Mutations of the SPAST gene are the chief cause of hereditary spastic paraplegia. Controversy exists in the medical community as to whether the etiology of the disease is haploinsufficiency or toxic gain‐of‐function properties of the mutant spastin proteins. In recognition of strong reasons that support each possible mechanism, here we present a novel perspective, based in part on new studies with mouse models and in part on the largest study to date on patients with the disease. We posit that haploinsufficiency does not cause the disease but makes the corticospinal tracts vulnerable to a second hit, which is usually the mutant spastin proteins but could also be proteins generated by mutations of other genes that may or may not cause the disease on their own.

中文翻译：

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基于 SPAST 的遗传性痉挛性截瘫病因的新假设。

SPAST基因的突变是遗传性痉挛性截瘫的主要原因。关于该疾病的病因是单倍剂量不足还是突变的 spastin 蛋白的毒性功能获得特性，医学界存在争议。认识到支持每种可能机制的有力理由，我们在这里提出了一个新的观点，部分基于对小鼠模型的新研究，部分基于迄今为止针对该疾病患者的最大研究。我们假设单倍体不足不会导致疾病，但会使皮质脊髓束容易受到第二次打击，这通常是突变的 spastin 蛋白，但也可能是由其他基因突变产生的蛋白质，这些基因本身可能会或可能不会导致疾病。