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Mutations in theTUBB3gene, encoding β-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously describedTUBA1AandTUBB2Bphenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in theTUBB3gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3. These new findings demonstrate that the spectrum ofTUBB3-related phenotype is broader than previously described and includes malformations of cortical development (MCD) associated with neuronal migration and differentiation defects, axonal guidance and tract organization impairment. Complementary functional studies revealed that the mutated βIII-tubulin causing the MCD phenotype results in a reduction of heterodimer formation, yet produce correctly formed microtubules (MTs) in mammalian cells. Further to this, we investigated the properties of the MT network in patients' fibroblasts and revealed that MCD mutations can alter the resistance of MTs to depolymerization. Interestingly, this finding contrasts with the increased MT stability observed in the case of CFEOM3-related mutations. These results led us to hypothesize that either MT dynamics or their interactions with various MT-interacting proteins could be differently affected byTUBB3variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of theTUBB3-related spectrum.

Mutations in the neuronal β-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects