Abstract
Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.
Highlights
Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC) is a leukodystrophy caused by sporadic, typically de novo, heterozygous mutations in the TUBB4A gene (Simons et al, 2013)
In wild type (WT) mice, Tubb4a gene expression is highest in the cerebellum, spinal cord and striatum, which are typically affected brain regions in H-ABC individuals
We investigated whether Tubb4a mutation affects microtubules dynamics in the distal axons of cortical neurons expressing mCherry-tagged end-binding protein 3 (EB3), a protein that forms comet-like structures at the growing plus-ends of microtubules from WT, Tubb4aD249N/+ and Tubb4aD249N/D249N mice (Figure 7A; Stepanova et al, 2003)
Summary
Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC) is a leukodystrophy caused by sporadic, typically de novo, heterozygous mutations in the TUBB4A gene (Simons et al, 2013). This gene encodes the tubulin beta 4A protein, which heterodimerizes with aÀtubulin to form subunits that assemble into microtubules. Monoallelic mutations in TUBB4A result in a spectrum of neurologic disorders ranging from an early onset leukoencephalopathy to adult-onset Dystonia type 4 (DYT4; Whispering Dysphonia). About 65% of published cases with TUBB4A mutations have H-ABC; the heterozygous mutation p
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