Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease.

[krabbe disease]

Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC ) gene . A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production . The currently used mouse model , twitcher , has a nonsense mutation not found in Krabbe patients , although it is similar to the human 30 kb deletion in abrogating GALC expression . Here , we identify a spontaneous mutation in GALC , GALCtwi-5 J , that precisely matches the E 130 K missense mutation in patients with infantile Krabbe disease . GALCtwi-5 J homozygotes show loss of enzymatic activity despite normal levels of precursor protein , and manifest a more severe phenotype than twitcher , with half the life span . Although neuropathological hallmarks such as gliosis , globoid cells and psychosine accumulation are present throughout the nervous system , the CNS does not manifest significant demyelination . In contrast , the PNS is severely hypomyelinated and lacks large diameter axons , suggesting primary dysmyelination , rather than a demyelinating process . Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression . Furthermore , our results argue against a causative relationship between psychosine accumulation , white matter loss and gliosis .

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krabbe disease

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