The original goal of this project was to develop, characterize and maintain a feline model of human NPC, to provide NPC tissues and kittens to other investigators, and to evaluate various treatment modalities. The overall goal of this Competitive Renewal is essentially the same.
The specific aims of this project are 1) to continue to maintain this colony of feline NPC and continue to make this model available to other investigators, 2) to further characterize the feline model by using antibodies generated against the feline NPC1 protein, and 3) to continue to evaluate a ganglioside synthesis inhibitor as therapy for NPC, because a pilot study has shown decreased ganglioside storage in cats treated with this inhibitor. NPC in human beings as well as in the feline model, is an autosomal recessive lysosomal storage disorder with a variety of clinical features including organomegaly, progressive neurologic abnormalities possibly related to neuronal ganglioside storage, and premature death. The primary cytologic defect is associated with defective intracellular transport of unesterified cholesterol. The NPC1 protein is now thought to also play a role in ganglioside transport. The gene responsible for the most common type of human NPC (NPC1) has been identified. Complementation studies using cat and human NPC fibroblasts support that the gene responsible for NPC in the feline model is orthologus to human NPC1. Feline specific PCR primers were generated and designed to amplify six overlapping bands which span the entire feline NPC open reading frame. The predicted feline amino acid sequence shows 91% homology to the human NPC1 protein. A single base substitution, resulting in a conserved cysteine to serine substitution, has been identified in all NPC affected cats evaluated, and is in the same area as several of the point mutations reported in human beings. Carriers are heterozygous for the same allele. A PCR-based assay has been developed that quickly and accurately identifies carriers, as well as affected kittens. This model will provide a unique and valuable resource with which to evaluate treatment modalities for NPC. Increased numbers of NPC-affected kittens will now be available, since carrier detection eliminates time-consuming breeding trials. Approximately 12 female and three male carriers will be maintained at CSU, with the goal of producing 15 to 20 affected kittens per year. Additional breeders and affected kittens will be made available to other investigators.
| Yüksel, Fatih; Do?an, Mansur; Karata?, Duran et al. (2013) Gastroesophageal reflux disease in children with chronic otitis media with effusion. J Craniofac Surg 24:380-3 |
| Walkley, S U; Thrall, M A; Haskins, M E et al. (2005) Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease. Neuropathol Appl Neurobiol 31:536-44 |
| Garver, William S; Somers, Kyra; Krishnan, Kumar et al. (2002) The Niemann-Pick C1 protein in feline fibroblasts. Mol Genet Metab 76:31-6 |
| Zervas, M; Somers, K L; Thrall, M A et al. (2001) Critical role for glycosphingolipids in Niemann-Pick disease type C. Curr Biol 11:1283-7 |
| Somers, K L; Brown, D E; Fulton, R et al. (2001) Effects of dietary cholesterol restriction in a feline model of Niemann-Pick type C disease. J Inherit Metab Dis 24:427-36 |
| Somers, K L; Wenger, D A; Royals, M A et al. (1999) Complementation studies in human and feline Niemann-Pick type C disease. Mol Genet Metab 66:117-21 |
| March, P A; Thrall, M A; Brown, D E et al. (1997) GABAergic neuroaxonal dystrophy and other cytopathological alterations in feline Niemann-Pick disease type C. Acta Neuropathol (Berl) 94:164-72 |
| Brown, D E; Thrall, M A; Walkley, S U et al. (1996) Metabolic abnormalities in feline Niemann-Pick type C heterozygotes. J Inherit Metab Dis 19:319-30 |
| Munana, K R; Luttgen, P J; Thrall, M A et al. (1994) Neurological manifestations of Niemann-Pick disease type C in cats. J Vet Intern Med 8:117-21 |
| Brown, D E; Thrall, M A; Walkley, S U et al. (1994) Feline Niemann-Pick disease type C. Am J Pathol 144:1412-5 |
