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TUBB2B – Congenital Fibrosis of the Extraocular Muscles

TUBB2B encodes a β-tubulin isotype essential for neuronal microtubule dynamics. A heterozygous missense variant c.1261G>A (p.Glu421Lys) was identified in a single multigenerational family segregating congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria, involving at least three affected relatives (PMID:23001566). Functional interrogation including exogenous expression of TUBB2B-E421K in developing callosal projection neurons and yeast genetics demonstrated incorporation of mutant αβ-heterodimers into microtubules, altered dynamics, reduced kinesin localization, and impaired homotopic axon connectivity (PMID:23001566). This substitution perturbs a kinesin-binding site, explaining its divergence from other TUBB2B substitutions. No additional unrelated probands have been reported with CFEOM due to TUBB2B, limiting genetic evidence. Collectively, the data support a Limited clinical validity classification, with Moderate experimental evidence for pathogenicity. Key Take-Home: TUBB2B c.1261G>A (p.Glu421Lys) warrants consideration in familial CFEOM with polymicrogyria given its mechanistic impact on axon guidance.

References

  • Human Molecular Genetics • 2012 • An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation. PMID:23001566

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single family with one heterozygous TUBB2B variant segregating CFEOM and polymicrogyria (PMID:23001566)

Genetic Evidence

Limited

One heterozygous missense variant c.1261G>A (p.Glu421Lys) in a single family (≥3 affected relatives) (PMID:23001566)

Functional Evidence

Moderate

In vitro biochemical assays, yeast genetics, and neuronal expression studies demonstrate altered microtubule dynamics and impaired axon connectivity consistent with CFEOM phenotype (PMID:23001566)