Deletion of TUBB4A mitigates the oligodendrocyte and neuronal deficits in human iPSCs derived from individuals affected by H-ABC

Authors

Hou, Z. A., Bates, R. D., Napit, P. R., Garcia, L., Bhagavatula, A., Hacker, J. L., Johnson, T., Gagne, A., Maguire, J. A., Takanohashi, A., French, D., Almad, A., Grinspan, J., Vanderver, A., Sase, S.

Abstract

TUBB4A-related leukodystrophy (TUBB4A-LD) is a rare neurologic disorder with a broad spectrum of phenotypes, including severe early infantile encephalopathy, late infantile Hypomyelination with Atrophy of the Basal ganglia and Cerebellum (H-ABC), and milder late infantile forms. H-ABC is closely associated with a recurrent pathogenic variant, p.Asp249Asn, in the gene encoding tubulin beta class IVA (TUBB4A), a microtubule component. H-ABC presents with progressive dystonia, mobility loss, aphasia, and swallowing dysfunction in childhood. H-ABC results in cell-autonomous deficits in oligodendrocytes (OLs), cerebellar granule neurons, and medium spiny neurons (MSNs). Antisense oligonucleotides targeting Tubb4a can alleviate symptoms in H-ABC mouse models. However, the efficacy and safety of TUBB4A knockout in human cells remain poorly understood. We studied patient-derived TUBB4AD249N, TUBB4A KO, and control individual pluripotent stem cells (iPSCs). TUBB4AD249N iPSC-derived OLs failed to mature, showing less complexity and myelination, reduced microtubule acetylation and detyrosination. TUBB4AD249N iPSC-derived MSNs also showed impaired maturation and neurite extension. TUBB4A KO in mutant iPSCs reduced cellular deficits and was well tolerated. These findings support that suppression of TUBB4A could be a safe, effective therapy for TUBB4A-LD.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Aug 2026.

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