Meta-analysis of age at onset in spastin-associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class -: art. no. e106
Meta-analysis of age at onset in spastin-associated hereditary spastic paraplegia provides no evidence for a correlation with mutational class -: art. no. e106
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DOI：
10.1136/jmg.40.9.e106
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发表时间：
2003-09-01
影响因子：
4
通讯作者：
Reid, E
中科院分区：
文献类型：
--
作者：
Yip, AG;Dürr, A;Reid, E
遗传性痉挛性截瘫（hereditary spastic paraplegias，HSP）是一组皮质脊髓束发育异常或在正常发育后发生变性的单基因疾病。HSP都具有进行性下肢痉挛性瘫痪的主要临床特征，并根据是否存在其他神经或非神经特征而细分为单纯型和复杂型。1 2单纯HSP倾向于与神经退行性变相关，而不是异常发育，并且单纯HSP的组织病理学研究显示皮质脊髓束轴突末端的长度依赖性“死亡”，最长的轴突首先参与。1 SPG 4基因（spastin）是最重要的纯HSP基因，约40%的确诊的常染色体显性纯HSP与SPG 4基因有关，少数为散发病例和家族史不确定的病例。3.4由616个氨基酸组成的spastin蛋白是一种广泛表达的AAA（ATPases associated with diverse cellular activities）蛋白。已经描述了100多种不同的痉挛蛋白突变，包括许多错义、无义、移码和剪接位点突变，以及较不常见的全外显子缺失。除了少数可能的例外，错义突变位于AAA盒中，从氨基酸342-599。剪接位点突变几乎完全涉及外显子5-16。无义突变和移码突变分散在基因中，最小的预测蛋白质由不到40个氨基酸组成，最大的562个氨基酸。2截短和剪接位点突变的分子病理机制可能是功能丧失。相关的异常转录可能是不稳定的，最近的数据表明，突变痉挛蛋白是缺乏无义和移码痉挛蛋白突变患者的成纤维细胞。这些类型的痉挛素突变可能与单倍不足有关，一旦功能性痉挛素水平低于临界阈值水平，就会发生疾病。对减少剂量的功能性痉挛素的耐受性可能非常低，因为一些“泄漏”（即产生野生型和异常剪接变体）剪接位点突变仅导致野生型mRNA表达的轻微降低。[8]另一方面，痉挛素错义突变可能通过不同的机制起作用。有人认为，spastin具有微管切断功能，spastin错义突变体与微管组成性结合，可能以显性负性方式阻断spastin或未鉴定的spastin相关蛋白的正常功能。9研究spastin错义突变是否具有与其他突变类型不同的分子病理机制的一种方法是检查突变类型是否与临床特征相关。在常染色体显性遗传的纯HSP家族中，主要可量化的临床变量是症状发作时的年龄，这表明
The hereditary spastic paraplegias (HSPs) are a group of single gene disorders in which the corticospinal tracts fail to develop normally, or degenerate after initially normal development. The HSPs all share the principal clinical feature of progressive lower limb spastic paralysis, and are subdivided into pure and complicated forms, depending on the presence of additional neurological or non-neurological features. 1 2 The pure HSPs tend to be associated with neurodegeneration, rather than abnormal development, and histopathological studies in pure HSP show a length-dependent ‘‘dying back’’of the terminal ends of the corticospinal tract axons, with the longest axons being involved first. 1 The SPG4 gene, spastin, is the most important pure HSP gene, being responsible for approximately 40% of definite autosomal dominant pure HSP and a smaller proportion of sporadic cases and cases with uncertain family history. 3 4 The 616 amino acid spastin protein is a widely expressed AAA (ATPases associated with diverse cellular activities) protein. 5 More than 100 different spastin mutations have been described, including numerous missense, nonsense, frameshift, and splice site mutations, as well as less frequent whole exon deletions. With only a few possible exceptions, the missense mutations are located in the AAA cassette, from amino acids 342–599. Splice site mutations almost exclusively involve exons 5–16. Nonsense and frameshift mutations are scattered across the gene, with the smallest predicted protein consisting of fewer than 40 amino acids, the largest 562 amino acids. 2 It is likely that the molecular pathological mechanism of truncating and splice site spastin mutations is loss of function. The associated abnormal transcripts may be unstable, and recent data show that mutant spastin protein is absent in fibroblasts from patients with nonsense and frameshift spastin mutations. 6 7 These classes of spastin mutation are probably associated with haploinsufficiency, with disease occurring once functioning spastin levels fall below a critical threshold level. Tolerance for reduced dosage of functioning spastin may be very low, as some ‘‘leaky’’(that is, creating both wild-type and aberrant splice variants) splice site mutations result in only slight reductions in wild-type mRNA expression. 8 On the other hand, spastin missense mutations may act via a different mechanism. It has been suggested that spastin has a microtubule severing function and that spastin missense mutants bind constitutively to microtubules, perhaps acting in a dominant negative fashion to block the normal function of spastin or unidentified spastin-related proteins. 9One approach to resolve the issue of whether spastin missense mutations have a different molecular pathological mechanism to other mutational types is to examine whether mutational class is correlated with clinical features. The main quantifiable clinical variable in autosomal dominant pure HSP families is age at onset of symptoms, and this shows