TUBB2A – Complex Cortical Dysplasia with Other Brain Malformations 5

TUBB2A encodes the neuron-specific β-tubulin isotype II essential for microtubule dynamics in cortical development. A heterozygous de novo missense variant c.743C>T (p.Ala248Val) was identified in a male proband with global developmental delay and early-onset seizures consistent with complex cortical dysplasia with other brain malformations 5 (PMID:35930870). No familial segregation has been described. Patient-derived iPSCs bearing p.Ala248Val maintain normal karyotype and trilineage differentiation potential but lack disease-relevant neuronal assays (PMID:35930870). Analogous TUBB2A variants in other tubulinopathy contexts disrupt microtubule function via impaired kinesin binding (p.Asp417Asn) (PMID:29547997) and altered GTPase-driven assembly kinetics (p.Thr178Met) (PMID:34869359), supporting a dominant-negative mechanism.

The current evidence supports a Limited gene-disease association owing to a single proband and preliminary functional data. Additional unrelated cases, segregation analyses, and disease-specific cellular or animal models are required to establish definitive pathogenicity. Key Take-home: Include TUBB2A in diagnostic panels for patients with cortical malformations, developmental delay, and epilepsy.

References

• Stem cell research • 2022 • Generation of an induced pluripotent stem cell line (DHMCi009-A) from an individual with TUBB2A tubulinopathy. PMID:35930870
• Human molecular genetics • 2018 • Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy. PMID:29547997
• Frontiers in cell and developmental biology • 2021 • Kinetically Stabilizing Mutations in Beta Tubulins Create Isotype-Specific Brain Malformations. PMID:34869359

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