The Experts below are selected from a list of 160013367 Experts worldwide ranked by ideXlab platform
David A. Keays - One of the best experts on this subject based on the ideXlab platform.
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A proteomic survey of microtubule-associated proteins in a R402H TUBA1A mutant mouse.
PLoS genetics, 2020Co-Authors: Ines Leca, Alexander William Phillips, Iris Hofer, Lukas Landler, Lyubov Ushakova, Thomas David Cushion, Gerhard Dürnberger, Karel Stejskal, Karl Mechtler, David A. KeaysAbstract:Microtubules play a critical role in multiple aspects of neurodevelopment, including the generation, migration and differentiation of neurons. A recurrent mutation (R402H) in the α-tubulin gene TUBA1A is known to cause lissencephaly with cerebellar and striatal phenotypes. Previous work has shown that this mutation does not perturb the chaperone-mediated folding of tubulin heterodimers, which are able to assemble and incorporate into the microtubule lattice. To explore the molecular mechanisms that cause the disease state we generated a new conditional mouse line that recapitulates the R402H variant. We show that heterozygous mutants present with laminar phenotypes in the cortex and hippocampus, as well as a reduction in striatal size and cerebellar abnormalities. We demonstrate that homozygous expression of the R402H allele causes neuronal death and exacerbates a cell intrinsic defect in cortical neuronal migration. Microtubule sedimentation assays coupled with quantitative mass spectrometry demonstrated that the binding and/or levels of multiple microtubule associated proteins (MAPs) are perturbed by the R402H mutation including VAPB, REEP1, EZRIN, PRNP and DYNC1l1/2. Consistent with these data we show that the R402H mutation impairs dynein-mediated transport which is associated with a decoupling of the nucleus to the microtubule organising center. Our data support a model whereby the R402H variant is able to fold and incorporate into microtubules, but acts as a gain of function by perturbing the binding of MAPs.
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Cytoarchitectural disruption of the superior colliculus and an enlarged acoustic startle response in the TUBA1A mutant mouse.
Neuroscience, 2011Co-Authors: Andrew Edwards, James Cleak, Guo-jen Huang, Christoph Daniel Treiber, Ruth Pidsley, Jonathan Flint, Martin W Breuss, Peter L. Oliver, David A. KeaysAbstract:The Jenna mutant mouse harbours an S140G mutation in TUBA1A that impairs tubulin heterodimer formation resulting in defective neuronal migration during development. The consequence of decreased neuronal motility is a fractured pyramidal cell layer in the hippocampus and wave-like perturbations in the cerebral cortex. Here, we extend our characterisation of this mouse investigating the laminar architecture of the superior colliculus (SC). Our results reveal that the structure of the SC in mutant animals is intact; however, it is significantly thinner with an apparent fusion of the intermediate grey and white layers. Birthdate labelling at E12.5 and E13.5 showed that the S140G mutation impairs the radial migration of neurons in the SC. A quantitative assessment of neuronal number in adulthood reveals a massive reduction in postmitotic neurons in mutant animals, which we attribute to increased apoptotic cell death. Consistent with the role of the SC in modulating sensorimotor gating, and the circuitry that modulates this behaviour, we find that Jenna mutants exhibit an exaggerated acoustic startle response. Our results highlight the importance of TUBA1A for correct neuronal migration and implicate postnatal apoptotic cell death in the pathophysiological mechanisms underlying the tubulinopathies.
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The role of TUBA1A in adult hippocampal neurogenesis and the formation of the dentate gyrus.
Developmental neuroscience, 2010Co-Authors: David A. Keays, James Cleak, Guo-jen Huang, Andrew Edwards, Andreas Braun, Christoph Daniel Treiber, Ruth Pidsley, Jonathan FlintAbstract:The multitubulin hypothesis holds that each tubulin isotype serves a unique role with respect to microtubule function. Here we investigate the role of the α-tubulin subunit TUBA1A in adult hippocampal neurogenesis and the formation of the dentate gyrus. Employing birth date labelling and immunohistological markers, we show that mice harbouring an S140G mutation in TUBA1A present with normal neurogenic potential, but that this neurogenesis is often ectopic. Morphological analysis of the dentate gyrus in adulthood revealed a disorganised subgranular zone and a dispersed granule cell layer. We have shown that these anatomical abnormalities are due to defective migration of prospero-homeobox-1-positive neurons and T-box-brain-2-positive progenitors during development. Such migratory defects may also be responsible for the cytoarchitectural defects observed in the dentate gyrus of patients with mutations in TUBA1A.
