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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 ( Tubb4a D249N/+  ) and the homozygous ( Tubb4a D249N/D249N  ) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC.  Tubb4a D249N/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  Tubb4a D249N/D249N   mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from  Tubb4a D249N/D249N   mice. Thus  Tubb4a D249N/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.

TUBB4A mutations result in both glial and neuronal degeneration in an H-ABC leukodystrophy mouse model