The long-term objective of this research is to understand the molecular basis of the neuronal ceroid lipofuscinoses (NCL; Batten Disease). NCL is the most common neurodegenerative disorder of childhood and is characterized the progressive mental deterioration, seizures, and vision loss. The hallmark of the disease is the accumulation of autofluorescent lipopigments in ultrastructural cytosomes in neurons and other tissues. Four major subtypes are now recognized on the basis of age of onset, clinical presentation, and ultrastructural morphology: infantile (INCL), found exclusively in Finland; late infantile (LNCL); juvenile (JNCL); and adult (Kufs disease). With the possible exception of the adult form, inheritance is autosomal recessive. The incidence of NCL is estimated at 1-5/100,000. Despite intensive effort, the basic biochemical defect in NCL continues to elude researchers. There is no effective treatment for this fatal disease.
The specific aim of this proposal is clone and characterize the gene for the juvenile form of NCL, CLN3. CLN3 has now been localized by genetic linkage with highly informative microsatellite markers to 16p12.1. It is proposed to refine the localization of CLN3 by more extensive linkage analysis and to isolate the DNA spanning this locus by directed cloning. These clones will be used for fine structure genetic and physical mapping, for screening panels of affected individuals for sub-microscopic deletions and rearrangements, and for the identification of candidate genes by exon trapping. With the identification of closely-linked highly informative flanking markers, DNA-based pre-natal and pre-symptomatic diagnosis can be offered to at-risk families well before the actual cloning and characterization of the disease gene. The identification of mutations within the gene will allow carrier testing in selected populations. Knowledge of the molecular defect in JNCL will help elucidate the biochemical pathways involved in the pathogenesis of the disease, shed light on the possible cause of the other ceroid lipofuscinoses, and provide a starting point for the design of rational therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS032099-03
Application #
2270077
Study Section
Neurology C Study Section (NEUC)
Project Start
1993-08-01
Project End
1996-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Lerner, T J (2001) Positional cloning of the JNCL gene, CLN3. Adv Genet 45:107-21
Lee, R L; Johnson, K R; Lerner, T J (1996) Isolation and chromosomal mapping of a mouse homolog of the Batten disease gene CLN3. Genomics 35:617-9
Haines, J L; Boustany, R M; Worster, T et al. (1995) Genome-wide search for CLN2, the gene causing late-infantile neuronal ceroid-lipofuscinosis (LNCL). Am J Med Genet 57:344-7
Lerner, T J; D'Arigo, K L; Haines, J L et al. (1995) Isolation of genes from the Batten candidate region using exon amplification. Batten Disease Consortium. Am J Med Genet 57:320-3
Mitchison, H M; Taschner, P E; O'Rawe, A M et al. (1994) Genetic mapping of the Batten disease locus (CLN3) to the interval D16S288-D16S383 by analysis of haplotypes and allelic association. Genomics 22:465-8
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