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Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway
Human molecular genetics, 2010Co-Authors: Guoling Tian, Jamel Chelly, Fiona Francis, Xavier H. Jaglin, David A. Keays, Nicholas J. CowanAbstract:Malformations of cortical development are characteristic of a plethora of diseases that includes polymicrogyria, periventricular and subcortical heterotopia and lissencephaly. Mutations in TUBA1A and TUBB2B, each a member of the multigene families that encode α- and β-tubulins, have recently been implicated in these diseases. Here we examine the defects that result from nine disease-causing mutations (I188L, I238V, P263T, L286F, V303G, L397P, R402C, 402H, S419L) in TUBA1A. We show that the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield and that these can co-polymerize with microtubules in vitro. We identify several kinds of defects that result from these mutations. Among these are various defects in the chaperone-dependent pathway leading to de novo tubulin heterodimer formation. These include a defective interaction with the chaperone prefoldin, a reduced efficiency in the generation of productive folding intermediates as a result of inefficient interaction with the cytosolic chaperonin, CCT, and, in several cases, a failure to stably interact with TBCB, one of five tubulin-specific chaperones that act downstream of CCT in the tubulin heterodimer assembly pathway. Other defects include structural instability in vitro, diminished stability in vivo, a compromised ability to co-assemble with microtubules in vivo and a suppression of microtubule growth rate in the neurites (but not the soma) of cultured neurons. Our data are consistent with the notion that some mutations in TUBA1A result in tubulin deficit, whereas others reflect compromised interactions with one or more MAPs that are essential to proper neuronal migration.
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Tuba8 is expressed at low levels in the developing mouse and human brain.
American journal of human genetics, 2010Co-Authors: Andreas Braun, Jonathan Flint, Nicholas J. Cowan, Martin W Breuss, Marion Claudia Salzer, David A. KeaysAbstract:To the Editor: Sheridan and colleagues recently reported that mutations in the tubulin gene TUBA8 result in polymicrogyria with optic nerve hypoplasia (PMGOH [MIM 613180]).1 This conclusion is based on the mapping of two consanguineous families of Pakistani origin to a 7.42 Mb region on chromosome 22q11.2 that contains ∼230 genes including TUBA8. Drawing on our previous finding that mutations in TUBA1A cause lissencephaly2 and that mutations in TUBB2B cause asymmetric polymicrogyria,3 Sheridan and colleagues sequenced TUBA8 and found a 14 bp deletion in intron 1 that affects splicing. They provide further evidence that TUBA8 is involved in the disease state by analyzing its expression in the developing mouse brain by in situ hybridization. They report that Tuba8 is widely expressed in developing neural structures, with strongest expression in the cortical plate at E15.5 and E18.5 and in the cortical plate, subplate, and hippocampus at P0.
Karine Poirier - One of the best experts on this subject based on the ideXlab platform.
