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The recent finding that some patients with fetal akinesia deformation sequence (FADS) carry variants in the TUBB2B gene has prompted us to add to the existing literature a first description of two fetal FADS cases carrying TUBA1A variants. Hitherto, only isolated cortical malformations have been described with TUBA1A mutation, including microlissencephaly, lissencephaly, central pachygyria and polymicrogyria-like cortical dysplasia, generalized polymicrogyria cortical dysplasia, and/or the "simplified" gyral pattern. The neuropathology of our fetal cases shows several common features of tubulinopathies, in particular, the dysmorphism of the basal ganglia, as the most pathognomonic sign. The cortical ribbon anomalies were extremely severe and concordant with the complex cortical malformation. In conclusion, we broaden the phenotypic spectrum of TUBA1A variants, to include FADS.
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Artrogripose , Lisencefalia , Malformações do Desenvolvimento Cortical , Polimicrogiria , Artrogripose/diagnóstico , Artrogripose/genética , Humanos , Lisencefalia/genética , Malformações do Desenvolvimento Cortical/genética , Mutação , Tubulina (Proteína)/genéticaRESUMO
INTRODUCTION: Becker muscular dystrophy (BMD) is a genetic and progressive neuromuscular disease caused by mutations in the dystrophin gene with no available cure. A case report and comprehensive review of BMD cases aim to provide important clues for early diagnosis and implications for clinical practice. Genes and pathways identified from microarray data of muscle samples from patients with BMD help uncover the potential mechanism and provide novel therapeutic targets for dystrophin-deficient muscular dystrophies. METHODS: We describe a BMD family with a 10-year-old boy as the proband and reviewed BMD cases from PubMed. Datasets from the Gene Expression Omnibus database were downloaded and integrated with the online software. RESULTS: The systematic review revealed the clinical manifestations and mutation points of the dystrophin gene. Gene ontology analysis showed that extracellular matrix organization and extracellular structure organization with enrichment of upregulated genes coexist in three datasets. We present the first report of TUBA1A involvement in the development of BMD/Duchenne muscular dystrophy (DMD). DISCUSSION: This study provides important implications for clinical practice, uncovering the potential mechanism of the progress of BMD/DMD, and provided new therapeutic targets.
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Distrofia Muscular de Duchenne , Criança , Família , Expressão Gênica , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , MutaçãoRESUMO
PURPOSE: TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials. METHODS: Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were age at disease onset, survival, and diagnostic delay. Phenotypical, neuroradiological, and histopathological features were descriptively illustrated. RESULTS: Mean age at disease onset was 4 (TUBA1A) and 6 months (TUBB2B), respectively. Mortality was equally estimated with 7% at 3.2 (TUBA1A) and 8.0 years (TUBB2B). Diagnostic delay was significantly higher in TUBB2B (12.3 years) compared with TUBA1A tubulinopathy (4.2 years). We delineated the isotype-dependent clinical, neuroradiological, and histopathological phenotype of affected individuals and present brain malformations associated with epilepsy and an unfavorable course of disease. CONCLUSION: The natural history of tubulinopathies is defined by the genotype and associated brain malformations. Defined data on estimated survival, diagnostic delay, and disease characteristics of TUBA1A and TUBB2B tubulinopathy will help to raise disease awareness and encourage future clinical trials to optimize genetic testing, family counseling, and supportive care.
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Diagnóstico Tardio , Tubulina (Proteína) , Estudos Transversais , Humanos , Mutação , Fenótipo , Tubulina (Proteína)/genéticaRESUMO
To illustrate the prenatal cerebral imaging features associated with tubulinopathy, we report on five affected fetuses from unrelated families, with a de-novo heterozygous variant in a tubulin gene (TUBA1A, TUBB2B or TUBB3). We identified two distinct prenatal imaging patterns related to tubulinopathy: a severe form, characterized by enlarged germinal matrices, microlissencephaly and a kinked brainstem; and a mild form which has not been reported previously in the prenatal literature. The latter form is associated with non-specific features, including an asymmetric brainstem, corpus callosal dysgenesis, a lack of Sylvian fissure operculization and distortion of the anterior part of the interhemispheric fissure with subsequent impacted medial borders of the frontal lobes, the combination of which, in the absence of additional extracerebral anomalies, is highly suggestive of tubulinopathy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.
