Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies

Schröter, Julian; Döring, Jan Henje; Garbade, Sven F.; Hoffmann, Georg F.; Kölker, Stefan; Ries, Markus; Syrbe, Steffen

doi:10.1038/s41436-020-01001-z

Cited by 11 publications

(20 citation statements)

References 39 publications

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“…More extensive MCDs are a relevant cause for termination of pregnancy, mirrored by the two fetal cases described here. TUBA1A -associated epilepsy shows various semiologies and predominantly manifests in the first year of life, which is supported by the results in our study [ 7 , 8 ]. We underline the role of tubulinopathies in infantile epilepsy reporting a high proportion of children with neonatal onset and refractory course of epilepsy.…”

Section: Discussionsupporting

confidence: 91%

“…The broad range of phenotypic severity observed here underscores the clinical variability of TUBA1A tubulinopathy [ 5 , 8 ]. ASD in association with isolated hypoplasia of the CC, as observed in i07, represents the mild end of the spectrum emphasizing the relevance of TUBA1A in ASD pathophysiology [ 19 ].…”

Section: Discussionmentioning

confidence: 78%

“…Their anti-epileptic treatment is challenging as epilepsy predominantly shows an infantile onset and treatment-resistant course with various semiologies [ 7 ]. As sole specific epilepsy syndrome, infantile spasms were reported in one third of the cases [ 8 ]. The different tubulin isotypes show sequence homology but differ in spatio-temporal expression suggesting unique, isotype-specific functions [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The different tubulin isotypes show sequence homology but differ in spatio-temporal expression suggesting unique, isotype-specific functions [ 9 ]. Tubulinopathies are predominantly caused by variants in TUBA1A , encoding the major CNS α-tubulin isotype, which accounts for a rapidly growing number of more than 170 cases [ 8 ]. TUBA1A tubulinopathy shows a more severe clinical and neuroradiological phenotype than β-tubulinopathies comprising a combination of MCDs and changes of extra-cortical structures such as cerebellum, corpus callosum (CC), basal ganglia, brainstem, and ventricles.…”

Section: Introductionmentioning

confidence: 99%

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Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

et al. 2022

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TUBA1A tubulinopathy is a rare neurodevelopmental disorder associated with brain malformations as well as early-onset and intractable epilepsy. As pathomechanisms and genotype-phenotype correlations are not completely understood, we aimed to provide further insights into the phenotypic and genetic spectrum. We here present a multicenter case series of ten unrelated individuals from four European countries using systematic MRI re-evaluation, protein structure analysis, and prediction score modeling. In two cases, pregnancy was terminated due to brain malformations. Amongst the eight living individuals, the phenotypic range showed various severity. Global developmental delay and severe motor impairment with tetraparesis was present in 63% and 50% of the subjects, respectively. Epilepsy was observed in 75% of the cases, which showed infantile onset in 83% and a refractory course in 50%. One individual presented a novel TUBA1A-associated electroclinical phenotype with evolvement from early myoclonic encephalopathy to continuous spike-and-wave during sleep. Neuroradiological features comprised a heterogeneous spectrum of cortical and extracortical malformations including rare findings such as cobblestone lissencephaly and subcortical band heterotopia. Two individuals developed hydrocephalus with subsequent posterior infarction. We report four novel and five previously published TUBA1A missense variants whose resulting amino acid substitutions likely affect longitudinal, lateral, and motor protein interactions as well as GTP binding. Assessment of pathogenic and benign variant distributions in synopsis with prediction scores revealed sections of variant enrichment and intolerance to missense variation. We here extend the clinical, neuroradiological, and genetic spectrum of TUBA1A tubulinopathy and provide insights into residue-specific pathomechanisms and genotype-phenotype correlations.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

et al. 2022

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“…Strikingly, these DEGAs tubulins, which form the basic building blocks of basal body microtubules, exhibited the topmost negative coefficient values compared to all other cilia DEGAs. TUBA1A represents the primary subunit gene linked to a group of tubulin disorders called “tubulinopathies” [ 33 , 34 ]. Other “tubulinopathies” genes include TUBA1A , TUBB2A , TUBB2B , TUBA8 , TUBB3 , TUBB , and TUBG1 [ 35 , 36 , 37 , 38 , 39 , 40 ], which were found to be DEGAs in various brain regions.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Chen

Alhassen

Monfared

et al. 2021

IJMS

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Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia’s structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (TUBA1A, TUBB2A, and TUBB2B) and SNAP-25 exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and SNAP-25 expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.

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Spectrum of brain malformations in fetuses with mild tubulinopathy

Hagege

Haratz

Malinger

et al. 2023

Ultrasound in Obstet & Gyne

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Objective To report on a large cohort of fetuses with mild forms of tubulinopathy and to define prenatal ultrasound and magnetic resonance imaging (MRI) features that can facilitate prenatal diagnosis. Methods This was a retrospective multicenter study of fetuses diagnosed between January 2007 and February 2022 with a mild tubulinopathy (without lissencephaly or microlissencephaly). We collected and reviewed brain imaging and genetic data, and defined major criteria as findings observed in ≥ 70% of the patients and minor criteria as those observed in ≥ 50% but < 70% of the patients. Results Our cohort included 34 fetuses. The mean gestational age at ultrasound screening, when suspicion of a central nervous system anomaly was first raised, was 24.2 (range, 17–33) weeks. Callosal anomalies (n = 19 (56%)) and abnormal ventricles (n = 18 (53%)) were the main reasons for referral. The mean gestational age at neurosonography was 28.3 (range, 23–34) weeks and that at MRI was 30.2 (range, 24–35) weeks. Major ultrasound criteria were midline distortion, ventricular asymmetry, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation. Minor ultrasound criteria were distortion of the cavum septi pellucidi, abnormal corpus callosum, absent or asymmetric olfactory sulci, ventriculomegaly and basal ganglia dysmorphism. Major MRI criteria were midline distortion, distortion of the cavum septi pellucidi, ventricular asymmetry, dilatation (generally unilateral) and/or distortion, dysmorphic and/or dilated frontal horn(s) and abnormal sulcation (mainly dysgyria). Minor MRI criteria were absent or asymmetric olfactory sulci, abnormal bulge of the pons, anteroposterior diameter of the pons ≤ 5th centile and brainstem asymmetry. A mutation was found in TUBB3 (44.1% of cases), TUBB (23.5%), TUBB2B (14.7%) or TUBA1A (17.6%). The mutation was inherited from a parent in 18/34 cases. The pregnancy was terminated in 23/34 cases. Conclusions Prenatal diagnosis of mild forms of tubulinopathy is possible but challenging. We have defined, in this large series of fetuses, major and minor criteria that can help identify this entity in utero. Most findings can be visualized on ultrasound. This evaluation is also important for prenatal counseling. Once a prenatal diagnosis of mild tubulinopathy is suspected, the family members should be referred for exome sequencing and MRI. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

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Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies

Cited by 11 publications

References 39 publications

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

Complementing the phenotypical spectrum of TUBA1A tubulinopathy and its role in early-onset epilepsies

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan

Spectrum of brain malformations in fetuses with mild tubulinopathy

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