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Mutations in tubulin genes are frequent causes of various foetal malformations of cortical development including microlissencephaly
Acta Neuropathologica Communications, 2014Co-Authors: Catherine Fallet-bianco, Laurence Loeuillet, Ferechte Razavi, Patrícia Dias, Cherif Beldjord, Karine Poirier, Fabien Guimiot, Karine Lascelles, Annie Laquerriere, Nathalie CarionAbstract:Complex cortical malformations associated with mutations in tubulin genes are commonly referred to as “Tubulinopathies”. To further characterize the mutation frequency and phenotypes associated with tubulin mutations, we studied a cohort of 60 foetal cases. Twenty-six tubulin mutations were identified, of which TUBA1A mutations were the most prevalent (19 cases), followed by TUBB2B (6 cases) and TUBB3 (one case). Three subtypes clearly emerged. The most frequent (n = 13) was microlissencephaly with corpus callosum agenesis, severely hypoplastic brainstem and cerebellum. The cortical plate was either absent (6/13), with a 2–3 layered pattern (5/13) or less frequently thickened (2/13), often associated with neuroglial overmigration (4/13). All cases had voluminous germinal zones and ganglionic eminences. The second subtype was lissencephaly (n = 7), either classical (4/7) or associated with cerebellar hypoplasia (3/7) with corpus callosum agenesis (6/7). All foetuses with lissencephaly and cerebellar hypoplasia carried distinct TUBA1A mutations, while those with classical lissencephaly harbored recurrent mutations in TUBA1A (3 cases) or TUBB2B (1 case). The third group was polymicrogyria-like cortical dysplasia (n = 6), consisting of asymmetric multifocal or generalized polymicrogyria with inconstant corpus callosum agenesis (4/6) and hypoplastic brainstem and cerebellum (3/6). Polymicrogyria was either unlayered or 4-layered with neuronal heterotopias (5/6) and occasional focal neuroglial overmigration (2/6). Three had TUBA1A mutations and 3 TUBB2B mutations. Foetal TUBA1A tubulinopathies most often consist in microlissencephaly or classical lissencephaly with corpus callosum agenesis, but polymicrogyria may also occur. Conversely, TUBB2B mutations are responsible for either polymicrogyria (4/6) or microlissencephaly (2/6).
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Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human
Nature Neuroscience, 2014Co-Authors: Michel Kielar, Karine Poirier, Francoise Phan Dinh Tuy, Sara Bizzotto, Cécile Lebrand, Camino Juan Romero, Renske Oegema, Grazia Maria Mancini, Nadia Bahi-buisson, Robert OlasoAbstract:Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Emil knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.
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The Wide Spectrum of Tubulinopathies: What Are the Key Features for the Diagnosis?
Brain, 2014Co-Authors: Nadia Bahi-buisson, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Stéphanie Valence, Franck J. Fourniol, Nicolas Lebrun, Marie Hully, Catherine Fallet Bianco, Caroline ElieAbstract:Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
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Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria
neurogenetics, 2013Co-Authors: Stéphanie Valence, Karine Poirier, Cécile Masson, Yoann Saillour, Tania Attié-bitach, Nicolas Lebrun, Pascale Sonigo, Bettina Bessières, Alexandra Benachi, Ferechté Encha-razaviAbstract:Polymicrogyria (PMG) is a clinically heterogeneous malformation of cortical development, characterized by a loss of the normal gyral pattern that is replaced by many small and infolded gyri separated by shallow sulci that are partly fused in their depths. Causes of PMG are heterogeneous and include acquired and genetic causes. There are more than 100 syndromes possibly associated with PMG but mutations in specific genes such as SRPX2 , GPR56 , TUBB2B , TUBB3 , NHEJ1 , TUBA1A , TUBA8 , and WDR62 have been reported only in a minority of patients.
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Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria
European Journal of Human Genetics, 2013Co-Authors: Karine Poirier, Nathalie Boddaert, Yoann Saillour, Franck Fourniol, Fiona Francis, Isabelle Souville, Stéphanie Valence, Isabelle Desguerre, Jean Marie Lepage, Marine Line JacquemontAbstract:De novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders, ranging from lissencephaly to perisylvian pachygyria. Recently, one family with polymicrogyria (PMG) and mutation in TUBA1A was reported. Hence, the purpose of our study was to determine the frequency of TUBA1A mutations in patients with PMG and better define clinical and imaging characteristics for TUBA1A -related PMG. We collected 95 sporadic patients with non-syndromic bilateral PMG, including 54 with perisylvian PMG and 30 PMG with additional brain abnormalities. Mutation analysis of the TUBA1A gene was performed by sequencing of PCR fragments corresponding to TUBA1A- coding sequences. Three de novo missense TUBA1A mutations were identified in three unrelated patients with PMG representing 3.1% of PMG and 10% of PMGs with complex cerebral malformations. These patients had bilateral perisylvian asymmetrical PMG with dysmorphic basal ganglia cerebellar vermian dysplasia and pontine hypoplasia. These mutations (p.Tyr161His; p.Val235Leu; p.Arg390Cys) appear distributed throughout the primary structure of the alpha-tubulin polypeptide, but their localization within the tertiary structure suggests that PMG-related mutations are likely to impact microtubule dynamics, stability and/or local interactions with partner proteins. These findings broaden the phenotypic spectrum associated with TUBA1A mutations to PMG and further emphasize that additional brain abnormalities, that is, dysmorphic basal ganglia, hypoplastic pons and cerebellar dysplasia are key features for the diagnosis of TUBA1A -related PMG.
