TY - JOUR
T1 - Missense mutation in mouse GALC mimics human gene defect and offers new insights into krabbe disease
AU - Potter, Gregory B.
AU - Santos, Marta
AU - Davisson, Muriel T.
AU - Rowitch, David H.
AU - Marks, Dan L.
AU - Bongarzone, Ernesto R.
AU - Petryniak, Magdalena A.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NS040511 to D.H.R., K08-NS062744 to M.A.P.; P40 RR001183 to M.T.D.; P30 NS061800 ‘Neuroscience Imaging Center at OHSU’ to Sue A. Aicher); Department of Human and Health Services (RNS065808A to E.R.B.); European Leukodystrophies Association Foundation (ELA 2010-036F34 to G.B.P.); Pollin Pediatric Research Prize, and a private donation from the Kinnune family to M.A.P.; and The Jackson Laboratory’s Cancer Center Core Grant (CA34196). D.H.R. is an HHMI Investigator.
PY - 2013/9
Y1 - 2013/9
N2 - 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-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease.GALCtwi-5J homozygotesshow loss of enzymatic activity despite normal levels of precursor protein, and manifest amore 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, theCNSdoes not manifest significant demyelination. In contrast, thePNSis 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.
AB - 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-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease.GALCtwi-5J homozygotesshow loss of enzymatic activity despite normal levels of precursor protein, and manifest amore 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, theCNSdoes not manifest significant demyelination. In contrast, thePNSis 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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U2 - 10.1093/hmg/ddt190
DO - 10.1093/hmg/ddt190
M3 - Article
C2 - 23620143
AN - SCOPUS:84881586406
SN - 0964-6906
VL - 22
SP - 3397
EP - 3414
JO - Human molecular genetics
JF - Human molecular genetics
IS - 17
M1 - ddt190
ER -