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Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/embriologia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/embriologia , Ultrassonografia Pré-Natal , Tronco Encefálico/anormalidades , Tronco Encefálico/diagnóstico por imagem , Tronco Encefálico/embriologia , Córtex Cerebral/anormalidades , Feminino , Feto/anormalidades , Feto/diagnóstico por imagem , Feto/embriologia , Variação Genética , Humanos , Malformações do Desenvolvimento Cortical/genética , Ilustração Médica , Microcefalia/diagnóstico por imagem , Microcefalia/embriologia , Gravidez , Tubulina (Proteína)/genéticaRESUMO
BACKGROUND: Previous literature has revealed long non-coding RNAs (lncRNAs) are crucial regulators for cell functions and gene expression. LncRNA fetal-lethal non-coding developmental regulatory RNA (FENDRR) was reported as a biological suppressor in several types of human cancers, yet relevant mechanisms and biological effects of FENDRR with regards to cervical cancer (CC) are not explored until now. METHODS: In this study, quantitative real-time polymerase chain reaction (qRT-PCR) analysis detected gene expression in tissues and cells. Gain- or loss-of-function experiments revealed the biological effects of FENDRR and miR-15a/b-5p on CC cell functions. Bioinformatics tools were used to predict the relevant genes. Mechanism experiments including RNA immunoprecipitation (RIP) assay, pull down assay and luciferase reporter assay depicted the binding situation and coexistence of indicated genes. RESULTS: FENDRR was downregulated in CC tissues and cells, which suppressed CC progression. MiR-15a-5p and miR-15b-5p shared binding sites with FENDRR and had interaction with FENDRR. Tubulin alpha1A (TUBA1A) was downregulated in CC tissues and positively modulated by FENDRR. TUBA1A was the target of miR-15a/b-5p. TUBA1A silencing rescued the effect of FENDRR overexpression on CC cell growth and migration. CONCLUSION: FENDRR inhibits CC progression through upregulating TUBA1A in a miR-15a/b-5p-dependent manner.
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Background and aim: The number of reports on the role of tubulin gene mutations (TUBA1A, TUBB2B, and TUBB3) in etiology of malformations of cortical development has peaked in recent years. We aimed to determine tubulin gene defects on a patient population with simple and complex malformations of cortical development, and investigate the relationship between tubulin gene mutations and disease phenotype. Materials and methods: We evaluated 47 patients with simple or complex malformations of cortical development, as determined by radiological examination, for demographic features, clinical findings and mutations on TUBA1A, TUBB2B, and TUBB3 genes. Results: According to the magnetic resonance imaging findings, 19 patients (40.5%) had simple malformations of cortical development and 28 (59.5%) patients had complex malformations of cortical development. Focal cortical dysplasia was the most common simple malformation, lissencephaly was the most common coexisting cortical malformation, and corpus callosum anomalies were the most common coexisting extracortical neurodevelopmental abnormalities. None of the patients had genetic alterations on TUBA1A, TUBB2B, and TUBB3 genes causing protein dysfunction. On the other hand, the frequencies of some polymorphisms were higher when compared to the literature. Conclusion: It is crucial to identify the etiology in patients with malformations of cortical development in order to provide appropriate genetic counseling and prenatal diagnosis. We consider that multicenter studies with higher patient numbers and also including other malformations of cortical development-related genes are required to determine underlying etiological factors of malformations of cortical development patients.