Jamel Chelly - One of the best experts on this subject based on the ideXlab platform.
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Tubulin-Related Malformations of Cortical Development
Cytoskeleton and Human Disease, 2012Co-Authors: Xavier H. Jaglin, Jamel Chelly, Nadia Bahi-buissonAbstract:The importance of the microtubule cytoskeleton during in utero brain development has emerged from a body of functional and genetic studies and was recently strengthened by the description of tubulin-related malformations of cortical development characterized by the disorganization of the cerebral cortex and the presence of ectopic neurons. Tubulin genes encoding specific isotypes of alpha- (TUBA1A, TUBA8) and beta-tubulins (TUBB2B, TUBB3) are associated with a spectrum of neuronal migration disorders ranging from a simplification of the folded aspect of the brain surface to a complete absence of folds (lissencephaly). The spectrum also encompasses forms of polymicrogyria characterized by an excessive number of small brain folds. Major axonal tract disruptions are also observed in combination with the aberrantly located neurons. Biochemical investigations have shown that an important number of the different mutations in TUBA1A, TUBB2B, and TUBB3 lead to folding and heterodimerization impairments, defective incorporation into microtubules, and/or alterations of microtubule dynamics and stability. This abnormal homeostasis of microtubules during neuronal polarization and migration might contribute to the disorganized cortical cytoarchitecture observed in patients as well as to the abnormal development of the major axon tracts connecting the cortex and various subcortical structures.
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Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway
Human molecular genetics, 2010Co-Authors: Guoling Tian, Jamel Chelly, Fiona Francis, Xavier H. Jaglin, David A. Keays, Nicholas J. CowanAbstract:Malformations of cortical development are characteristic of a plethora of diseases that includes polymicrogyria, periventricular and subcortical heterotopia and lissencephaly. Mutations in TUBA1A and TUBB2B, each a member of the multigene families that encode α- and β-tubulins, have recently been implicated in these diseases. Here we examine the defects that result from nine disease-causing mutations (I188L, I238V, P263T, L286F, V303G, L397P, R402C, 402H, S419L) in TUBA1A. We show that the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield and that these can co-polymerize with microtubules in vitro. We identify several kinds of defects that result from these mutations. Among these are various defects in the chaperone-dependent pathway leading to de novo tubulin heterodimer formation. These include a defective interaction with the chaperone prefoldin, a reduced efficiency in the generation of productive folding intermediates as a result of inefficient interaction with the cytosolic chaperonin, CCT, and, in several cases, a failure to stably interact with TBCB, one of five tubulin-specific chaperones that act downstream of CCT in the tubulin heterodimer assembly pathway. Other defects include structural instability in vitro, diminished stability in vivo, a compromised ability to co-assemble with microtubules in vivo and a suppression of microtubule growth rate in the neurites (but not the soma) of cultured neurons. Our data are consistent with the notion that some mutations in TUBA1A result in tubulin deficit, whereas others reflect compromised interactions with one or more MAPs that are essential to proper neuronal migration.
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Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype.
Acta neuropathologica, 2010Co-Authors: Magalie Lecourtois, Jamel Chelly, Karine Poirier, Xavier H. Jaglin, Gaëlle Friocourt, Alice Goldenberg, Pascale Saugier-veber, Annie LaquerriereAbstract:Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks’ gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.
