DTI tractography of lissencephaly caused by TUBA1A mutation

Kamiya, Kazutaka; Tanaka, Fumine; Ikeno, Mitsuru; Okumura, Akihisa; Aoki, Shigeki

doi:10.1007/s10072-014-1662-3

Cited by 11 publications

(5 citation statements)

References 7 publications

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“…Given that neuronal migration in lissencephaly is altered, especially of those neurons destined to upper cortical layers, improper position of neurons would ultimately lead to failure of proper development of short- to medium-range cortico-cortical association connections predominantly. These results are in agreement with other investigators (Poretti et al, 2013; Kamiya et al, 2014). However, due to the known limitations of diffusion tensor imaging (Jones et al, 2013), a larger study with co-registered histological slices is needed in order to characterize intracortical fibers in patients with various types of lissencephaly.…”

Section: Discussionsupporting

confidence: 94%

Structural and Diffusion MRI Analyses With Histological Observations in Patients With Lissencephaly

Vasung

Rezayev

Yun

et al. 2019

Front. Cell Dev. Biol.

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The development of cortical convolutions, gyri and sulci, is a complex process that takes place during prenatal development. Lissencephaly, a rare genetic condition characterized by the lack of cortical convolutions, offers a model to look into biological processes that lead to the development of convolutions. Retrospective, qualitative, and quantitative analyses of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed in patients with lissencephaly ( N = 10) and age-/sex-matched controls ( N = 10). In order to identify microstructural correlates of structural MRI and DTI findings, postmortem brains of patients with lissencephaly ( N = 4) and age-matched controls ( N = 4) were also examined with histology. Patients with lissencephaly had significantly smaller gyrification index and volumes of hemispheric white and gray matter, compared to the age-/sex-matched control group. However, there was no significant difference between groups in the subcortical gray matter volumes. Although the majority of patients with lissencephaly had a preserved normal-like appearance of major fissures and primary sulci, the spatial distribution of agyric cortical regions was different in patients with lissencephaly-1 ( LIS1 ) and doublecortin ( DCX ) mutations. Lastly, in patients with lissencephaly, the spatiotemporal distribution of projection pathways was preserved while short- to medium-range cortico-cortical pathways were absent or fewer in number. Our results indicate that in the patients with lissencephaly cortical system is affected more than the subcortical one.

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Section: Discussionsupporting

confidence: 94%

Structural and Diffusion MRI Analyses With Histological Observations in Patients With Lissencephaly

Vasung

Rezayev

Yun

et al. 2019

Front. Cell Dev. Biol.

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“…Interestingly, the TUBA1A-R402H neurons that reached the cortical plate exhibited significantly less GFP fluorescence than TUBA1A-R402C expressing neurons in the cortical plate, suggesting that TUBA1A-R402H may be more detrimental to neuronal migration than TUBA1A-R402C. These data are consistent with published patient data in which patients with TUBA1A-R402H mutations tend to display more severe lissencephaly phenotypes than patients with TUBA1A-R402C mutations (Poirier et al 2007;Fallet-Bianco et al 2008;Morris-Rosendahl et al 2008;Kumar et al 2010;Bahi-Buisson et al 2014;Kamiya et al 2014;Keays et al 2007). In budding yeast, the interference of dynein activity also scales with the percentage of mutant α-tubulin in the cell.…”

Section: Discussionsupporting

confidence: 89%

“…Numerous studies have described the lissencephaly spectrum phenotype observed in tubulinopathy patients harboring heterozygous TUBA1A-R402C and R402H mutations (Keays et al 2007;Poirier et al 2007;Morris-Rosendahl et al 2008;Kumar et al 2010;Fallet-Bianco et al 2008;Bahi-Buisson et al 2014;Fallet-Bianco et al 2014;Kamiya et al 2014), but whether these mutations alone are sufficient to dominantly disrupt cortical migration has not been established. To examine how TUBA1A-R402C and TUBA1A-R402H impact neuronal migration, we performed in utero electroporation to introduce ectopic TUBA1A expression in the ventricular zone of C57Bl6 wild-type mice (Figure 1).…”

Section: Mutations To Conserved Residue R402 Dominantly Disrupt Cortimentioning

confidence: 99%

TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity

Aiken

Moore

Bates

2018

Preprint

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Tubulinopathies' are severe human brain malformations associated with mutations in tubulin genes. Despite the identification of many tubulin mutations in patients, we do not understand how these mutations impact the microtubule cytoskeleton, how the changes to microtubule function lead to brain malformations, or how different tubulin isotypes regulate microtubules to support normal neurodevelopment. TUBA1A α-tubulin is the most commonly affected tubulin isotype in tubulinopathy patients. Heterozygous mutations in TUBA1A have been identified in patients with diverse cortical malformations including microlissencephaly, lissencephaly, pachygyria, and polymicrogyria. Here we focus on mutations affecting the conserved arginine at position 402 (R402), which account for 30% of all reported TUBA1A mutations in patients. We demonstrate that exogenous expression of TUBA1A-R402C and TUBA1A-R402H patient alleles is sufficient to dominantly disrupt cortical neuron migration in the developing mouse brain, recapitulating the human lissencephaly phenotype. Intriguingly, ectopic expression of TUBA1A-R402C/H alleles does not alter morphology, axonal trafficking, or microtubule polymerization rates in cultured neurons, but does lead to subtle changes in axonal microtubule orientation. Further, we find that budding yeast α-tubulin with analogous R402C and R402H mutations assembles into microtubules but disrupts the activity of the microtubule motor dynein. The level of dynein impairment scales with abundance of R402 mutant α-tubulin in the cell. Together, our results support a model in which tubulinopathy mutations at R402 poison the microtubule network in young neurons by creating defective binding sites for dynein at the microtubule surface.

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“…Similarly, neurodevelopmental alterations are present in iPSC derived from idiopathic ASD subjects, where morphometric analyses revealed a developmental acceleration in differentiating neurons and the transcriptomic signature exhibited a temporal dysregulation in a group of genes involved in biological processes such as neuron differentiation, cell morphogenesis and synaptic signaling (Schafer et al, 2019). Patterns of neuronal migration observed using MRI demonstrates a persistence of radial coherent structures in a post-natal brain that mirrors those observed in embryonic weeks 15-28 (Kamiya et al, 2014), which implies disruption of radial scaffold or unit formation and function of radial glial progenitors in a developing brain with a mutation in TUBA1A, a protein associated with microcephaly, lissencephaly, intractable epilepsy, and developmental delay (Casingal et al, 2022). NSCs within the SVZ display more proliferative markers, including Ki-67 and BrdU, but appear to stall before completing neurogenesis or mitosis (Marchetto et al, 2017;Varghese et al, 2017;Guarnieri et al, 2018;Grasselli et al, 2020).…”

Section: Introductionmentioning

confidence: 62%

Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study

Takahashi

Allan²,

Peres³

et al. 2023

Front. Neurosci.

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IntroductionAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain.MethodsWe used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR.ResultsThrough MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens.ConclusionThese findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.

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DTI tractography of lissencephaly caused by TUBA1A mutation

Cited by 11 publications

References 7 publications

Structural and Diffusion MRI Analyses With Histological Observations in Patients With Lissencephaly

Structural and Diffusion MRI Analyses With Histological Observations in Patients With Lissencephaly

TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity

Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study

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