A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H‐ABC) is a rare childhood leukodystrophy first described by van der Knaap et al.1 Patients with the disease have extrapyramidal movement abnormalities, spasticity, cerebellar ataxia, and sometimes epilepsy.1 Diagnosis of H‐ABC is made principally by magnetic resonance imaging (MRI) showing marked atrophy or disappearance of the putamen; this and atrophy of the caudate nucleus, cerebellar atrophy, and hypomyelination are regarded as the cardinal diagnostic criteria. In addition, progressive loss of myelin is seen in most patients on serial MRI.2
H‐ABC is a rare disorder that has been demonstrated to be inherited as a dominant de novo mutation in TUBB4A.2TUBB4A encodes β‐tubulin, which dimerizes with α‐tubulin as the major subunits of microtubules. TUBB4A is expressed predominately in the brain, and recent cell type–specific expression profiling has identified Tubb4a as highly expressed in oligodendrocytes compared to neurons, astrocytes, and microglia.7 Since the identification of TUBB4A mutations in H‐ABC, TUBB4A mutations have been associated with a spectrum of disease symptoms that vary in serverity.8 On the mildest end is adult onset dystonia type 4 (DYT4) or whispering dysphonia, characterized by extrapyramidal movement abnormalities without any white matter abnormalities on MRI. The second disease phenotype in order of severity is mild, isolated hypomyelination. Other phenotypes include classical H‐ABC and severe isolated hypomyelination with variable cerebellar atrophy and clinically a devastating encephalopathy.2
At present, it is hypothesized that in H‐ABC a microtubule defect resulting from the TUBB4A mutations primarily affects axons, with secondary effects on glia resulting in the myelin sheath changes.5 It is possible that the cell type primarily affected could be dependent upon specific mutations of TUBB4A. Models that could be used to explore the effects of these mutations on axons and glia have been lacking until now. A potential model of TUBB4A‐related disease is the myelin mutant rat, called taiep.9 This rat develops a progressive neurologic disease resulting from hypomyelination followed by demyelination of the brain, optic nerves, and certain tracts of the spinal cord.10 Progressive accumulation of microtubules in oligodendrocytes was correlated with failure to develop normal myelin (hypomyelination) and subsequent demyelination.12 We previously mapped the taiep mutation to a 5 to 9cM region around D9Rat44 of rat chromosome 9.13 We have now identified a mutation in Tubb4a in the taiep rat in an amino acid that is located in a domain involved in interactions between the α‐ and β‐tubulin dimers. Thus, taiep is an ideal model in which to study the mechanism of microtubule accumulation in the oligodendrocyte cell body and throughout its processes.
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