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Tubulin-related cortical dysgeneses: microtubule dysfunction underlying neuronal migration defects
Trends in genetics : TIG, 2009Co-Authors: Xavier H. Jaglin, Jamel ChellyAbstract:The fine tuning of proliferation and neurogenesis, neuronal migration and differentiation and connectivity underlies the proper development of the cerebral cortex. Mutations in genes involved in these processes are responsible for neurodevelopmental disorders, such as cortical dysgeneses, which are usually associated with severe mental retardation and epilepsy. Over the past few years, the importance of cytoskeleton components in cellular processes crucial for cortical development has emerged from a body of functional data. This was reinforced by the association of mutations in the LIS1 and DCX genes, which both encode proteins involved in microtubule (MT) homeostasis, with cerebral cortex developmental disorders. The recent discovery of patients with lissencephaly and bilateral asymmetrical polymicrogyria (PMG) carrying mutations in the α- and β-tubulin-encoding genes TUBA1A and TUBB2B further supports this view, and also raises interesting questions about the specific roles played by certain tubulin isotypes during the development of the cortex.
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Neuropathological phenotype of a distinct form of lissencephaly associated with mutations in TUBA1A
Brain, 2008Co-Authors: Catherine Fallet-bianco, Laurence Loeuillet, Cherif Beldjord, Jamel Chelly, Karine Poirier, Yoann Saillour, Philippe Loget, Francoise Chapon, Laurent Pasquier, Fiona FrancisAbstract:Lissencephalies are congenital malformations responsible for epilepsy and mental retardation in children. A number of distinct lissencephaly syndromes have been characterized, according to the aspect and the topography of the cortical malformation, the involvement of other cerebral structures and the identified genetic defect. A mutation in TUBA1A, coding for alpha 1 tubulin, was recently identified in a mutant mouse associated with a behavioural disorder and a disturbance of the laminar cytoarchitectony of the isocortex and the hippocampus. Mutations of TUBA1A were subsequently found in children with mental retardation and brain malformations showing a wide spectrum of severities. Here we describe four fetuses with TUBA1A mutations and a prenatal diagnosis of major cerebral dysgeneses leading to a termination of pregnancy due to the severity of the prognosis. The study of these fetuses at 23, 25, 26 and 35 gestational weeks shows that mutations of TUBA1A are associated with a neuropathological phenotypic spectrum which consistently encompasses five brain structures, including the neocortex, hippocampus, corpus callosum, cerebellum and brainstem. Less constantly, abnormalities were also identified in basal ganglia, olfactory bulbs and germinal zones. At the microscopical level, migration abnormalities are suggested by abnormal cortical and hippocampal lamination, and heterotopic neurons in the cortex, cerebellum and brainstem. There are also numerous neuronal differentiation defects, such as the presence of immature, randomly oriented neurons and abnormal axon tracts and fascicles. Thus, the TUBA1A phenotype is distinct from LIS1, DCX, RELN and ARX lissencephalies. Compared with the phenotypes of children mutated for TUBA1A, these prenatally diagnosed fetal cases occur at the severe end of the TUBA1A lissencephaly spectrum. This study emphasizes the importance of neuropathological examinations in cases of lissencephaly for improving our knowledge of the distinct pathogenetic and pathophysiological mechanisms.
Xavier H. Jaglin - One of the best experts on this subject based on the ideXlab platform.
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Mutation of the α-tubulin TUBA1A leads to straighter microtubules and perturbs neuronal migration.
The Journal of cell biology, 2017Co-Authors: Richard Belvindrah, Kathiresan Natarajan, Preety Shabajee, Elodie Bruel-jungerman, Jennifer Bernard, Marie Goutierre, Imane Moutkine, Xavier H. Jaglin, Mythili Savariradjane, Theano IrinopoulouAbstract:Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement that are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype TUBA1A is associated with cortical malformations in humans. In this study, we provide detailed in vivo and in vitro analyses of TUBA1A mutants. In mice carrying a TUBA1A missense mutation (S140G), neurons accumulate, and glial cells are dispersed along the rostral migratory stream in postnatal and adult brains. Live imaging of TUBA1A-mutant neurons revealed slowed migration and increased neuronal branching, which correlated with directionality alterations and perturbed nucleus–centrosome (N–C) coupling. TUBA1A mutation led to increased straightness of newly polymerized MTs, and structural modeling data suggest a conformational change in the α/β-tubulin heterodimer. We show that Tuba8, another α-tubulin isotype previously associated with cortical malformations, has altered function compared with TUBA1A. Our work shows that TUBA1A plays an essential, noncompensated role in neuronal saltatory migration in vivo and highlights the importance of MT flexibility in N–C coupling and neuronal-branching regulation during neuronal migration.
