Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice.
Loss-of-function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as Unverricht-Lundborg disease (EPM1). The primary cellular events and mechanisms underlying the disease are unknown. We found that mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in the human disease. The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis. This mouse model of EPM1 provides evidence that cystatin B, a non-caspase cysteine protease inhibitor, has a role in preventing cerebellar apoptosis.
Pennacchio
L A
LA
Department of Biological Sciences, Stanford University School of Medicine, California 94305-5120, USA.
Bouley
D M
DM
Higgins
K M
KM
Scott
M P
MP
Noebels
J L
JL
Myers
R M
RM
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001259:Ataxia / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002531:Cerebellum / Q000473:pathology*; D003318:Corneal Opacity / Q000235:genetics; D055313:Cystatin B; D015891:Cystatins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype
C524994:CSTB protein, human; C524992:Cstb protein, mouse; D015891:Cystatins; D015853:Cysteine Proteinase Inhibitors; D017931:DNA Primers; D055313:Cystatin B