2022
DOI: 10.1126/sciadv.abj9229
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H-ABC– and dystonia-causing TUBB4A mutations show distinct pathogenic effects

Abstract: Mutations in the brain-specific β-tubulin 4A (TUBB4A) gene cause a broad spectrum of diseases, ranging from dystonia (DYT-TUBB4A) to hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Currently, the mechanisms of how TUBB4A variants lead to this pleiotropic manifestation remain elusive. Here, we investigated whether TUBB4A mutations causing either DYT-TUBB4A (p.R2G and p.Q424H) or H-ABC (p.R2W and p.D249N) exhibit differential effects at th… Show more

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Cited by 10 publications
(10 citation statements)
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“…Additionally, a disease-causing mutant identified in the human β-tubulin isotype, TUBB3 -D417H, results in a straightened heterodimer conformation and intrinsically faster microtubule polymerization rates in vitro ( Ti et al, 2016 ). Similarly, disease-causing mutations identified in TUBB4A that result in dystonia and hypomyelination with atrophy of the basal ganglia, also impact tubulin conformation and microtubule dynamics ( Krajka et al, 2022 ). However, these mutants had the opposite effect and instead promoted a curved tubulin conformation over a straightened state, with decreased microtubule polymerization rates in vitro and in cells ( Krajka et al, 2022 ).…”
Section: Microtubule Regulationmentioning
confidence: 99%
See 1 more Smart Citation
“…Additionally, a disease-causing mutant identified in the human β-tubulin isotype, TUBB3 -D417H, results in a straightened heterodimer conformation and intrinsically faster microtubule polymerization rates in vitro ( Ti et al, 2016 ). Similarly, disease-causing mutations identified in TUBB4A that result in dystonia and hypomyelination with atrophy of the basal ganglia, also impact tubulin conformation and microtubule dynamics ( Krajka et al, 2022 ). However, these mutants had the opposite effect and instead promoted a curved tubulin conformation over a straightened state, with decreased microtubule polymerization rates in vitro and in cells ( Krajka et al, 2022 ).…”
Section: Microtubule Regulationmentioning
confidence: 99%
“…Similarly, disease-causing mutations identified in TUBB4A that result in dystonia and hypomyelination with atrophy of the basal ganglia, also impact tubulin conformation and microtubule dynamics ( Krajka et al, 2022 ). However, these mutants had the opposite effect and instead promoted a curved tubulin conformation over a straightened state, with decreased microtubule polymerization rates in vitro and in cells ( Krajka et al, 2022 ). These data highlight the significant contributions of individual regions of the heterodimer to conformation states, and how this can intrinsically alter microtubule dynamics.…”
Section: Microtubule Regulationmentioning
confidence: 99%
“…The diversity of pathogenic phenotypes necessitates further study to understand the molecular mechanisms underlying their pathogenicity. Experimental approaches to dissect the effect of these tubulin pathogenic mutations on microtubule dynamics, microtubule assembly and microtubule interactions with associated proteins would contribute to a better molecular understanding of tubulinopathies [71][72][73]. These additional data could refine current phenotype predictors and increase their performance.…”
Section: Plos Computational Biologymentioning
confidence: 99%
“…Also, rats harboring mutation in the Tubulin beta 4a gene (Tubb4a), which exhibit hypo- and/or de-myelination, also show elevated Tau expression in oligodendrocytes (in culture) ( Song et al, 1999 ). The Tubb4a mutation has been shown to affect microtubule dynamics such as its elongation, length, duration, and the frequency of them in oligodendrocytes of dystonia or hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) ( Figure 2B ( Krajka et al, 2022 ). Similarly, a Tubb4a mutagenesis result in abnormal myelination and microtubule accumulation in oligodendrocytes (not in axon of neurons) ( Duncan et al, 1992 ) ( Figure 2A ).…”
mentioning
confidence: 99%
“… (A) A model of hypomyelination and/or demyelination through Tubb4a and possibly Tau in Taubb4a mutant mice. (B) A possibly molecular pathogenesis through Tubb4a mutation in oligodendrocytes ( Krajka et al, 2022 ). (C) Up-regulation or accumulation of 3R-Tau in ischemic stroke model mice and a possible model of pathogenesis of demyelination through Tau in the mice.…”
mentioning
confidence: 99%