Missense mutation in mouse GALC mimics human gene defect and offers new insights into 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,weidentify aspontaneousmutation inGALC,GALC twi-5J ,that precisely matchesthe E130K missense mu- tationinpatientswithinfantileKrabbedisease.GALC twi-5J homozygotesshowlossofenzymaticactivitydespite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks suchasgliosis, globoidcells andpsychosineaccumulationarepresent throughoutthenervoussystem,theCNSdoesnotmanifestsignificantdemyelination.Incontrast,thePNSisse- 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.