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

Victor Krajka, Franca Vulinovic, Mariya Genova, Kerstin Tanzer, A S Jijumon, Satish Bodakuntla, Stephanie Tennstedt, Helge Mueller-Fielitz, Britta Meier, Carsten Janke, Christine Klein*, Aleksandar Rakovic

*Corresponding author for this work

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 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.

Original languageEnglish
Article numbereabj9229
JournalScience Advances
Volume8
Issue number10
Pages (from-to)eabj9229
DOIs
Publication statusPublished - 03.2022

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