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mutations in the β tubulin gene tubb5 cause microcephaly with structural brain abnormalities
Cell Reports, 2012Co-Authors: Martin W Breuss, Karine Poirier, Xavier H. Jaglin, Andreas Braun, Guoling Tian, Julian Iktsen Heng, Thomas Gstrein, Linh Ngo, Matilda Haas, Nadia BahibuissonAbstract:The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.
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Tubulin-Related Malformations of Cortical Development
Cytoskeleton and Human Disease, 2012Co-Authors: Xavier H. Jaglin, Jamel Chelly, Nadia Bahi-buissonAbstract:The importance of the microtubule cytoskeleton during in utero brain development has emerged from a body of functional and genetic studies and was recently strengthened by the description of tubulin-related malformations of cortical development characterized by the disorganization of the cerebral cortex and the presence of ectopic neurons. Tubulin genes encoding specific isotypes of alpha- (TUBA1A, TUBA8) and beta-tubulins (TUBB2B, TUBB3) are associated with a spectrum of neuronal migration disorders ranging from a simplification of the folded aspect of the brain surface to a complete absence of folds (lissencephaly). The spectrum also encompasses forms of polymicrogyria characterized by an excessive number of small brain folds. Major axonal tract disruptions are also observed in combination with the aberrantly located neurons. Biochemical investigations have shown that an important number of the different mutations in TUBA1A, TUBB2B, and TUBB3 lead to folding and heterodimerization impairments, defective incorporation into microtubules, and/or alterations of microtubule dynamics and stability. This abnormal homeostasis of microtubules during neuronal polarization and migration might contribute to the disorganized cortical cytoarchitecture observed in patients as well as to the abnormal development of the major axon tracts connecting the cortex and various subcortical structures.
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Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway
Human molecular genetics, 2010Co-Authors: Guoling Tian, Jamel Chelly, Fiona Francis, Xavier H. Jaglin, David A. Keays, Nicholas J. CowanAbstract:Malformations of cortical development are characteristic of a plethora of diseases that includes polymicrogyria, periventricular and subcortical heterotopia and lissencephaly. Mutations in TUBA1A and TUBB2B, each a member of the multigene families that encode α- and β-tubulins, have recently been implicated in these diseases. Here we examine the defects that result from nine disease-causing mutations (I188L, I238V, P263T, L286F, V303G, L397P, R402C, 402H, S419L) in TUBA1A. We show that the expression of all the mutant proteins in vitro results in the generation of tubulin heterodimers in varying yield and that these can co-polymerize with microtubules in vitro. We identify several kinds of defects that result from these mutations. Among these are various defects in the chaperone-dependent pathway leading to de novo tubulin heterodimer formation. These include a defective interaction with the chaperone prefoldin, a reduced efficiency in the generation of productive folding intermediates as a result of inefficient interaction with the cytosolic chaperonin, CCT, and, in several cases, a failure to stably interact with TBCB, one of five tubulin-specific chaperones that act downstream of CCT in the tubulin heterodimer assembly pathway. Other defects include structural instability in vitro, diminished stability in vivo, a compromised ability to co-assemble with microtubules in vivo and a suppression of microtubule growth rate in the neurites (but not the soma) of cultured neurons. Our data are consistent with the notion that some mutations in TUBA1A result in tubulin deficit, whereas others reflect compromised interactions with one or more MAPs that are essential to proper neuronal migration.
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Human lissencephaly with cerebellar hypoplasia due to mutations in TUBA1A: expansion of the foetal neuropathological phenotype.
