Abstract
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.
Highlights
Complex brain malformations associated with dominant or de novo missense mutations in tubulin genes TUBA1A, TUBB2B, TUBB3, tubulin beta chain (TUBB) or TUBG1 are commonly referred to as “tubulinopathies” [1,2,3]
Specific phenotypes may be more frequently associated with mutations of particular isoforms (e.g., TUBA1A to lissencephaly or TUBB2B to polymicrogyria) [11,12,13], and at the single gene level, distinct mutations can cause either polymicrogyria or axon guidance disorders [14] depending on the variant’s impact on the dynamic properties of the cytoskeleton
A novel missense variant c.155A > G (p.N52S) in TUBB (NM_178014) was detected by targeted next-generation sequencing in patient 1, who presented dysmorphic basal ganglia and cerebellar dysgenesis with normal head circumference and corpus callosum
Summary
Complex brain malformations associated with dominant or de novo missense mutations in tubulin genes TUBA1A, TUBB2B, TUBB3, TUBB or TUBG1 are commonly referred to as “tubulinopathies” [1,2,3]. Specific phenotypes may be more frequently associated with mutations of particular isoforms (e.g., TUBA1A to lissencephaly or TUBB2B to polymicrogyria) [11,12,13], and at the single gene level, distinct mutations can cause either polymicrogyria or axon guidance disorders (e.g., in TUBB3) [14] depending on the variant’s impact on the dynamic properties of the cytoskeleton. Patients with TUBB mutations exhibit neurological features including microcephaly, dysgenesis of the cerebellum and the basal ganglia, agenesis of the corpus callosum and congenital symmetrical circumferential skin creases (CSC-KT) [21,22]. We performed comparative functional studies using primary fibroblasts of two patients presenting different TUBB-related clinical features: pure neurological or CSC-KT phenotype. The analysis of TUBB-mutated fibroblasts showed multiple defects in MT polymerization, vesicle trafficking and cell migration
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