Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
Mutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
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DOI：
10.1212/wnl.0b013e3182556c05
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发表时间：
2012-05-01
期刊：
影响因子：
9.9
通讯作者：
Baloh, R. H.
中科院分区：
文献类型：
--
作者：
Harms, M. B.;Ori-McKenney, K. M.;Baloh, R. H.
目的：鉴定下肢为主的14q32连锁显性脊髓性肌萎缩症（SMA-LED，OMIM 158600）的基因。方法：采用靶外显子捕获和二代测序技术分析3个SMA-LED家族成员14q32连锁区间的73个基因。其他显性 SMA 家族中的候选基因测序使用 PCR 和合并目标捕获方法。对患者成纤维细胞进行生化分析。结果：对原始SMA-LED家族中14q32区间的所有候选基因进行区域外显子组测序，仅发现一个与疾病状态分离的错义突变——DYNC1H1尾部结构域的突变（I584L）。对另外 32 名下肢主要 SMA 的先证者进行 DYNC1H1 测序，发现另外 2 个杂合尾部结构域突变（K671E 和 Y970C），证实同一结构域中的多个不同突变可以导致相似的表型。对从患者来源的成纤维细胞中纯化的动力蛋白进行生化分析表明，I584L 突变主要破坏动力蛋白复合物的稳定性和功能。结论：我们证明细胞质动力蛋白重链 (DYNC1H1) 尾部结构域的突变会导致脊髓性肌萎缩，并提供了人类 DYNC1H1 突变破坏动力蛋白复合物组装和功能的实验证据。最近在一个患有腓骨肌萎缩症（20 型）的家庭和一名智力低下的儿童中发现了 DYNC1H1 突变。这两种表型与此处描述的脊髓性肌萎缩症患者部分重叠，表明动力蛋白功能障碍与人类涉及神经元发育和维持的一系列表型相关。神经病学（R）2012；78：1714-1720
Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600).Methods: Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed.Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state-a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function.Conclusions: We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 20) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance. Neurology (R) 2012;78:1714-1720