TY - JOUR
T1 - Targeted disruption of the Cln3 gene provides a mouse model for Batten disease
AU - Mitchison, Hannah M.
AU - Bernard, David J.
AU - Greene, Nicholas D.E.
AU - Cooper, Jonathan D.
AU - Junaid, Mohammed A.
AU - Pullarkat, Raju K.
AU - De Vos, Nanneke
AU - Breuning, Martijn H.
AU - Owens, Jennie W.
AU - Mobley, William C.
AU - Gardiner, R. Mark
AU - Lake, Brian D.
AU - Taschner, Peter E.M.
AU - Nussbaum, Robert L.
N1 - Funding Information:
We thank Lisa Garrett, Amy Chen, and Theresa Hernandez for help and advice with gene targeting and mouse colony manage- ment. We thank Michael Eckhaus, Sharon Suchy, Marlene Dressman, Elina Hellsten, Steve Nussinowitz, and members of the Gardiner lab for helpful discussion and suggestions. We also thank Sara Mole and Kit-Yi Leung for comments on the manuscript. We thank E. Kominami, Juntendo University, Tokyo, Japan, for the generous gift of antisera to subunit c. This work was supported by the Division of Intramural Research, National Institutes of Health (U.S.A.) (H.M.M., D.J.B., R.L.N., J.W.O.), the Medical Research Council (UK) (N.D.E.G., H.M.M.), the Remy Foundation (J.D.C.); the Natalie Fund and the Batten Disease Support and Research foundation (W.C.M.); NIH Grants NS 30147 (M.A.J., R.K.P.) and NS 30152 (M.H.B., P.E.M.T.). We also thank the Children’s Brain Diseases Foundation (U.S.A.) for support.
PY - 1999/10
Y1 - 1999/10
N2 - Batten disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3- deficient mouse provides a valuable model for studying Batten disease.
AB - Batten disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3- deficient mouse provides a valuable model for studying Batten disease.
UR - http://www.scopus.com/inward/record.url?scp=0032744277&partnerID=8YFLogxK
U2 - 10.1006/nbdi.1999.0267
DO - 10.1006/nbdi.1999.0267
M3 - Article
C2 - 10527801
AN - SCOPUS:0032744277
SN - 0969-9961
VL - 6
SP - 321
EP - 334
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 5
ER -