Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia
Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia
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DOI：
10.1093/brain/awx095
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发表时间：
2017-06-01
期刊：
影响因子：
14.5
通讯作者：
Schuele, Rebecca
中科院分区：
文献类型：
--
作者：
Minnerop, Martina;Kurzwelly, Delia;Schuele, Rebecca
尽管进行了广泛的努力，但仍有一半患有罕见运动障碍的患者，如遗传性痉挛性截瘫和小脑共济失调，仍然无法解释遗传原因，这涉及新基因和已知基因中未被识别的突变。非编码DNA变异被怀疑占罕见疾病未发现原因的很大一部分。在这里，我们确定了位于POLR 3A内含子深处的突变是遗传性痉挛性截瘫和小脑共济失调的常见原因。首先，一个隐性痉挛性共济失调家族的全外显子组测序结果将我们的注意力转向POLR 3A的内含子变异，POLR 3A是一个先前与7型低髓鞘化脑白质营养不良相关的基因。接下来，我们筛选了一组遗传性痉挛性截瘫和小脑共济失调病例（n = 618）的POLR 3A突变，并在3.1%的索引病例中鉴定了复合杂合POLR 3A突变。有趣的是，>80%的P0 LR 3A突变携带者呈现相同的深度内含子突变（c.1909 + 22 G>A），其以组织和发育阶段特异性方式激活隐蔽剪接位点，并导致新的独特和统一的表型。该表型的特征在于发作性进行性痉挛性共济失调，经常发生震颤，累及中枢感觉束和牙齿问题（缺牙，早期发作的严重和侵袭性牙周病）。携带c.1909 + 22 G>A的病例显示沿着上级小脑脚的高信号，而不是与经典POLR 3A突变相关的典型髓鞘形成不足的磁共振成像模式。这些高信号可能代表了在这些患者中观察到的小脑症状的结构相关性。1139例痉挛性共济失调相关表型患者的c.1909 + 22 G>A变异显著高于无关的神经和非神经表型患者及健康对照组（P = 1.3 × 10 - 4）。在这项研究中，我们证明了（i）POLR 3A的常染色体隐性突变是遗传性痉挛性共济失调的常见原因，约占迄今遗传未分类的常染色体隐性和散发病例的3%;（ii）在POLR 3A相关综合征中，特别是当内含子突变存在时，髓鞘形成不足，因此不能再被认为是POLR 3A疾病的统一特征。此外，我们的研究结果表明，通过探索人类基因组的非编码序列，可以在揭示孟德尔疾病的原因方面取得实质性进展。
Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in similar to 3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909 + 22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909 + 22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909 + 22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 x 10(-4)). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.