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首页> 外文期刊>Journal of neurology >Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1
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Mutation screen reveals novel variants and expands the phenotypes associated with DYNC1H1

机译：突变筛选揭示了新颖的变体并扩展了与DYNC1H1相关的表型

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摘要

Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) encodes a necessary subunit of the cytoplasmic dynein complex, which traffics cargo along microtubules. Dominant DYNC1H1 mutations are implicated in neural diseases, including spinal muscular atrophy with lower extremity dominance (SMA-LED), intellectual disability with neuronal migration defects, malformations of cortical development, and Charcot-Marie-Tooth disease, type 2O. We hypothesized that additional variants could be found in these and novel motoneuron and related diseases. Therefore, we analyzed our database of 1024 whole exome sequencing samples of motoneuron and related diseases for novel single nucleotide variations. We filtered these results for significant variants, which were further screened using segregation analysis in available family members. Analysis revealed six novel, rare, and highly conserved variants. Three of these are likely pathogenic and encompass a broad phenotypic spectrum with distinct disease clusters. Our findings suggest that DYNC1H1 variants can cause not only lower, but also upper motor neuron disease. It thus adds DYNC1H1 to the growing list of spastic paraplegia related genes in microtubule-dependent motor protein pathways.
机译：动力蛋白，胞质1，重链1（DYNC1H1）编码胞质动力蛋白复合物的必要亚基，其沿微管运输货物。 DYNC1H1突变与神经疾病有关，包括具有下肢优势的脊髓性肌萎缩症（SMA-LED），具有神经元迁移缺陷的智力残疾，皮质发育畸形和2型Charcot-Marie-Tooth病。我们假设可以在这些和新型运动神经元及相关疾病中发现其他变异。因此，我们分析了我们的1024个运动神经元和相关疾病的完整外显子组测序样品的数据库，以发现新的单核苷酸变异。我们对这些结果进行了重大变异的过滤，然后使用分离分析对可用的家族成员进行了进一步筛选。分析揭示了六个新颖，罕见和高度保守的变体。其中三个可能是致病性的，涵盖了具有明显疾病簇的广泛表型谱。我们的发现表明DYNC1H1变体不仅可以引起较低的运动神经元疾病，还可以引起较高的运动神经元疾病。因此，它将DYNC1H1添加到微管依赖性运动蛋白途径中与痉挛性截瘫相关基因的列表中。

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