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Malformações do Desenvolvimento Cortical , Tubulina (Proteína)/genética , Adolescente , Criança , Pré-Escolar , Consanguinidade , Feminino , Humanos , Lactente , Desequilíbrio de Ligação , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Mutations in the microtubule cytoskeleton are linked to cognitive and locomotor defects during development, and neurodegeneration in adults. How these mutations impact microtubules, and how this alters function at the level of neurons is an important area of investigation. Using a forward genetic screen in mice, we identified a missense mutation in Tuba1a α-tubulin that disrupts cortical and motor neuron development. Homozygous mutant mice exhibit cortical dysgenesis reminiscent of human tubulinopathies. Motor neurons fail to innervate target muscles in the limbs and show synapse defects at proximal targets. To directly examine effects on tubulin function, we created analogous mutations in the α-tubulin isotypes in budding yeast. These mutations sensitize yeast cells to microtubule stresses including depolymerizing drugs and low temperatures. Furthermore, we find that mutant α-tubulin is depleted from the cell lysate and from microtubules, thereby altering ratios of α-tubulin isotypes. Tubulin-binding cofactors suppress the effects of the mutation, indicating an important role for these cofactors in regulating the quality of the α-tubulin pool. Together, our results give new insights into the functions of Tuba1a, mechanisms for regulating tubulin proteostasis, and how compromising these may lead to neural defects.
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Mutação/genética , Sistema Nervoso/embriologia , Tubulina (Proteína)/genética , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Modelos Animais de Doenças , Embrião de Mamíferos/patologia , Epistasia Genética , Feminino , Testes Genéticos , Masculino , Camundongos Endogâmicos C57BL , Microtúbulos/metabolismo , Dados de Sequência Molecular , Atividade Motora , Placa Motora/patologia , Neurônios Motores/patologia , Sistema Nervoso/patologia , Junção Neuromuscular/patologia , Fenótipo , Polimerização , Multimerização Proteica , Estabilidade Proteica , Saccharomyces cerevisiae/metabolismo , Sinapses/patologia , Tubulina (Proteína)/químicaRESUMO
Malformations of the cerebral cortex are an important cause of developmental disabilities and epilepsy. Neurological disorders caused by abnormal neuronal migration have been observed to occur with mutations in tubulin genes. The α- and ß-tubulin genes encode cytoskeletal proteins, which play a role in the developing brain. TUBA1A mutations are associated with a wide spectrum of neurological problems, which are characterized by peculiar clinical details and neuroradiologic patterns. This manuscript describes the case of a nine-year-old girl with microcephaly, mild facial dysmorphisms, epileptic seizures, and severe developmental delay, with a de novo heterozygous c.320A>G [p.(His 107 Arg)] mutation in TUBA1A gene, and the clinical aspects and neuroimaging features of "lissencephaly syndrome" are summarized. This case shows that TUBA1A mutations lead to a variety of brain malformations ranging from lissencephaly with perisylvian pachygyria to diffuse posteriorly predominant pachygyria, combined with internal capsule dysgenesis, cerebellar dysplasia, and callosal hypotrophy. This peculiar neuroradiological pattern, in combination with the usually severe clinical presentation, suggests the need for future molecular studies to address the mechanisms of TUBA1A mutation-induced neuropathology.
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Epilepsia/genética , Malformações do Desenvolvimento Cortical/genética , Mutação de Sentido Incorreto , Tubulina (Proteína)/genética , Criança , Epilepsia/diagnóstico , Feminino , Heterozigoto , Humanos , Malformações do Desenvolvimento Cortical/diagnóstico , SíndromeRESUMO
The human cerebral cortex is peculiar for a six-layered cellular-sheet structure with convolution, which is a consequence of neuronal migration. Dysfunctions of the pathways contributing to this mechanism typically lead to lissencephaly manifesting smooth brain surfaces. To investigate the unknown mechanism underlying neuronal migration disorders, we generated induced pluripotent stem (iPS) cells from two patients with lissencephaly. Whole gene expression study for iPS cells derived from a patient with a LIS1 deletion showed reduced expression of the coiled-coil-helix-coiled-coil-helix domain containing 2 gene (CHCHD2), which was also confirmed in iPS cells derived from a patient with a TUBA1A mutation. CHCHD2 expression was detected in neuronal cells differentiated from normal iPS cells in a time-dependent manner, as well as in the brain of a fetus at 26-28 week gestational age, suggesting development-dependent expression. Migrating neuronal cells showed CHCHD2 expression, suggesting its functional relevance to neuronal migration.
