Unit of Neuromuscular and Neurodegenerative Disorders, Department Neurosciences, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
Confocal Microscopy Core Facility, Research Laboratories, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.
Int J Mol Sci. 2020 Feb 18;21(4):1385. doi: 10.3390/ijms21041385.
Tubulinopathies are rare neurological disorders caused by alterations in tubulin structure and function, giving rise to a wide range of brain abnormalities involving neuronal proliferation, migration, differentiation and axon guidance. TUBB is one of the ten β-tubulin encoding genes present in the human genome and is broadly expressed in the developing central nervous system and the skin. Mutations in TUBB are responsible for two distinct pathological conditions: the first is characterized by microcephaly and complex structural brain malformations and the second, also known as "circumferential skin creases Kunze type" (CSC-KT), is associated to neurological features, excess skin folding and growth retardation. We used a combination of immunocytochemical and cellular approaches to explore, on patients' derived fibroblasts, the functional consequences of two TUBB variants: the novel mutation (p.N52S), associated with basal ganglia and cerebellar dysgenesis, and the previously reported variant (p.M73T), linked to microcephaly, corpus callosum agenesis and CSC-KT skin phenotype. Our results demonstrate that these variants impair microtubule (MT) function and dynamics. Most importantly, our studies show an altered epidermal growth factor (EGF) and transferrin (Tf) intracellular vesicle trafficking in both patients' fibroblasts, suggesting a specific role of TUBB in MT-dependent vesicular transport.
微管病是由微管结构和功能改变引起的罕见神经疾病，导致广泛的脑异常，涉及神经元增殖、迁移、分化和轴突导向。TUBB 是人类基因组中十个β-微管编码基因之一，在中枢神经系统和皮肤的发育中广泛表达。TUBB 突变负责两种不同的病理情况：第一种特征是小头畸形和复杂的结构性脑畸形，第二种也称为“环形皮肤皱褶 Kunze 型”（CSC-KT），与神经特征、皮肤过度折叠和生长迟缓有关。我们使用免疫细胞化学和细胞方法的组合，在患者来源的成纤维细胞上探索了两种 TUBB 变体的功能后果：与基底节和小脑发育不良相关的新突变（p.N52S），以及先前报道的与小头畸形、胼胝体发育不全和 CSC-KT 皮肤表型相关的变体（p.M73T）。我们的结果表明，这些变体损害了微管（MT）的功能和动力学。最重要的是，我们的研究表明，在两名患者的成纤维细胞中，表皮生长因子（EGF）和转铁蛋白（Tf）的细胞内囊泡运输都发生了改变，这表明 TUBB 在 MT 依赖性囊泡运输中具有特定作用。
