Mutations in α- and β-tubulin encoding genes: Implications in brain malformations

Romaniello, Romina; Arrigoni, Filippo; Bassi, Maria Teresa; Borgatti, Renato

doi:10.1016/j.braindev.2014.06.002

Cited by 97 publications

(60 citation statements)

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“…Consistent with this hypothesis, distinct roles of tubulin isotypes have been implicated. In humans, mutations of different tubulin isotypes cause distinct neurological disorders (for reviews, see Chakraborti et al, 2016;Romaniello et al, 2015). In Drosophila, a testis-specific isotype cannot be replaced by a somatic isotype (Fackenthal et al, 1993;Hoyle and Raff, 1990).…”

Section: Introductionmentioning

confidence: 99%

Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos

Honda

Tsuchiya

Sumiyoshi

et al. 2017

Journal of Cell Science

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Microtubules (MTs) are polymers composed of α-and β-tubulin heterodimers that are generally encoded by genes at multiple loci. Despite implications of distinct properties depending on the isotype, how these heterodimers contribute to the diverse MT dynamics in vivo remains unclear. Here, by using genome editing and depletion of tubulin isotypes following RNAi, we demonstrate that four tubulin isotypes (hereafter referred to as α1, α2, β1 and β2) cooperatively confer distinct MT properties in Caenorhabditis elegans early embryos. GFP insertion into each isotype locus reveals their distinct expression levels and MT incorporation rates. Substitution of isotype coding regions demonstrates that, under the same isotype concentration, MTs composed of β1 have higher switching frequency between growth and shrinkage compared with MTs composed of β2. Lower concentration of β-tubulins results in slower growth rates, and the two α-tubulins distinctively affect growth rates of MTs composed of β1. Alteration of ratio and concentration of isotypes distinctively modulates both growth rate and switching frequency, and affects the amplitude of mitotic spindle oscillation. Collectively, our findings demonstrate that MT dynamics are modulated by the combination (ratio and concentration) of tubulin isotypes with distinct properties, which contributes to create diverse MT behaviors in vivo.

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Section: Introductionmentioning

confidence: 99%

Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos

Honda

Tsuchiya

Sumiyoshi

et al. 2017

Journal of Cell Science

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“…On the contrary, mutations in Tubulin β-3 (TUBB3) gene cause epilepsy only in about 15% of cases, while seizures has never been described in Tubulin β (TUBB) gene [7].…”

Section: Tubulin Clinical Phenotypes and Epileptogenesismentioning

confidence: 99%

“…The epilepsy described to date in patients carrying mutations in the TUBA1A gene (about 50% of the cases) present various seizures patterns, including early-onset epileptic seizures as infantile spasms, tonic, early generalized tonic-clonic, and focal seizures [7]. These may evolve in atypical absence seizures or myoclonic and atonic drop seizures in later childhood.…”

Section: Tubulin α-1a (Tuba1a) Gene [Orpha171680 Omim 611603]mentioning

confidence: 99%

“…Tubulin proteins play a key role in several cellular processes crucial for a proper cortical development during neuronal proliferation, migration, differentiation, cortical laminar organization, and axonal guidance of the radial glia (axon outgrowth and maintenance) [7].…”

Section: Multigene Tubulin Familymentioning

confidence: 99%

“…Among MCDs-related genes, a key role is played by genes encoding microtubules (MTs), proteins with the function of providing structures and forces needed by neurons to migrate and to develop axonal and dendritic processes [6]. In recent years, mutations in the tubulin multigene family have been suggested to be involved in the alteration of the dynamic properties and functions of microtubules in several ways, leading to a broad spectrum of disorders of brain development, namely "Tubunopathies" [4,7,8].…”

Section: Introductionmentioning

confidence: 99%

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Epilepsy in Multigene Tubulin Family Mutations

