ArticleHuman molecular genetics2012
An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 132 citations in OpenAlex.
- Variant-to-gene mapping identifiesbioRxiv : the preprint server for biology · 2026Article
- Congenital Mirror Movements in A Family with TUBB2B Mutation.Movement disorders clinical practice · 2026Article
- Clinical and MRI differences in congenital fibrosis of extraocular muscles patients with KIF21A and TUBB3 variants.Japanese journal of ophthalmology · 2026Observational
- Article
- Strabismus in Genetic Syndromes: A Review.Clinical & experimental ophthalmology · 2025Review
- Targeting TUBB2B inhibits triple-negative breast cancer growth and brain-metastatic colonization.Journal of experimental & clinical cancer research : CR · 2025Article
- Multiplexed CRISPRi Reveals a Transcriptional Switch Between KLF Activators and Repressors in the Maturing Neocortex.bioRxiv : the preprint server for biology · 2025Article
- Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization.eLife · 2024Article
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.Nature communications · 2024Article
- Presynaptic perspective: Axonal transport defects in neurodevelopmental disorders.The Journal of cell biology · 2024Review
- Tubulin CFEOM mutations both inhibit or activate kinesin motor activity.Molecular biology of the cell · 2024Article
- Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization.bioRxiv : the preprint server for biology · 2024Article
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.medRxiv : the preprint server for health sciences · 2023Article
- Insights on the Role of α- and β-Tubulin Isotypes in Early Brain Development.Molecular neurobiology · 2023Review
- Phenotype, genotype, and management of congenital fibrosis of extraocular muscles type 1 in 16 Chinese families.Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie · 2023Article
- Deciphering the Tubulin Language: Molecular Determinants and Readout Mechanisms of the Tubulin Code in Neurons.International journal of molecular sciences · 2023Review
- The tubulin database: Linking mutations, modifications, ligands and local interactions.PloS one · 2023Article
- Editorial: Tubulinopathies: fundamental and clinical challenges.Frontiers in cellular neuroscience · 2023Article
- TUBB3 and KIF21A in neurodevelopment and disease.Frontiers in neuroscience · 2023Review
- Genetics of strabismus.Frontiers in ophthalmology · 2023Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Funding
Abstract
Microtubules are essential components of axon guidance machinery. Among β-tubulin mutations, only those in TUBB3 have been shown to cause primary errors in axon guidance. All identified mutations in TUBB2B result in polymicrogyria, but it remains unclear whether TUBB2B mutations can cause axon dysinnervation as a primary phenotype. We have identified a novel inherited heterozygous missense mutation in TUBB2B that results in an E421K amino acid substitution in a family who segregates congenital fibrosis of the extraocular muscles (CFEOM) with polymicrogyria. Diffusion tensor imaging of brains of affected family members reveals aberrations in the trajectories of commissural projection neurons, implying a paucity of homotopic connections. These observations led us to ask whether axon dysinnervation is a primary phenotype, and why the E421K, but not other, TUBB2B substitutions cause CFEOM. Expression of exogenous Tubb2b-E421K in developing callosal projection neurons is sufficient to perturb homotopic connectivity, without affecting neuronal production or migration. Using in vitro biochemical assays and yeast genetics, we find that TUBB2B-E421K αβ-heterodimers are incorporated into the microtubule network where they alter microtubule dynamics and can reduce kinesin localization. These data provide evidence that TUBB2B mutations can cause primary axon dysinnervation. Interestingly, by incorporating into microtubules and altering their dynamic properties, the E421K substitution behaves differently than previously identified TUBB2B substitutions, providing mechanistic insight into the divergence between resulting phenotypes. Together with previous studies, these findings highlight that β-tubulin isotypes function in both conserved and divergent ways to support proper human nervous system development.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.