Missense mutation in mouse GALCmimics human gene defect and offers new insights into

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 spontaneousmutation inGALC,GALCtwi-5J, that preciselymatches the E130Kmissensemu-tation inpatientswith infantileKrabbedisease.GALCtwi-5Jhomozygotesshow lossof enzymatic activitydespite normal levels of precursor protein, andmanifest 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 thenervoussystem, theCNSdoesnotmanifest significant demyelination. In contrast, thePNS isse-verely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a de-myelinating 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