Neurobiology of Disease (Oct 1999)
Targeted Disruption of the Cln3 Gene Provides a Mouse Model for Batten Disease
- Hannah M. Mitchison,
- David J. Bernard,
- Nicholas D.E. Greene,
- Jonathan D. Cooper,
- Mohammed A. Junaid,
- Raju K. Pullarkat,
- Nanneke de Vos,
- Martijn H. Breuning,
- Jennie W. Owens,
- William C. Mobley,
- R.Mark Gardiner,
- Brian D. Lake,
- Peter E.M. Taschner,
- Robert L. Nussbaum
Affiliations
- Hannah M. Mitchison
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- David J. Bernard
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Nicholas D.E. Greene
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Jonathan D. Cooper
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Mohammed A. Junaid
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Raju K. Pullarkat
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Nanneke de Vos
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Martijn H. Breuning
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Jennie W. Owens
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- William C. Mobley
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- R.Mark Gardiner
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Brian D. Lake
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Peter E.M. Taschner
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Robert L. Nussbaum
- Department of Paediatrics, Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom; Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Neurology and Neurological Sciences, Program in Neuroscience, Stanford University, Stanford, California, 94305-5489; New York State Institute for Basic Research in Developmental Disabilities, Staten Island, 10314, New York; Department of Genetics, Section of Human Genetics, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands; Veterinary Resource Program, Office of Research Services, National Institutes of Health, Bethesda, Maryland, 20892-4472; Department of Histopathology, Great Ormond Street Hospital for Children, London, WC1N 3JH, United Kingdom
- Journal volume & issue
-
Vol. 6,
no. 5
pp. 321 – 334
Abstract
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.
