TUBB3 – Complex Cortical Dysplasia with Other Brain Malformations 1

TUBB3 encodes the neuron-specific β-III tubulin isotype critical for microtubule dynamics, axon guidance, and neuronal migration. Heterozygous de novo missense variants in TUBB3 cause Complex Cortical Dysplasia with Other Brain Malformations 1, presenting with cortical disorganization, corpus callosum hypoplasia, seizures, and global developmental delay.

Clinical Validity

Autosomal dominant de novo inheritance is demonstrated by at least 14 unrelated probands carrying heterozygous TUBB3 missense variants across >10 years of studies (PMID:20829227, PMID:26639658). No conflicting evidence has been reported.

Genetic Evidence

Fourteen unrelated de novo TUBB3 missense variants (e.g., c.533C>T (p.Thr178Met), c.905C>T (p.Ala302Val)) meet ClinGen PS2 criteria, with absent parental segregation and consistent cortical dysplasia phenotypes, supporting strong genetic evidence (PMID:20829227, PMID:26639658).

Functional Evidence

Yeast modelling, cellular assays, and a knock-in mouse demonstrate that pathogenic TUBB3 variants impair heterodimer formation, alter microtubule dynamic instability, and disrupt kinesin and netrin-1/DCC interactions, recapitulating axon guidance defects without cortical lamination anomalies (PMID:20074521, PMID:29382549, PMID:31226147).

Mechanism

Missense variants exert a dominant-negative effect on microtubule polymerization dynamics, leading to axonal misrouting and cortical malformations consistent with neuroimaging findings.

Conclusion

TUBB3 is definitively associated with complex cortical dysplasia with other brain malformations 1. Inclusion of TUBB3 in diagnostic gene panels is recommended for patients with malformations of cortical development, callosal hypoplasia, and epilepsy.

Key Take-home: De novo TUBB3 missense variants cause dominantly inherited cortical brain malformations via dominant-negative disruptions of microtubule dynamics.

References

• Human molecular genetics • 2010 • Mutations in the neuronal β-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects PMID:20829227
• American journal of medical genetics. Part A • 2016 • A novel TUBB3 mutation in a sporadic patient with asymmetric cortical dysplasia PMID:26739025
• American journal of medical genetics. Part A • 2016 • Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development PMID:26639658
• Cell • 2010 • Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance PMID:20074521
• Neuroscience • 2018 • Human TUBB3 Mutations Disrupt Netrin Attractive Signaling PMID:29382549
• PLoS one • 2019 • Disease-associated mutations in human TUBB3 disturb netrin repulsive signaling PMID:31226147

Evidence Based Scoring (AI generated)