H-ABC- and dystonia-causing TUBB4A mutations show distinct pathogenic effects

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 variants lead to this pleiotropic manifestation remain elusi...

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Bibliographic Details
Published in:Science advances 2022-03, Vol.8 (10), p.eabj9229
Main Authors: Krajka, Victor, Vulinovic, Franca, Genova, Mariya, Tanzer, Kerstin, Jijumon, A S, Bodakuntla, Satish, Tennstedt, Stephanie, Mueller-Fielitz, Helge, Meier, Britta, Janke, Carsten, Klein, Christine, Rakovic, Aleksandar
Format: Article
Language:English
Subjects:
Basal Ganglia - metabolism
Basal Ganglia - pathology
Biomedicine and Life Sciences
Cellular Neuroscience
Cerebellum - metabolism
Dystonia - genetics
Dystonia - pathology
Genetics
Human genetics
Human health and pathology
Humans
Life Sciences
Mutation
Neurobiology
Neurons and Cognition
SciAdv r-articles
Tubulin - genetics
Tubulin - metabolism
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Summary: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 variants lead to this pleiotropic manifestation remain elusive. Here, we investigated whether mutations causing either DYT-TUBB4A (p.R2G and p.Q424H) or H-ABC (p.R2W and p.D249N) exhibit differential effects at the molecular and cellular levels. Using live-cell imaging of disease-relevant oligodendrocytes and total internal reflection fluorescence microscopy of whole-cell lysates, we observed divergent impact on microtubule polymerization and microtubule integration, partially reflecting the observed pleiotropy. Moreover, in silico simulations demonstrated that the mutants rarely adopted a straight heterodimer conformation in contrast to wild type. In conclusion, for most of the examined variants, we deciphered potential molecular disease mechanisms that may lead to the diverse clinical manifestations and phenotype severity across and within each TUBB4A-related disease.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abj9229