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Células-Tronco Pluripotentes Induzidas/metabolismo , Lisencefalia/patologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Encéfalo/embriologia , Encéfalo/metabolismo , Diferenciação Celular , Proteínas de Ligação a DNA , Regulação para Baixo , Feminino , Deleção de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Lactente , Lisencefalia/genética , Lisencefalia/metabolismo , Masculino , Proteínas Associadas aos Microtúbulos/genética , Mutação de Sentido Incorreto , Neurônios/patologia , Tubulina (Proteína)/genéticaRESUMO
Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. Identification of the genetic basis of these disorders has brought fascinating insights into the mechanisms of brain development, as well as benefits to patients through improved molecular diagnosis and genetic counseling. This review explores the clinical presentation, radiological features, histological findings and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in patients with 'smooth brain' phenotypes.
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Lisencefalia/genética , Animais , Heterogeneidade Genética , Humanos , Lisencefalia/patologia , Imageamento por Ressonância Magnética , Mutação , Neuroimagem , FenótipoRESUMO
Tubulin plays an essential role in cortical development, and TUBA1A encodes a major neuronal α-tubulin. Neonatal mutations in TUBA1A are associated with severe brain malformations, and approximately 70% of patients with reported cases of TUBA1A mutations exhibit lissencephaly. We report the case of a 1-year-old boy with the TUBA1A nascent mutation c.1204C >T, p.Arg402Cys, resulting in lissencephaly, developmental delay, and seizures, with a brain MRI showing normal cortical formation in the bilateral frontal lobes, smooth temporo-parieto-occipital gyri and shallow sulcus. This case has not been described in any previous report; thus, the present case provides new insights into the broad disease phenotype and diagnosis associated with TUBA1A mutations. In addition, we have summarized the gene mutation sites, neuroradiological findings, and clinical details of cases previously described in the literature and discussed the differences that exist between individual cases of TUBA1A mutations through a longitudinal comparative analysis of similar cases. The complexity of the disease is revealed, and the importance of confirming the genetic diagnosis from the beginning of the disease is emphasized, which can effectively shorten the diagnostic delay and help clinicians provide genetic and therapeutic counseling.
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Microtubules are dynamic cytoskeletal structures involved in several cellular functions, such as intracellular trafficking, cell division and motility. More than other cell types, neurons rely on the proper functioning of microtubules to conduct their activities and achieve complex morphologies. Pathogenic variants in genes encoding for α and ß-tubulins, the structural subunits of microtubules, give rise to a wide class of neurological disorders collectively known as "tubulinopathies" and mainly involving a wide and overlapping range of brain malformations resulting from defective neuronal proliferation, migration, differentiation and axon guidance. Although tubulin mutations have been classically linked to neurodevelopmental defects, growing evidence demonstrates that perturbations of tubulin functions and activities may also drive neurodegeneration. In this study, we causally link the previously unreported missense mutation p.I384N in TUBA1A, one of the neuron-specific α-tubulin isotype I, to a neurodegenerative disorder characterized by progressive spastic paraplegia and ataxia. We demonstrate that, in contrast to the p.R402H substitution, which is one of the most recurrent TUBA1A pathogenic variants associated to lissencephaly, the present mutation impairs TUBA1A stability, reducing the abundance of TUBA1A available in the cell and preventing its incorporation into microtubules. We also show that the isoleucine at position 384 is an amino acid residue, which is critical for α-tubulin stability, since the introduction of the p.I384N substitution in three different tubulin paralogs reduces their protein level and assembly into microtubules, increasing their propensity to aggregation. Moreover, we demonstrate that the inhibition of the proteasome degradative systems increases the protein levels of TUBA1A mutant, promoting the formation of tubulin aggregates that, as their size increases, coalesce into inclusions that precipitate within the insoluble cellular fraction. Overall, our data describe a novel pathogenic effect of p.I384N mutation that differs from the previously described substitutions in TUBA1A, and expand both phenotypic and mutational spectrum related to this gene.
