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

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