Mutations in the Β-tubulin gene TUBB2B result in asymmetrical polymicrogyria

Institut Cochin, Université Paris Descartes CNRS (UMR 8104), Paris, France.
Nature Genetics (Impact Factor: 29.35). 06/2009; 41(6):746-52. DOI: 10.1038/ng.380
Source: PubMed


Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.

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    • "Microtubule stability may be diminished during the critical process of cell migration [28]. All mutations reported thus far in TUBA1A, TUBB2B, and TUBB3 are heterozygous missense mutations [3,4,29-31]. Missense mutations in the absence of nonsense mutations, frameshifts, or genomic deletions support altered protein function, rather than haploinsufficiency, as the primary genetic etiology of these tubulin-related disorders [28]. "
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    ABSTRACT: Background Owing to the number of genetic mutations that contribute to malformations of cortical development, identification of causative mutations in candidate genes is challenging. To overcome these challenges, we performed whole-exome sequencing in this study. Case presentation A Japanese patient presented with microcephaly and severe developmental delay. Brain magnetic resonance imaging showed the presence of colpocephaly associated with lateral ventricle dilatation and the presence of a simplified gyral pattern. Hypoplasia of the corpus callosum and cerebellar vermis were also noted. Because Sanger sequencing is expensive, laborious, and time-consuming, whole-exome sequencing was performed and a de novo missense mutation in TUBA1A (E27Q) was identified. Conclusion The novel mutation identified in this study was located in the genetic region that encodes the N-terminal domain of TUBA1A, a region of TUBA1A with few reported mutations. Retrospective assessment of the clinical and radiological features of this patient―i.e., microcephaly, lissencephaly (pachygyria) with cerebellar hypoplasia, and corpus callosum hypoplasia―indicated that the TUBA1A mutation did not lead to any contradictions. Because rapid and comprehensive mutation analysis by whole-exome sequencing is time- and cost-effective, it might be useful for genetic counseling of patients with sporadic malformations of cortical development.
    BMC Research Notes 07/2014; 7(1):465. DOI:10.1186/1756-0500-7-465
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    • "Genetic mutations have been identified in association with PMG, but in none is PMG the sole or specific abnormality. A single PMG syndrome may have multiple genetic aetiologies and, conversely, single genetic causes may give rise to variable PMG patterns [5-7]. Even combined analysis of clinical and imaging features, pathology and genetics fails to identify the underlying aetiology in the majority of cases. "
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    ABSTRACT: Polymicrogyria (PMG) is a complex cortical malformation which has so far defied any mechanistic or genetic explanation. Adopting a broad definition of an abnormally folded or festooned cerebral cortical neuronal ribbon, this review addresses the literature on PMG and the mechanisms of its development, as derived from the neuropathological study of many cases of human PMG, a large proportion in fetal life. This reveals the several processes which appear to be involved in the early stages of formation of polymicrogyric cortex. The most consistent feature of developing PMG is disruption of the brain surface with pial defects, over-migration of cells, thickening and reduplication of the pial collagen layers and increased leptomeningeal vascularity. Evidence from animal models is consistent with our observations and supports the notion that disturbance in the formation of the leptomeninges or loss of their normal signalling functions are potent contributors to cortical malformation. Other mechanisms which may lead to PMG include premature folding of the neuronal band, abnormal fusion of adjacent gyri and laminar necrosis of the developing cortex. The observation of PMG in association with other and better understood forms of brain malformation, such as cobblestone cortex, suggests mechanistic pathways for some forms of PMG. The role of altered physical properties of the thickened leptomeninges in exerting mechanical constraints on the developing cortex is also considered. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0080-3) contains supplementary material, which is available to authorized users.
    07/2014; 2(1):80. DOI:10.1186/PREACCEPT-1342027701333555
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    • "Migrating cortical neurons extend a leading process that guides their migration and has a cytoskeletal architecture similar to axons (Marín et al., 2010). Moreover, cortical neuron migration is impaired in both APC-and b2B-tubulin-defi- cient rodent models (Jaglin et al., 2009; Yokota et al., 2009), while mutations in human b2B-tubulin cause defects in axon tracts and cortical neuron migration (Jaglin et al., 2009; Cederquist et al., 2012; Romaniello et al., 2012). Therefore, based on our data in growth cones, we hypothesized that cortical neuron migration might be impaired by blocking the b2B-tubulin 3 0 UTR APC binding site. "
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    ABSTRACT: Adenomatous polyposis coli (APC) is a microtubule plus-end scaffolding protein important in biology and disease. APC is implicated in RNA localization, although the mechanisms and functional signifi- cance remain unclear. We show APC is an RNA-bind- ing protein and identify an RNA interactome by HITS-CLIP. Targets were highly enriched for APC- related functions, including microtubule organiza- tion, cell motility, cancer, and neurologic disease. Among the targets is b2B-tubulin, known to be required in human neuron and axon migration. We show b2B-tubulin is synthesized in axons and local- izes preferentially to dynamic microtubules in the growth cone periphery. APC binds the b2B-tubulin 30 UTR; experiments interfering with this interaction reduced b2B-tubulin mRNA axonal localization and expression, depleted dynamic microtubules and the growth cone periphery, and impaired neuron migration. These results identify APC as a platform binding functionally related protein and RNA net- works, and suggest a self-organizing model for the microtubule to localize synthesis of its own subunits.
    Cell 07/2014; 158(2):368-382. DOI:10.1016/j.cell.2014.05.042 · 32.24 Impact Factor
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