Coriell Institute for Medical Research
Niemann-Pick C Disease Resource

NPC1 Mutations THR137MET 424_425insGA 451_452delAG PRO401THR ARG404TRP GLN421TER PRO433LEU TYR509SER PRO543LEU 2336_2337insT TYR825CYS 2972_2973delAG PRO1007ALA THR1036MET VAL1165MET 3612_3613insGdelTA PRO237SER ILE1061THR

In the diagram above, the positions of the mutations found in the NPC1 protein in samples in this collection are shown in red. By clicking on the red marker a list of samples in the Repository with those mutations will appear. The top of the diagram faces into the lumen of the endosomes and lysosomes while the cytoplasmic side is at the bottom. Mutations are indicated at the amino acid which is changed or the first amino acid that is changed for insertions, deletions and splicing errors. The figure was modified from Davies and Ioannou, J Biol Chem. 275:24367-74 (2000) with permission.

Niemann Pick C Cell Line Collection

Niemann Pick type C (NPC) disease is an autosomal recessive disorder of lipid storage which can lead to neurological, psychiatric, and visceral problems as well as the failure to thrive. The defect results in the inappropriate accumulation of lipids and defective cholesterol esterification. There is great variety in the presentation of symptoms and the age of onset can range from infancy to adulthood. Half of the Niemann-Pick C patients are diagnosed by the age of 5 years while about 15% are diagnosed after age 20. The disease is quite rare with an estimated frequency of about 1 case per 150,000 births. More than 95% of the cases are NPC1.

Two genes have been identified, NPC1 and NPC2. The NPC1 gene is found on chromosome 18q11-q12, encompasses 56 kb, has 25 exons and encodes a large membrane protein (1278 amino acids) with 13 transmembrane domains some of which are distantly related to the patched gene, the receptor for sonic hedgehog, a major regulator of development. The area of homology includes the sterol sensing domain. The protein is localized in endosomes and lysosomes, however, the true function of this protein is not yet known. The NPC2 gene is found on chromosome 14q24.3 and encodes a small protein (151 amino acids) that is found in lysosomes and is also secreted. NPC is characterized by a defect in the cholesterol esterification pathway resulting in the accumulation of cholesterol which can be detected by staining with filipin (see Park et al., 2003). The biochemical phenotypes of cell lines with defective NPC1 or NPC2 proteins are very similar and can be distinguished by complementation assays. Analysis of mutations has shown that they can occur in almost all portions of the NPC1 gene. They are found in the luminal domains, most of the transmembrane domains and some in the cytoplasmic domains. Much work remains to understand how these mutations lead to the NPC disorder, at the molecular, cellular or systemic level. Recent reviews discuss the genes of this devastating disorder in detail (Sturley et al., 2004; Vanier and Millat, 2004; and Scott and Ioannou, 2004).

The Ara Parseghian Medical Research Foundation in collaboration with the Mayo Clinic have collected cell lines derived from skin biopsies from a large number of individuals with NPC and determined the mutations for these lines. For many of these lines the level of cholesterol esterification, filipin staining and the complementation group have been determined (see Park et al., 2003). These cell lines have been deposited in the Human Genetic Cell Repository so that researchers world-wide will have access to this important resource for NPC research. In addition to providing the cell lines and the determination of mutations, the Ara Parseghian Medical Research Foundation, in collaboration with researchers at the University of Arizona, has performed clinical interviews with many of the patients in order to obtain detailed clinical information. For the lines which were included in the clinical study, the results of the mutations, the biochemical tests and the clinical surveys are provided in an  Excel spreadsheet . The data include demographic data, clinical history, and a behavioral assessment. Please see the on-line catalog to view our complete holdings of NPC1 and NPC2 cell lines. Tables of current mutations NPC1 and NPC2 are also available.

Davies J.P., Ioannou Y.A. Topological analysis of Niemann-Pick C1 protein reveals that the membrane orientation of the putative sterol-sensing domain is identical to those of 3-hydroxy-3-methylglutaryl-CoA reductase and sterol regulatory element binding protein cleavage-activating protein. J. Biol. Chem. 2003. 275:24367-24374. PMID: 10821832.

Park W.D., O'Brien J.F., Lundquist P.A., Kraft D.L., Vockley C.W., Karnes P.S., Patterson M.C., and Snow K. (2003) Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum. Mutat. 22:313-325. PMID: 12955717

Scott C. and Ioannou Y.A. The NPC1 protein: structure implies function. (2004) Biochim Biophys Acta. 1685:8-13. PMID: 15465421

Sturley S.L., Patterson, M.C. Balch, W. and Liscum, L. (2004) The pathophysiology and mechanisms of NP-C disease. Biochim. Biophys. Acta 1685:83-87. PMID: 15465429

Vanier M.T. and Millat G. Structure and function of the NPC2 protein. (2004) Biochim. Biophys. Acta 1685:14-21. PMID: 15465422

Vanier M.T., and Millat G. Niemann-Pick disease type C. (2003) Clin. Genet. 64:269-81. PMID: 12974729

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