Acta neuropathologica, 2010Co-Authors: Magalie Lecourtois, Jamel Chelly, Karine Poirier, Xavier H. Jaglin, Gaëlle Friocourt, Alice Goldenberg, Pascale Saugier-veber, Annie LaquerriereAbstract:Neuronal migration disorders account for a substantial number of cortical malformations, the most severe forms being represented by lissencephalies. Classical lissencephaly has been shown to result from mutations in LIS1 (PAFAH1B1; MIM#601545), DCX (Doublecortin; MIM#300121), ARX (Aristaless-related homeobox gene; MIM#300382), RELN (Reelin; MIM#600514) and VLDLR (Very low density lipoprotein receptor; MIM#224050). More recently, de novo missense mutations in the alpha-tubulin 1a gene (TUBA1A) located on chromosome 12q13.12, have also been associated with more or less severe defects of cortical development, resulting in complete agyria in the most severe cases of lissencephaly. We report here the cerebral lesions in a 36 weeks’ gestation female foetus with a novel de novo missense mutation in the TUBA1A gene, presenting the most severe antenatal phenotype reported so far. Using routine immunohistochemistry and confocal microscopy, we show evidence for defects in axonal transport in addition to defects in neuronal migration and differentiation, giving new insights to the pathophysiology of this form of lissencephaly.
Nadia Bahi-buisson - One of the best experts on this subject based on the ideXlab platform.
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Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly.
Neurogenetics, 2015Co-Authors: Mara Cavallin, Laurence Hubert, Vincent Cantagrel, Arnold Munnich, Nathalie Boddaert, Catherine Vincent-delorme, Jean Christophe Cuvellier, Cécile Masson, Claude Besmond, Nadia Bahi-buissonAbstract:To the editorKIF5C(NM_004522.2) mutationwas originallyreportedinafamily with congenital microcephaly and frontalpolymicrogyria.Thesepatientscarriedagermlinemosaicmu-tation (p.Glu237Val) [1]. Recently, a mutation affecting thesame residue (p.Glu237Lys) was reported in a patient withpostnatal microcephaly and frontal pachygyria [2].Pachygyria is considered to be at the less severe end of thespectrum of lissencephaly and encompasses a broader spec-trum of clinical features [3]. Pachygyria and lissencephalyhave a shared genetic basis (LIS1, DCX, TUBA1A)butpachygyria can also be observed in other conditions (ACTB,ACTG1,RELN,DYNC1H1mutations).However,themajorityof sporadic cases of pachygyria remains unexplained.
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Mutations in Eml1 lead to ectopic progenitors and neuronal heterotopia in mouse and human
Nature Neuroscience, 2014Co-Authors: Michel Kielar, Karine Poirier, Francoise Phan Dinh Tuy, Sara Bizzotto, Cécile Lebrand, Camino Juan Romero, Renske Oegema, Grazia Maria Mancini, Nadia Bahi-buisson, Robert OlasoAbstract:Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen HeCo mice display this phenotype, and our study revealed that misplaced apical progenitors contribute to heterotopia formation. While HeCo neurons migrated at the same speed as wild type, abnormally distributed dividing progenitors were found throughout the cortical wall from embryonic day 13. We identified Eml1, encoding a microtubule-associated protein, as the gene mutated in HeCo mice. Full-length transcripts were lacking as a result of a retrotransposon insertion in an intron. Emil knockdown mimicked the HeCo progenitor phenotype and reexpression rescued it. We further found EML1 to be mutated in ribbon-like heterotopia in humans. Our data link abnormal spindle orientations, ectopic progenitors and severe heterotopia in mouse and human.
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The Wide Spectrum of Tubulinopathies: What Are the Key Features for the Diagnosis?
