial ₁ , Naomi N Molleman ₁ , Marinka Zegers ₁ , Paul W J van Vught ₁ , Reinier Snetselaar ₁ , Raymon Vijzelaar ₁ , W Ludo van der Pol ₁ , Leonard H van den Berg ₁

Affiliation

Objective

To assess the association between copy number (CN) variation in the survival motor neuron (SMN) locus and multifocal motor neuropathy (MMN), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS) susceptibility and to determine the association of SMN1 and SMN2 CN with MMN, PMA, and PLS disease course.

Methods

In this monocenter study, we used multiplex ligation-dependent probe amplification to determine SMN1 and SMN2 CN in Dutch patients with MMN, PMA, and PLS and controls. We stratified clinical parameters for SMN1 and SMN2 CN. We analyzed SMN1 and SMN2 exons 1–6, intron 6, and exon 8 CN to study the genetic architecture of SMN1 duplications.

Results

SMN1 and SMN2 CN were determined in 132 patients with MMN, 150 patients with PMA, 104 patients with PLS, and 956 control subjects. MMN and PLS were not associated with CN variation in SMN1 or SMN2. By contrast, patients with PMA more often than controls carried SMN1 duplications (≥3 SMN1 copies, 12.0% vs 5.0%, odds ratio 2.69 (1.43–4.91), p 0.0020). SMN1 and SMN2 CN status was not associated with MMN, PLS, or PMA disease course. In case of SMN1 exon 7 duplications, exons 1–6, exon 8, and introns 6 and 7 were also duplicated, suggesting full SMN1 duplications.

Conclusions

SMN1 duplications are associated with PMA, but not with PLS and MMN. SMN1 duplications in PMA are balanced duplications. The results of this study highlight the primary effect of altered SMN CN on lower motor neurons.

中文翻译：

SMN1 重复与进行性肌肉萎缩有关，但与多灶性运动神经病变和原发性侧索硬化无关

客观的

评估存活运动神经元 ( SMN ) 基因座中拷贝数 (CN) 变异与多灶性运动神经病 (MMN)、进行性肌萎缩 (PMA) 和原发性侧索硬化 (PLS) 易感性之间的关联，并确定SMN1的关联和SMN2 CN 具有 MMN、PMA 和 PLS 病程。

方法

在这项单中心研究中，我们使用多重连接依赖性探针扩增来确定荷兰 MMN、PMA 和 PLS 患者和对照组的SMN1和SMN2 CN。我们对SMN1和SMN2 CN 的临床参数进行了分层。我们分析了SMN1和SMN2外显子 1-6、内含子 6 和外显子 8 CN，以研究SMN1重复的遗传结构。

结果

在 132 名 MMN 患者、150 名 PMA 患者、104 名 PLS 患者和 956 名对照受试者中测定了SMN1和SMN2 CN。MMN 和 PLS 与SMN1或SMN2 中的CN 变异无关。相比之下，PMA 患者比对照组更常携带SMN1重复（≥3 个SMN1拷贝，12.0% 对 5.0%，优势比 2.69 (1.43–4.91)，p = 0.0020）。SMN1和SMN2 CN 状态与 MMN、PLS 或 PMA 病程无关。在SMN1外显子 7 重复的情况下，外显子 1-6、外显子 8 和内含子 6 和 7 也被复制，表明完全SMN1重复。