Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function,FEBS Letters

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Tubulin mutations in neurodevelopmental disorders as a tool to decipher microtubule function
FEBS Letters ( IF 3.0 ) Pub Date : 2020-11-01 , DOI: 10.1002/1873-3468.13958
Geneviève Fourel ₁ , Cécile Boscheron ₂

Affiliation

Malformations of cortical development (MCDs) are a group of severe brain malformations associated with intellectual disability and refractory childhood epilepsy. Human missense heterozygous mutations in the 9 α‐tubulin and 10 β‐tubulin isoforms forming the heterodimers that assemble into microtubules (MTs) were found to cause MCDs. However, how a single mutated residue in a given tubulin isoform can perturb the entire microtubule population in a neuronal cell remains a crucial question. Here, we examined 85 MCD‐associated tubulin mutations occurring in TUBA1A, TUBB2, and TUBB3 and their location in a three‐dimensional (3D) microtubule cylinder. Mutations hitting residues exposed on the outer microtubule surface are likely to alter microtubule association with partners, while alteration of intradimer contacts may impair dimer stability and straightness. Other types of mutations are predicted to alter interdimer and lateral contacts, which are responsible for microtubule cohesion, rigidity, and dynamics. MCD‐associated tubulin mutations surprisingly fall into all categories, thus providing unexpected insights into how a single mutation may impair microtubule function and elicit dominant effects in neurons.

中文翻译：

神经发育障碍中的微管蛋白突变作为破译微管功能的工具

皮质发育畸形 (MCD) 是一组与智力障碍和难治性儿童癫痫相关的严重脑畸形。发现 9 种 α-微管蛋白和 10 种 β-微管蛋白同种型中的人类错义杂合突变形成组装成微管 (MT) 的异源二聚体，可导致 MCD。然而，给定微管蛋白同种型中的单个突变残基如何扰乱神经元细胞中的整个微管群仍然是一个关键问题。在这里，我们检查了 85 个发生在 TUBA1A、TUBB2 和 TUBB3 中的 MCD 相关微管蛋白突变及其在三维 (3D) 微管圆柱体中的位置。击中暴露在微管外表面的残基的突变可能会改变微管与伴侣的联系，而二聚体内部接触的改变可能会损害二聚体的稳定性和直线度。预计其他类型的突变会改变二聚体和横向接触，这对微管内聚力、刚性和动力学负责。MCD 相关的微管蛋白突变出人意料地属于所有类别，从而为单个突变如何损害微管功能并在神经元中引发显性效应提供了意想不到的见解。

更新日期：2020-11-01

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