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Glioblastoma (GBM) is the most common, aggressive, and chemorefractory primary brain tumor in adults. Identifying novel drug targets is crucial for GBM treatment. Here, we demonstrate that tubulin alpha 1a (TUBA1A) is significantly upregulated in GBM compared to low-grade gliomas (LGG) and normal tissues. High TUBA1A expression is associated with poor survival in GBM patients. TUBA1A knockdown results in mitotic arrest and reduces tumor growth in mice. TUBA1A interacts with the polo-like kinase 3 (PLK3) in the cytoplasm to inhibit its activation. This interaction licenses activation of the anaphase-promoting complex or cyclosome (APC/C) to ensure proper Foxm1-mediated metaphase-to-anaphase transition and mitotic exit. Overall, our findings demonstrate that targeting TUBA1A attenuates GBM cell growth by suppressing mitotic progression in a PLK3-dependent manner.
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Proteínas de Ciclo Celular , Glioblastoma , Animais , Humanos , Camundongos , Anáfase , Ciclossomo-Complexo Promotor de Anáfase/genética , Ciclossomo-Complexo Promotor de Anáfase/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Metáfase , Mitose , Quinases Polo-Like , Proteínas Serina-Treonina Quinases/genética , Tubulina (Proteína) , Proteínas Supressoras de TumorRESUMO
Introduction: Tubulin genes have been related to severe neurological complications and the term "tubulinopathy" now refers to a heterogeneous group of disorders involving an extensive family of tubulin genes with TUBA1A being the most common. A review was carried out on the complex and severe brain abnormalities associated with this genetic anomaly. Methods: A literature review of the cases of TUBA1A-tubulopathy was performed to investigate the molecular findings linked with cerebral anomalies and to describe the clinical and neuroradiological features related to this genetic disorder. Results: Clinical manifestations of TUBA1A-tubulinopathy patients are heterogeneous and severe ranging from craniofacial dysmorphism, notable developmental delay, and intellectual delay to early-onset seizures, neuroradiologically associated with complex abnormalities. TUBA1A-tubulinopathy may display various and complex cortical and subcortical malformations. Discussion: A range of clinical manifestations related to different cerebral structures involved may be observed in patients with TUBA1A-tubulinopathy. Genotype-phenotype correlations are discussed here. Individuals with cortical and subcortical anomalies should be screened also for pathogenic variants in TUBA1A.
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Variants in different neuronal tubulin isotypes cause severe neurodevelopmental disorders with cerebral malformations accompanied by developmental delay, motor impairment, and epilepsy, known as tubulinopathies. Induced pluripotent stem cells were generated from peripheral blood mononuclear cells from a female subject carrying the heterozygous de novo variant c.[521C > T] (p.[Ala174Val]) in the TUBA1A gene. PBMCs were reprogrammed using the CytoTune™-iPS 2.0 Sendai Reprogramming Kit (Invitrogen) and showed a normal karyotype, expression of pluripotency markers, and spontaneous in vitro differentiation into all three germ layers. The generated iPSCs represent a useful tool to study the pathophysiology of TUBA1A tubulinopathy.
