TUBB2A related epilepsy: novel variants and genotype-phenotype correlation

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• Mutations in TUBB2A are associated with neurological disorders.
• Understanding the clinical spectrum and pathogenic mechanisms of TUBB2A variants is crucial for epilepsy research.

Purpose of the Study:

• To delineate the clinical phenotypes of epilepsy patients with TUBB2A variants.
• To explore the pathogenesis of novel TUBB2A variants using cellular models.

Main Methods:

• Clinical data analysis of 28 epilepsy patients with TUBB2A variants.
• Functional studies using TUBB2A-FLAG and TUBB2A-EGFP plasmids in HEK293T cells.
• 3D structure prediction to analyze variant locations.

Main Results:

• Epilepsy onset ranged from neonatal to 8 years, with 61% starting before age 1.
• Common seizure types included epileptic spasms and focal seizures (32% each).
• All patients exhibited developmental delay, and 93% had malformation of cortical development (MCD).
• All identified variants were missense.
• Novel and reported variants affected spindle apparatus morphology and microtubule dynamics.
• Variants near the α-β tubulin dimer interface had a pronounced effect on microtubule behavior.
• Severe phenotypes like pachygyria were more common with variants perturbing tubulin dimer linkage.

Conclusions:

• TUBB2A variants are a significant cause of early-onset epilepsy with developmental delay and MCD.
• Variants impacting tubulin structure and microtubule dynamics are pathogenic.
• The location of variants, particularly near the tubulin dimer interface, correlates with phenotype severity.