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Target: TUBB2B


Research on TUBB2B

1. Target Summary:

TUBB2B (Tubulin Beta-2B) is a gene that encodes a beta-tubulin protein, which is a crucial component of microtubules. Microtubules are essential for various cellular processes, including maintaining cell shape, intracellular transport, and cell division. Mutations in TUBB2B are associated with a range of neurodevelopmental disorders, collectively referred to as tubulinopathies, which can lead to malformations of cortical development (MCD) such as lissencephaly and polymicrogyria. Additionally, TUBB2B is implicated in certain cancers, including hepatocellular carcinoma.

2. Mechanism:

TUBB2B functions as part of the microtubule cytoskeleton, which is vital for neuronal migration, differentiation, and overall brain development. Mutations in TUBB2B can disrupt the normal dynamics of microtubules, leading to impaired neuronal migration and abnormal cortical development. Specifically, TUBB2B mutations can affect the stability and assembly of microtubules, which in turn can alter the transport of organelles and signaling molecules within neurons. This disruption can result in various neurodevelopmental defects, including cortical malformations and associated neurological symptoms such as epilepsy and intellectual disability (Maillard et al., 2023; Jurgens et al., 2021).

3. Approved Drugs:

As of now, there are no specific drugs approved that directly target TUBB2B mutations. However, research is ongoing to explore potential therapeutic interventions, including microtubule-stabilizing agents that may help mitigate the effects of TUBB2B-related disorders (Nóbrega et al., 2020).

4. Hypotheses:

  1. Disruption of Microtubule Dynamics: It is hypothesized that mutations in TUBB2B lead to specific neurodevelopmental disorders by disrupting microtubule dynamics, which are critical for neuronal migration and cortical organization.
  2. Phenotype Correlation: Different mutations in TUBB2B may correlate with specific phenotypes of neurodevelopmental disorders, suggesting that certain mutations could predict clinical outcomes (Bahi-Buisson et al., 2014).
  3. Therapeutic Targeting: Targeting the pathways affected by TUBB2B mutations may provide therapeutic benefits for patients with associated neurodevelopmental disorders.

5. Validation:

The association of TUBB2B mutations with neurodevelopmental disorders has been validated through various studies. For instance, a study found that TUBB2B mutations were present in 16.9% of patients with complex cortical malformations (Bahi-Buisson et al., 2014). Additionally, the presence of TUBB2B mutations has been linked to specific clinical features, such as epilepsy and cognitive impairment, reinforcing the gene's role in these disorders (Romaniello et al., 2019).

6. Clinical Trials:

Currently, there are no specific clinical trials targeting TUBB2B mutations. However, there is a growing interest in conducting trials that focus on the natural history of tubulinopathies and exploring potential therapeutic interventions (Schroter et al., 2021).

7. Involved Pathways:

TUBB2B is involved in several cellular pathways, including:
  • Microtubule Dynamics: Essential for maintaining cellular structure and function.
  • Neuronal Migration Pathways: Critical for proper brain development and organization.
  • Cell Cycle Regulation: Microtubules play a role in mitosis and cellular division.

8. Associated Genes:

TUBB2B is part of a larger family of tubulin genes, including:
  • TUBA1A: Often associated with similar neurodevelopmental disorders.
  • TUBB3: Also linked to cortical malformations.
  • TUBB2A: Shares functional similarities with TUBB2B.

9. Target Expression:

TUBB2B is expressed in various tissues, with particularly high expression levels in the brain during development. Its expression is crucial for proper neuronal function and development, and dysregulation can lead to significant developmental issues.

10. Additional Context:

TUBB2B mutations are part of a broader category of genetic disorders known as tubulinopathies, which encompass a range of clinical presentations, including severe brain malformations and associated neurological symptoms. The complexity of these disorders reflects the diverse roles that tubulins play in cellular processes.

11. References:

  • Maillard, C., Roux, C. J., & Charbit-Henrion, F. (2023). Tubulin mutations in human neurodevelopmental disorders. Seminars in Cell & Developmental Biology. PMID: 35915025.
  • Jurgens, J. A., Barry, B. J., & Lemire, G. (2021). Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development. European Journal of Human Genetics. PMID: 33649541.
  • Nóbrega, C., et al. (2020). Potential Role of Microtubule Stabilizing Agents in Neurodevelopmental Disorders. Frontiers in Cellular Neuroscience. PMID: 5578018.
  • Bahi-Buisson, N., Poirier, K., & Fourniol, F. (2014). The wide spectrum of tubulinopathies: what are the key features for the diagnosis? Brain: A Journal of Neurology. PMID: 24860126.
  • Romaniello, R., Zucca, C., & Arrigoni, F. (2019). Epilepsy in Tubulinopathy: Personal Series and Literature Review. Cells. PMID: 31269740.
  • Schroter, J., Doring, J. H., & Garbade, S. F. (2021). Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies. Genetics in Medicine. PMID: 33082561.