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Células-Tronco Pluripotentes Induzidas , Diferenciação Celular/fisiologia , Reprogramação Celular , Diástase Muscular , Feminino , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismoRESUMO
Tubulin proteins play a role in the cortical development. Mutations in the tubulin genes affect patients with brain malformations. The present report describes two cases of developmental and epileptic encephalopathy (DEE) due to tubulinopathy. Case 1, a 23-year-old boy, was found to have a brain malformation with moderate ventriculomegaly prenatally. Hypotonia was noted at birth. Seizures were noted on the 1st day with multifocal discharges on the EEGs, which became intractable to many anticonvulsants. Brain MRI showed marked dilated ventricles and pachy/polymicrogyri. He became a victim of DEE. A de novo mutation in TUBB2B was proven through next-generation sequencing (NGS). Case 2, a mature male baby, began to have myoclonic jerks of his limbs 4 h after birth. EEG showed focal sharp waves from central and temporal regions. Brain MRI showed lissencephaly, type I. The seizures were refractory initially. A de novo mutation in TUBA1A was proven at the 6th week through NGS. He showed the picture of DEE at 1 year and 2 months of age. The clinical features of the tubulinopathies include motor delay, intellectual disabilities, epilepsy, and other deficits. Our cases demonstrated the severe form of tubulinopathy due to major tubulin gene mutations. NGS makes the early identification of genetic etiology possible for clinical evaluation.
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Familial apparently balanced translocations (ABTs) are usually not associated with a phenotype; however, rarely, ABTs segregate with discordant phenotypes in family members carrying identical rearrangements. The current study was a follow-up investigation of four familial ABTs, where whole exome sequencing (WES) was implemented as a diagnostic tool to identify the underlying genetic aetiology of the patients' phenotypes. Data were analysed using an in-house bioinformatics pipeline alongside VarSome Clinical. WES findings were validated with Sanger sequencing, while the impact of splicing and missense variants was assessed by reverse-transcription PCR and in silico tools, respectively. Novel candidate variants were identified in three families. In family 1, it was shown that the de novo pathogenic STXBP1 variant (NM_003165.6:c.1110+2T>G) affected splicing and segregated with the patient's phenotype. In family 2, a likely pathogenic TUBA1A variant (NM_006009.4:c.875C>T, NP_006000.2:p.(Thr292Ile)) could explain the patient's symptoms. In family 3, an SCN1A variant of uncertain significance (NM_006920.6:c.5060A>G, NP_008851.3:p.(Glu1687Gly)) required additional evidence to sufficiently support causality. This first report of WES application in familial ABT carriers with discordant phenotypes supported our previous findings describing such rearrangements as coincidental. Thus, WES can be recommended as a complementary test to find the monogenic cause of aberrant phenotypes in familial ABT carriers.
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Mutação de Sentido Incorreto , Translocação Genética , Humanos , Sequenciamento do Exoma , Linhagem , FenótipoRESUMO
Developing neurons undergo dramatic morphological changes to appropriately migrate and extend axons to make synaptic connections. The microtubule cytoskeleton, made of α/ß-tubulin dimers, drives neurite outgrowth, promotes neuronal growth cone responses, and facilitates intracellular transport of critical cargoes during neurodevelopment. TUBA1A constitutes the majority of α-tubulin in the developing brain and mutations to TUBA1A in humans cause severe brain malformations accompanied by varying neurological defects, collectively termed tubulinopathies. Studies of TUBA1A function in mammalian cells have been limited by the presence of multiple genes encoding highly similar tubulin proteins, which leads to α-tubulin antibody promiscuity and makes genetic manipulation challenging. Here, we test mutant tubulin levels and assembly activity and analyze the impact of TUBA1A reduction on growth cone composition, neurite extension, and commissural axon architecture during brain development. We present a novel tagging method for studying and manipulating TUBA1A in cells without impairing tubulin function. Using this tool, we show that a TUBA1A loss-of-function mutation TUBA1A N102D (TUBA1A ND ), reduces TUBA1A protein levels and prevents incorporation of TUBA1A into microtubule polymers. Reduced Tuba1a α-tubulin in heterozygous Tuba1a ND/+ mice leads to grossly normal brain formation except a significant impact on axon extension and impaired formation of forebrain commissures. Neurons with reduced Tuba1a as a result of the Tuba1a ND mutation exhibit slower neuron outgrowth compared to controls. Neurons deficient in Tuba1a failed to localize microtubule associated protein-1b (Map1b) to the developing growth cone, likely impacting stabilization of microtubules. Overall, we show that reduced Tuba1a is sufficient to support neuronal migration and cortex development but not commissure formation, and provide mechanistic insight as to how TUBA1A tunes microtubule function to support neurodevelopment.
