The neuronal cytoskeleton performs incredible feats during nervous system development. Extension of neuronal processes, migration, and synapse formation rely on the proper regulation of microtubules. Mutations that disrupt the primary α‐tubulin expressed during brain development, TUBA1A, are associated with a spectrum of human brain malformations. One model posits that TUBA1A mutations lead to a reduction in tubulin subunits available for microtubule polymerization, which represents a haploinsufficiency mechanism. We propose an alternative model for the majority of tubulinopathy mutations, in which the mutant tubulin polymerizes into the microtubule lattice to dominantly “poison” microtubule function. Nine distinct α‐tubulin and ten β‐tubulin genes have been identified in the human genome. These genes encode similar tubulin proteins, called isotypes. Multiple tubulin isotypes may partially compensate for heterozygous deletion of a tubulin gene, but may not overcome the disruption caused by missense mutations that dominantly alter microtubule function. Here, we describe disorders attributed to haploinsufficiency versus dominant negative mechanisms to demonstrate the hallmark features of each disorder. We summarize literature on mouse models that represent both knockout and point mutants in tubulin genes, with an emphasis on how these mutations might provide insight into the nature of tubulinopathy patient mutations. Finally, we present data from a panel of TUBA1A tubulinopathy mutations generated in yeast α‐tubulin that demonstrate that α‐tubulin mutants can incorporate into the microtubule network and support viability of yeast growth. This perspective on tubulinopathy mutations draws on previous studies and additional data to provide a fresh perspective on how TUBA1A mutations disrupt neurodevelopment.

中文翻译：

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脑发育障碍中的微管蛋白突变：为什么单倍剂量不足不能解释 TUBA1A 微管蛋白病。

神经元细胞骨架在神经系统发育过程中表现出令人难以置信的壮举。神经元过程的扩展、迁移和突触形成依赖于微管的适当调节。破坏大脑发育过程中表达的初级 α-微管蛋白TUBA1A 的突变与一系列人类大脑畸形有关。一种模型假设TUBA1A突变导致可用于微管聚合的微管蛋白亚基减少，这是一种单倍剂量不足机制。我们为大多数微管蛋白病突变提出了一种替代模型，其中突变微管蛋白聚合到微管晶格中以显着“毒化”微管功能。在人类基因组中已经鉴定出九个不同的α-微管蛋白和十个β-微管蛋白基因。这些基因编码类似的微管蛋白，称为同种型。多种微管蛋白同种型可能会部分补偿微管蛋白基因的杂合缺失，但可能无法克服主要改变微管功能的错义突变造成的破坏。在这里，我们描述了归因于单倍剂量不足与显性负机制的疾病，以展示每种疾病的标志性特征。我们总结了代表微管蛋白基因敲除和点突变的小鼠模型的文献，重点是这些突变如何提供对微管蛋白病患者突变性质的深入了解。最后，我们展示了一组数据TUBA1A在酵母α微管蛋白产生tubulinopathy突变证明，α微管蛋白突变体可以掺入酵母生长的微管网络和支持生存能力。这种关于微管蛋白病突变的观点借鉴了以前的研究和其他数据，为TUBA1A突变如何破坏神经发育提供了新的视角。