Title | An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Cederquist GY, Luchniak A, Tischfield MA, Peeva M, Song Y, Menezes MP, Chan W-M, Andrews C, Chew S, Jamieson RV, Gomes L, Flaherty M, Grant PEllen, Gupta ML, Engle EC |
Journal | Hum Mol Genet |
Volume | 21 |
Issue | 26 |
Pagination | 5484-99 |
Date Published | 2012 Dec 15 |
ISSN | 1460-2083 |
Keywords | Alleles, Amino Acid Substitution, Axons, Brain, Female, Fibrosis, Heterozygote, Humans, Kinesin, Male, Malformations of Cortical Development, Microtubules, Mutation, Missense, Neurogenesis, Neurons, Oculomotor Muscles, Pedigree, Phenotype, Protein Binding, Tubulin |
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. |
DOI | 10.1093/hmg/dds393 |
Alternate Journal | Hum. Mol. Genet. |
PubMed ID | 23001566 |
PubMed Central ID | PMC3516133 |
Grant List | HD018655 / HD / NICHD NIH HHS / United States R01GM094313 / GM / NIGMS NIH HHS / United States R01 EY012498 / EY / NEI NIH HHS / United States P30 HD018655 / HD / NICHD NIH HHS / United States R01 GM094313 / GM / NIGMS NIH HHS / United States / / Howard Hughes Medical Institute / United States T32 EY007143 / EY / NEI NIH HHS / United States R01EY12498 / EY / NEI NIH HHS / United States |
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