Brain, 2014Co-Authors: Nadia Bahi-buisson, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Stéphanie Valence, Franck J. Fourniol, Nicolas Lebrun, Marie Hully, Catherine Fallet Bianco, Caroline ElieAbstract:Complex cortical malformations associated with mutations in tubulin genes: TUBA1A, TUBA8, TUBB2B, TUBB3, TUBB5 and TUBG1 commonly referred to as tubulinopathies, are a heterogeneous group of conditions with a wide spectrum of clinical severity. Among the 106 patients selected as having complex cortical malformations, 45 were found to carry mutations in TUBA1A (42.5%), 18 in TUBB2B (16.9%), 11 in TUBB3 (10.4%), three in TUBB5 (2.8%), and three in TUBG1 (2.8%). No mutations were identified in TUBA8. Systematic review of patients' neuroimaging and neuropathological data allowed us to distinguish at least five cortical malformation syndromes: (i) microlissencephaly (n = 12); (ii) lissencephaly (n = 19); (iii) central pachygyria and polymicrogyria-like cortical dysplasia (n = 24); (iv) generalized polymicrogyria-like cortical dysplasia (n = 6); and (v) a 'simplified' gyral pattern with area of focal polymicrogyria (n = 19). Dysmorphic basal ganglia are the hallmark of tubulinopathies (found in 75% of cases) and are present in 100% of central pachygyria and polymicrogyria-like cortical dysplasia and simplified gyral malformation syndromes. Tubulinopathies are also characterized by a high prevalence of corpus callosum agenesis (32/80; 40%), and mild to severe cerebellar hypoplasia and dysplasia (63/80; 78.7%). Foetal cases (n = 25) represent the severe end of the spectrum and show specific abnormalities that provide insights into the underlying pathophysiology. The overall complexity of tubulinopathies reflects the pleiotropic effects of tubulins and their specific spatio-temporal profiles of expression. In line with previous reports, this large cohort further clarifies overlapping phenotypes between tubulinopathies and although current structural data do not allow prediction of mutation-related phenotypes, within each mutated gene there is an associated predominant pattern of cortical dysgenesis allowing some phenotype-genotype correlation. The core phenotype of TUBA1A and TUBG1 tubulinopathies are lissencephalies and microlissencephalies, whereas TUBB2B tubulinopathies show in the majority, centrally predominant polymicrogyria-like cortical dysplasia. By contrast, TUBB3 and TUBB5 mutations cause milder malformations with focal or multifocal polymicrogyria-like cortical dysplasia with abnormal and simplified gyral pattern.
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Tubulin-Related Malformations of Cortical Development
Cytoskeleton and Human Disease, 2012Co-Authors: Xavier H. Jaglin, Jamel Chelly, Nadia Bahi-buissonAbstract:The importance of the microtubule cytoskeleton during in utero brain development has emerged from a body of functional and genetic studies and was recently strengthened by the description of tubulin-related malformations of cortical development characterized by the disorganization of the cerebral cortex and the presence of ectopic neurons. Tubulin genes encoding specific isotypes of alpha- (TUBA1A, TUBA8) and beta-tubulins (TUBB2B, TUBB3) are associated with a spectrum of neuronal migration disorders ranging from a simplification of the folded aspect of the brain surface to a complete absence of folds (lissencephaly). The spectrum also encompasses forms of polymicrogyria characterized by an excessive number of small brain folds. Major axonal tract disruptions are also observed in combination with the aberrantly located neurons. Biochemical investigations have shown that an important number of the different mutations in TUBA1A, TUBB2B, and TUBB3 lead to folding and heterodimerization impairments, defective incorporation into microtubules, and/or alterations of microtubule dynamics and stability. This abnormal homeostasis of microtubules during neuronal polarization and migration might contribute to the disorganized cortical cytoarchitecture observed in patients as well as to the abnormal development of the major axon tracts connecting the cortex and various subcortical structures.
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Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations
Journal of medical genetics, 2008Co-Authors: Nadia Bahi-buisson, Karine Poirier, Nathalie Boddaert, Yoann Saillour, Laetitia Castelnau, Nicole Philip, Gunnar M. Buyse, Laurent Villard, Sylvie Joriot, Stéphane MarretAbstract:Objective: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to 5 previously described patients with TUBA1A mutations. Results: We detected de novo TUBA1A mutations in 6 patients and highlight the existence of a prominent form of TUBA1A-related lissencephaly. In 4 patients, the mutations identified c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R) have not been reported before and in 2 others, the mutation corresponds to a recurrent missense mutation c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific of TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia / tetraplegia. Conclusions: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A-related lissencephalies from those related to LIS1, DCX and ARX genes.
