Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve Hypoplasia

Abdollahi, M.R.; Morrison, Ewan E.; Sirey, Tamara; Molnár, Zoltán; Hayward, Bruce E.; Carr, Ian; Springell, Kelly; Woods, C. Geoff; Ahmed, Mushtaq; Hattingh, Louise; Corry, Peter; Pilz, Daniela T.; Stoodley, Neil; Crow, Yanick J.; Taylor, Graham R.; Bonthron, David T.; Sheridan, Eamonn

doi:10.1016/j.ajhg.2009.10.007

Cited by 155 publications

(121 citation statements)

References 32 publications

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“…7 Mutations of TUBA1A have been consistently associated with lissencephaly 8 and, more rarely, with polymicrogyria. 9 Mutations of TUBA8 have been associated with recessive polymicrogyria with optic nerve hypoplasia, 3 and mutations of TUBB3 cause frontal polymicrogyria or simplified and disorganized gyral patterning. 10 De novo TUBB2B mutations, all missense, have been identified in four patients and in one fetus with bilateral, asymmetrical and anteriorly predominant polymicrogyria.…”

Section: Discussionmentioning

confidence: 99%

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

et al. 2012

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The purpose of the study is to explore the causative role of TUBB2B gene mutations in patients with different malformations of cortical development. We collected and evaluated clinical and MRI data of a cohort of 128 consecutive patients (61 females and 67 males) in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, who were mutation-negative to other possible causative genes. Mutation analysis of the TUBB2B gene was performed. We identified three new TUBB2B mutations in three unrelated patients (3 out of 128; 2.3%) with a diffuse and rather symmetrical cortical abnormality, including diffuse polymicrogyria in two and bilateral regional pachygyria in one. One patient harbored a p.Asp417Asn amino-acid substitution in the C-terminal domain of the protein; one patient a p.Asn256Ser amino-acid substitution in the intermediate domain and one patient a p.Leu117Pro amino-acid substitution in the N-terminal domain. The localization of each mutation within the secondary structure of the b2-tubulin polypeptide suggests that these mutations might alter the proper functions of microtubules. The phenotypic spectrum associated with TUBB2B mutations is wider than previously reported and includes diffuse, symmetric malformations of cortical development. Keywords: malformations of cortical development; TUBB2B; tubulins; mutation analysis INTRODUCTION Polymicrogyria is a common cortical malformation characterized by an excessive number of abnormally small gyri that result in an irregular cortical surface with lumpy aspect. Brain pathology demonstrates abnormal development or loss of neurons in middle and deep cortical layers, variably associated with an unlayered cortical structure. 1,2 Several genes have been associated with polymicrogyria, including GPR56, SRPX2, TUBB2B, TUBB3, PAX6, TBR2, KIAA1279, NHEJ1, RAB3GAP1 and TUBA8 2-4 with all but GPR56, TUBB3 and TUBB2B found in rare syndromes. Mutations in TUBB2B have been reported in four patients and in one fetus with complex brain dysgenesis with asymmetrical, anteriorly predominant polymicrogyria. 5 We performed TUBB2B mutation analysis in 128 patients in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, to investigate how common TUBB2B mutations are in this spectrum of malformations and whether previously suggested imaging criteria need to be expanded.

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Section: Discussionmentioning

confidence: 99%

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

et al. 2012

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“…24,25 Mutations in the TUBA8 gene have been associated with optic atrophy and bilateral PMG. 26 The aims of this study were to determine the frequency of mutations in the TUBA1A, TUBB2B, and TUBB3 tubulin genes; to describe the associated neuroradiological patterns in a sample of patients affected by MCDs of unknown origin; and to review the literature describing the spectrum of MCDs associated with mutations in the tubulin genes.…”

Section: Discussionmentioning

confidence: 99%

Brain malformations and mutations in α‐ and β‐tubulin genes: a review of the literature and description of two new cases

Romaniello

Arrigoni

Cavallini

et al. 2014

Develop Med Child Neuro

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ABBREVIATIONS MCDsMalformations of cortical development PMG Polymicrogyria AIM The aim of this study was to determine the frequency of mutations in tubulin genes (TUBB2B, TUBA1A, and TUBB3) in patients with malformations of cortical development (MCDs) of unknown origin.METHOD In total, 79 out of 156 patients (41 males, 38 females; age range 8mo-55y (mean age 13y 3mo, SD 11y 2mo) with a neuroradiological diagnosis of MCDs were enrolled in the study. The 77 excluded patients were excluded for the following reasons: suspected or proven diagnosis of pre-or perinatal ischaemic insult (n=13); syndromic disease (n=10); congenital infection (n=14); pregnancy complicated by twin-to-twin transfusion syndrome (n=2); proven mutations in known genes (n=13); poor magnetic resonance imaging (MRI) quality, or lack of informed consent (n=25). A genetic analysis of the TUBA1A, TUBB2B and TUBB3 genes was carried out by direct sequencing of the coding regions of the relevant genes for each participant. Previously described patients with mutations in the TUBB2B and TUBA1A genes were reviewed; clinical and neuroradiological findings were compared and discussed.RESULTS Two novel heterozygous mutations were detected: a heterozygous mutation in exon 4 of the TUBA1A gene (c.1160C>T) in a 5-year-old female with microcephaly, severe intellectual disability, and absence of language, and a c.1080 _1084del CCTGAinsACATCTTC in exon 4 of the TUBB2B gene in a 31-year-old female with microcephaly, spastic tetraparesis, severe intellectual disability, and scoliosis. Different types of cortical abnormalities, cerebellar vermis hypoplasia, and optic nerve hypoplasia/atrophy were detected on MRI. Dysmorphisms of the basal ganglia and the hippocampi with abnormalities of the midline commissural structures were present in both cases. INTERPRETATIONThe consistent presence of hypoplastic and disorganized white matter tracts suggests that, in addition to defects in neuronal migration, disruption of axon growth and guidance is a peculiar feature of tubulin-related disorders.

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“…Only one mutation was reported of the TUBA8A gene, observed in two related families associated to generalized PMG and optic nerve hypoplasia [43]. Braun et al showed in their study, the expression at very low levels of the TUBA8 gene in the developing brain in mice and humans suggesting its role is not pathogenic at all [24].…”

Section: Tubulin α-8 (Tuba8) [Orpha2509 Omim 613180]mentioning

confidence: 99%

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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Mutation of the Variant α-Tubulin TUBA8 Results in Polymicrogyria with Optic Nerve Hypoplasia

Cited by 155 publications

References 32 publications

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

Brain malformations and mutations in α‐ and β‐tubulin genes: a review of the literature and description of two new cases

Epilepsy in Multigene Tubulin Family Mutations

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