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BACKGROUND: Congenital mirror movements are involuntary movements of a side of the body imitating intentional movements on the opposite side, appearing in early childhood and persisting beyond 7 years of age. Congenital mirror movements are usually idiopathic but have been reported in association with various brain malformations. METHODS: We describe clinical, genetic, and radiologic features in 9 individuals from 5 families manifesting congenital mirror movements. RESULTS: The brain malformations associated with congenital mirror movements were: dysplastic corpus callosum in father and daughter with a heterozygous p.Met1* mutation in DCC; hypoplastic corpus callosum, dysgyria, and malformed vermis in a mother and son with a heterozygous p.Thr312Met mutation in TUBB3; dysplastic corpus callosum, dysgyria, abnormal vermis, and asymmetric ventricles in a father and 2 daughters with a heterozygous p.Arg121Trp mutation in TUBB; hypoplastic corpus callosum, dysgyria, malformed basal ganglia and abnormal vermis in a patient with a heterozygous p.Glu155Asp mutation in TUBA1A; hydrocephalus, hypoplastic corpus callosum, polymicrogyria, and cerebellar cysts in a patient with a homozygous p.Pro312Leu mutation in POMGNT1. CONCLUSION: DCC, TUBB3, TUBB, TUBA1A, POMGNT1 cause abnormal axonal guidance via different mechanisms and result in congenital mirror movements associated with brain malformations.
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Encéfalo/anormalidades , Transtornos dos Movimentos/congênito , Transtornos dos Movimentos/diagnóstico , Malformações do Sistema Nervoso/complicações , Malformações do Sistema Nervoso/diagnóstico , Adulto , Criança , Pré-Escolar , Receptor DCC/genética , Feminino , Humanos , Lactente , Masculino , Transtornos dos Movimentos/genética , N-Acetilglucosaminiltransferases/genética , Malformações do Sistema Nervoso/genética , Tubulina (Proteína)/genéticaRESUMO
Tubulin α-1 A (TUBA1A) mutations cause a wide spectrum of brain abnormalities. Although many mutations have been identified and functionally verified, there are clearly many more, and the relationship between TUBA1A mutations and brain malformations remains unclear. The aim of this study was to identify a TUBA1A mutation in a fetus with severe brain abnormalities, verify it functionally, and determine the mechanism of the mutation-related pathogenesis. A de novo missense mutation of the TUBA1A gene, c.167C>G p.T56R/P.THR56Arg, was identified by exon sequencing. Computer simulations showed that the mutation results in a disruption of lateral interactions between the microtubules. Transfection of 293T cells with TUBA1A p.T56R showed that the mutated protein is only partially incorporated into the microtubule network, resulting in a decrease in the rate of microtubule re-integration in comparison with the wild-type protein. The mechanism of pathological changes induced by the mutant gene was determined by knockdown and overexpression. It was found that knockdown of TUBA1A reduced the generation of neural progenitor cells, while overexpression of wild-type or mutant TUBA1A promoted neurogenesis. Our identification and functional verification of the novel TUBA1A mutation extends the TUBA1A gene-phenotype database. Loss-of-function of TUBA1A was shown to play an important role in early neurogenesis of TUBA1A mutation-related brain malformations.