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Target: TUBB2A


Research on TUBB2A

1. Target Summary:

TUBB2A (Tubulin Beta 2A Class IIa) is a gene that encodes a beta-tubulin protein, which is a critical component of microtubules. Microtubules are essential for various cellular processes, including maintaining cell shape, intracellular transport, and neuronal function. Mutations in TUBB2A are associated with a range of neurodevelopmental disorders known as tubulinopathies, which can lead to brain malformations, developmental delays, and epilepsy (Cai et al., 2020; Cushion et al., 2014).

2. Mechanism:

TUBB2A plays a crucial role in the assembly and stability of microtubules. Microtubules are dynamic structures composed of alpha and beta-tubulin heterodimers that undergo polymerization and depolymerization. Mutations in TUBB2A can disrupt this process by altering the protein's ability to bind GTP, which is necessary for microtubule stability and dynamics. For instance, specific mutations can impair the interaction between tubulin dimers, leading to reduced microtubule assembly and increased susceptibility to disassembly (Romaniello et al., 2015; Park et al., 2021). This disruption can affect neuronal migration and cortical development, resulting in the phenotypic manifestations observed in tubulinopathies, such as lissencephaly and polymicrogyria (Cai et al., 2020).

3. Approved Drugs:

Currently, there are no specific approved drugs targeting TUBB2A mutations. Management of symptoms associated with TUBB2A-related disorders typically involves supportive care, including antiepileptic medications for seizure management and therapies for developmental delays (Bahi-Buisson & Maillard, 1993).

4. Hypotheses:

  1. Disruption of Microtubule Dynamics: It is hypothesized that mutations in TUBB2A lead to impaired microtubule dynamics, which disrupts neuronal migration and cortical development, resulting in malformations (Cai et al., 2020).
  2. Genotype-Phenotype Correlation: There may be specific mutation "hot spots" within the TUBB2A gene that correlate with distinct clinical phenotypes, such as the severity of developmental delays or the presence of epilepsy (Cai et al., 2020).
  3. Role of Environmental Modifiers: The variability in clinical presentation among patients with TUBB2A mutations may be influenced by additional genetic or environmental factors that modify the expression of the disorder (Bahi-Buisson & Maillard, 1993).

5. Validation:

The association of TUBB2A mutations with neurodevelopmental disorders is supported by multiple studies documenting the clinical features of affected individuals. For example, a study by Cai et al. (2020) reported nine patients with TUBB2A mutations, all exhibiting developmental delays and varying degrees of cortical dysplasia. Additionally, the functional impact of specific mutations has been demonstrated in vitro, showing impaired tubulin and microtubule function (Cushion et al., 2014).

6. Clinical Trials:

As of now, there are no specific clinical trials targeting TUBB2A mutations. However, ongoing research is focused on understanding the underlying mechanisms of tubulinopathies and exploring potential therapeutic approaches (Verstockt et al., 2023).

7. Involved Pathways:

TUBB2A is involved in several cellular pathways related to microtubule dynamics, including:
  • Neuronal Migration Pathways: Disruptions in microtubule function can affect neuronal migration during brain development.
  • Axonal Guidance Pathways: Proper microtubule dynamics are essential for axon outgrowth and guidance, which are critical for establishing neural circuits (Romaniello et al., 2015).

8. Associated Genes:

TUBB2A is part of a larger family of tubulin genes, including:
  • TUBA1A: Associated with similar neurodevelopmental disorders.
  • TUBB2B: Another beta-tubulin gene involved in microtubule dynamics.
  • TUBB3: Known to be associated with various brain malformations (Cai et al., 2020).

9. Target Expression:

TUBB2A is predominantly expressed in the brain during development and continues to be expressed in neurons into adulthood. This expression pattern is crucial for maintaining neuronal function and integrity (Park et al., 2021).

10. Additional Context:

TUBB2A-related tubulinopathies represent a spectrum of disorders characterized by varying degrees of severity and clinical presentation. The understanding of TUBB2A's role in neurodevelopment is still evolving, and further research is needed to explore potential therapeutic interventions and management strategies for affected individuals (Bahi-Buisson & Maillard, 1993).

11. References:

  • Bahi-Buisson, N., & Maillard, C. (1993). Tubulinopathies Overview. No journal info.
  • Cai, S., Li, J., & Wu, Y. (2020). De novo mutations of TUBB2A cause infantile-onset epilepsy and developmental delay. Journal of Human Genetics, 65(7), 675-683. PMID: 32203252.
  • Cushion, T. D., Paciorkowski, A. R., & Pilz, D. T. (2014). De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. American Journal of Human Genetics, 94(4), 634-640. PMID: 24702957.
  • Park, K., Hoff, K. J., & Wethekam, L. (2021). Kinetically Stabilizing Mutations in Beta Tubulins Create Isotype-Specific Brain Malformations. Frontiers in Cell and Developmental Biology, 9, 1-12. PMID: 34869359.
  • Romaniello, R., Arrigoni, F., & Bassi, M. T. (2015). Mutations in alpha- and beta-tubulin encoding genes: implications in brain malformations. Brain & Development, 37(3), 245-253. PMID: 25008804.
  • Verstockt, B., Verstockt, S., & Cremer, J. (2023). Distinct transcriptional signatures in purified circulating immune cells drive heterogeneity in disease location in IBD. BMJ Open Gastroenterology, 10(1), e000892. PMID: 36746519.