The long term aim of this project is to find the gene on chromosome 16 responsible the juvenile form of Batten disease using the 'reverse genetics' approach. Batten disease or ceroid lipofuscinosis is a devastating neurodegenerative disease characterized by progressive blindness, seizures and dementia. In many cell types autofluorescent lipopigment is stored. Inheritance is autosomal recessive. The juvenile form of Batten disease or Spielmeyer-Vogt disease (CLN3) is the most frequent type of ceroid lipofuscinosis. It is linked to markers on chromosome 16. Large numbers of cosmids from chromosome 16 are available. Using fluorescence in situ hybridization cosmids will be rapidly mapped to the interval between the two loci that flank the CLN3 gene. A crucial feature of the 'reverse genetics' approach to a gene is the reduction of the chromosomal region where the gene can be and thus minimize the number of 'candidate genes' to be studied. By combining population genetic and family studies the chromosomal region around CLN3 will be substantially reduced. In The Netherlands a cluster of patients is known in the South-Western part the country. Genetic polymorphisms which show an association with the mutation in this community will be looked for. The chromosomal region defined by these genetic markers will be cloned in overlapping cosmids and yeast artificial chromosomes, a physical map will be constructed, and expressed sequences (genes) will be identified. It is estimated that at least a number of candidate genes can be identified and analysed within the timespan of this project. Isolation of the gene responsible for the juvenile form of Batten disease will provide opportunities for early diagnosis in families at risk, screening for carriers of the mutation, and will help prevent the birth of affected children. When the gene has been found the pathophysiology of this and possibly other forms of Batten disease can be studied. This research may lead to preventive measures or treatment in patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (SRC (55))
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Leiden University
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Taschner, P E M; Losekoot, M; Breuning, M H et al. (2005) [From gene to disease; from CLN1, CLN2 and CLN3 to neuronal ceroid lipofuscinosis] Ned Tijdschr Geneeskd 149:300-3
Taschner, P E; Franken, P F; van Berkel, L et al. (1999) Genetic heterogeneity of neuronal ceroid lipofuscinosis in The Netherlands. Mol Genet Metab 66:339-43
Mitchison, H M; Bernard, D J; Greene, N D et al. (1999) Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten Mouse Model Consortium [corrected] Neurobiol Dis 6:321-34
Munroe, P B; Mitchison, H M; O'Rawe, A M et al. (1997) Spectrum of mutations in the Batten disease gene, CLN3. Am J Hum Genet 61:310-6
Mitchison, H M; Taschner, P E; Kremmidiotis, G et al. (1997) Structure of the CLN3 gene and predicted structure, location and function of CLN3 protein. Neuropediatrics 28:12-4
Mitchison, H M; Munroe, P B; O'Rawe, A M et al. (1997) Genomic structure and complete nucleotide sequence of the Batten disease gene, CLN3. Genomics 40:346-50
Taschner, P E; de Vos, N; Breuning, M H (1997) Rapid detection of the major deletion in the Batten disease gene CLN3 by allele specific PCR. J Med Genet 34:955-6
Munroe, P B; O'Rawe, A M; Mitchison, H M et al. (1997) Strategy for mutation detection in CLN3: characterisation of two Finnish mutations. Neuropediatrics 28:15-7
Taschner, P E; de Vos, N; Breuning, M H (1997) Cross-species homology of the CLN3 gene. Neuropediatrics 28:18-20
Taschner, P E; de Vos, N; Thompson, A D et al. (1995) Chromosome 16 microdeletion in a patient with juvenile neuronal ceroid lipofuscinosis (Batten disease). Am J Hum Genet 56:663-8

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