The long term goal of this project is to identify the gene responsible for Niemann-Pick Type C (NP-C), to study its role in the pathogenesis of the disorder and to use this information to aid in the treatment of this disease. NP-C is an autosomal- recessive, neurovisceral lipid storage disorder and presents as variable hepatosplenomegaly, vertical supranuclear ophthalmoplegia, progressive ataxia, dystonia, and dementia. Using human positional cloning and crosses with spontaneous mouse models, we have identified the gene responsible for this disorder. First, we used a 0.1cM mouse genetic linkage map in the region containing m-npc using a series of intersubspecific mouse backcrosses. We next integrated the murine genetic map with the human genetic and physical maps using cloned DNA fragments generated from the contig of human DNA containing the NP-C gene. Finally we evaluated genes as candidates for NP-C from a pool of cDNA clones and trapped exon fragments isolated from the human physical contig. Using Northern blot, Southern blot, SSCP and sequencing analyses using samples isolated from spontaneous mouse mutants in comparison to their isogenic wild type controls we found that one gene, NPC1 has a retrotransposon insertion resulting in a loss-of-function of the normal gene product in mutant mice. We have also found mutations in human individuals with NPC. We have also established a natural history study in order to determine the timecourse of disease prevention and as a basis for therapeutic interventions. We are using antisense approaches to mimic animal models of this disease to assess therapeutic interventions. We are assessing changes in gene expression to identify potential biomarkers and exploring screens to identify potential interventions.

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