Romaniello¹,

Borgatti²

2015

J Neurol Neurophysiol

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Mutations in α-and β-tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation, and axon guidance and maintenance. Motor and language developmental disorders, cognitive impairment and epilepsy are the main clinical associated symptoms. Frequency and severity of these disorders are largely related with the involvement of specific tubulin genes and their functions.The present study summarizes all the published data on tubulin family gene mutations and the associated clinical phenotype in order to define epilepsy recurrence and its characteristics.Mutations disrupting the stability of microtubules, mainly mechanisms involving neuronal migration and organization, may play an important role in epileptogenicity. Moreover, since mutations in the α-and β-tubulin genes are responsible for a large spectrum of cortical and brain malformations, they do not show a high specificity and correlation with an epileptic phenotype unlike other MCDs-related genes. Usually seizures start early (in the first year of life) and they are more often generalized (infantile spasms, tonic, tonic-clonic) as expression of a diffuse cortical maldevelopment.Mutations in the TUBA1A gene, causing various degrees of agyria-pachigyria spectrum, classical lissencephaly or polymicrogyria, represent among tubulin genes, the major responsible of epilepsy (about 50% of the cases).Disorders of cortical development as polymicrogyria, various types of gyral disorganization and schizencephaly were also described in cases carrying TUBB2B gene mutations showing epilepsy in the 40%.As far as mutations in the TUBB4A gene are concerned, despite the brain phenotype is represented by a form of leukoencephalopathy characterized by hypomielination with atrophy of the basal ganglia and cerebellum and not by MCDs, epilepsy is present in about 40% of the mutated subjects.On the contrary, mutations in the TUBB3 gene cause epilepsy only in 15% of cases, while seizures have never been described in association with TUBB gene.

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Congenital Zika Virus Infection

et al. 2016

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IMPORTANCE Recent studies have reported an increase in the number of fetuses and neonates with microcephaly whose mothers were infected with the Zika virus (ZIKV) during pregnancy. To our knowledge, most reports to date have focused on select aspects of the maternal or fetal infection and fetal effects. OBJECTIVE To describe the prenatal evolution and perinatal outcomes of 11 neonates who had developmental abnormalities and neurological damage associated with ZIKV infection in Brazil. DESIGN, SETTING, AND PARTICIPANTS We observed 11 infants with congenital ZIKV infection from gestation to 6 months in the state of Paraíba, Brazil. Ten of 11 women included in this study presented with symptoms of ZIKV infection during the first half of pregnancy, and all 11 had laboratory evidence of the infection in several tissues by serology or polymerase chain reaction. Brain damage was confirmed through intrauterine ultrasonography and was complemented by magnetic resonance imaging. Histopathological analysis was performed on the placenta and brain tissue from infants who died. The ZIKV genome was investigated in several tissues and sequenced for further phylogenetic analysis. MAIN OUTCOMES AND MEASURES Description of the major lesions caused by ZIKV congenital infection. RESULTS Of the 11 infants, 7 (63.6%) were female, and the median (SD) maternal age at delivery was 25 (6) years. Three of 11 neonates died, giving a perinatal mortality rate of 27.3%. The median (SD) cephalic perimeter at birth was 31 (3) cm, a value lower than the limit to consider a microcephaly case. In all patients, neurological impairments were identified, including microcephaly, a reduction in cerebral volume, ventriculomegaly, cerebellar hypoplasia, lissencephaly with hydrocephalus, and fetal akinesia deformation sequence (ie, arthrogryposis). Results of limited testing for other causes of microcephaly, such as genetic disorders and viral and bacterial infections, were negative, and the ZIKV genome was found in both maternal and neonatal tissues (eg, amniotic fluid, cord blood, placenta, and brain). Phylogenetic analyses showed an intrahost virus variation with some polymorphisms in envelope genes associated with different tissues. CONCLUSIONS AND RELEVANCE Combined findings from clinical, laboratory, imaging, and pathological examinations provided a more complete picture of the severe damage and developmental abnormalities caused by ZIKV infection than has been previously reported. The term congenital Zika syndrome is preferable to refer to these cases, as microcephaly is just one of the clinical signs of this congenital malformation disorder.

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Mutations in α- and β-tubulin encoding genes: Implications in brain malformations

Cited by 97 publications

References 42 publications

Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos

Tubulin isotype substitution revealed that isotype combination modulates microtubule dynamics in C. elegans embryos

Epilepsy in Multigene Tubulin Family Mutations

Congenital Zika Virus Infection

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