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TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

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 ?-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.

SUBMITTER: Sferra A

PROVIDER: S-EPMC7073044 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

Sferra Antonella A Petrini Stefania S Bellacchio Emanuele E Nicita Francesco F Scibelli Francesco F Dentici Maria Lisa ML Alfieri Paolo P Cestra Gianluca G Bertini Enrico Silvio ES Zanni Ginevra G

International journal of molecular sciences 20200218 4

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 mi ...[more]

PMID: 32085672

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Project description:BACKGROUND:Many diseases are associated with complex patterns of symptoms and phenotypic manifestations. Parsimonious explanations aim at reconciling the multiplicity of phenotypic traits with the perturbation of one or few biological functions. For this, it is necessary to characterize human phenotypes at the molecular and functional levels, by exploiting gene annotations and known relations among genes, diseases and phenotypes. This characterization makes it possible to implement tools for retrieving functions shared among phenotypes, co-occurring in the same patient and facilitating the formulation of hypotheses about the molecular causes of the disease. RESULTS:We introduce PhenPath, a new resource consisting of two parts: PhenPathDB and PhenPathTOOL. The former is a database collecting the human genes associated with the phenotypes described in Human Phenotype Ontology (HPO) and OMIM Clinical Synopses. Phenotypes are then associated with biological functions and pathways by means of NET-GE, a network-based method for functional enrichment of sets of genes. The present version considers only phenotypes related to diseases. PhenPathDB collects information for 18 OMIM Clinical synopses and 7137 HPO phenotypes, related to 4292 diseases and 3446 genes. Enrichment of Gene Ontology annotations endows some 87.7, 86.9 and 73.6% of HPO phenotypes with Biological Process, Molecular Function and Cellular Component terms, respectively. Furthermore, 58.8 and 77.8% of HPO phenotypes are also enriched for KEGG and Reactome pathways, respectively. Based on PhenPathDB, PhenPathTOOL analyzes user-defined sets of phenotypes retrieving diseases, genes and functional terms which they share. This information can provide clues for interpreting the co-occurrence of phenotypes in a patient. CONCLUSIONS:The resource allows finding molecular features useful to investigate diseases characterized by multiple phenotypes, and by this, it can help researchers and physicians in identifying molecular mechanisms and biological functions underlying the concomitant manifestation of phenotypes. The resource is freely available at http://phenpath.biocomp.unibo.it .

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TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

Publications

TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

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