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Niemann-Pick Type C-2a: Biological Overview | References

Mutations in either of the two human Niemann-Pick type C (NPC) genes, NPC1 and NPC2, cause a fatal neurodegenerative disease associated with abnormal cholesterol accumulation in cells. npc1a, the Drosophila NPC1 ortholog, NPC1, regulates sterol homeostasis and is essential for molting hormone (20-hydroxyecdysone; 20E) biosynthesis. While only one npc2 gene is present in yeast, worm, mouse and human genomes, a family of eight npc2 genes (npc2a-h) exists in Drosophila. Among the encoded proteins, Npc2a (Flybase term: Niemann-Pick Type C-2, abbreviated NPC2) has the broadest expression pattern and is most similar in sequence to vertebrate Npc2. Mutation of npc2a results in abnormal sterol distribution in many cells, as in Drosophila npc1a or mammalian NPC mutant cells. In contrast to the ecdysteroid-deficient, larval-lethal phenotype of npc1a mutants, npc2a mutants are viable and fertile with relatively normal ecdysteroid level. Mutants in npc2b (CG3153), another npc2 gene, are also viable and fertile, with no significant sterol distribution abnormality. However, npc2a; npc2b double mutants are not viable but can be rescued by feeding the mutants with 20E or cholesterol, the basic precursor of 20E. It is concluded that npc2a functions redundantly with npc2b in regulating sterol homeostasis and ecdysteroid biosynthesis, probably by controlling the availability of sterol substrate. Moreover, npc2a; npc2b double mutants undergo apoptotic neurodegeneration, thus constituting a new fly model of human neurodegenerative disease (Huang, 2007).

Cholesterol, an essential component of eukaryotic cell membranes, also serves as the precursor of many steroid hormones and thus plays vital roles in many developmental processes. Cells in the body maintain proper cholesterol levels through elegant homeostatic regulatory systems. Defects in cholesterol homeostasis and metabolism have been linked directly or indirectly to many disease conditions (Huang, 2007).

Niemann-Pick type C (NPC) disease is one such cholesterol homeostasis-related disorder characterized by aberrant accumulation of free cholesterol in late endosome and lysosome-like compartments (Patterson, 2003). Normal cells take up exogenous cholesterol through the receptor-mediated low density lipoprotein (LDL) endocytic pathway. LDL-derived free cholesterol must then leave the endosomal compartment, a process that is blocked in NPC disease cells, to move to other membrane compartments, including the endoplasmic reticulum (ER), and to control homeostatic responses. NPC disease is a progressive neurodegenerative disorder in which the degeneration of cerebellar Purkinje neurons is most prominent. Although the link between cholesterol homeostasis defects and neurodegeneration remains enigmatic, the deficiency of oxysterol and/or neurosteroid has recently been implicated as partially responsible for this neurodegeneration (Griffin, 2004; Langmade, 2006; Huang, 2007 and references therein).

Mutations in either of two different human genes, NPC1 and NPC2, result in Niemann-Pick type C disease, with NPC1 mutations accounting for about 95% of known cases (Patterson, 2003). The large Npc1 protein has 13 transmembrane domains and a sterol-sensing domain (SSD) (Carstea, 1997; Loftus, 1997). Npc2, a small, secreted protein that binds cholesterol strongly, was first found as an abundant component of human epididymal fluid and later linked through human genetics to the inherited cause of NPC disease in about 5% of the families studied. The crystal structure of Npc2 has been determined and found to contain a cavity that genetic analyses show to be the likely binding site for cholesterol (Friedland, 2003; Ko, 2003). Npc2 may serve as a lysosomal cholesterol transporter, rapidly transporting cholesterol to acceptor membranes (Cheruku, 2006). Although Npc1 and Npc2 are different types of cholesterol-binding proteins, they appear to be in a common pathway or process based on the virtually indistinguishable phenotypes of the human patients carrying one or the other homozygous mutation (Huang, 2007).

To uncover the disease mechanisms as well as the biological function(s) of NPC proteins, useful NPC disease models have been established in yeast, worms, flies and mice (Berger, 2005; Higaki, 2004; Li, 2004; Malathi, 2004). Drosophila NPC models have been developed using npc1a (also referred to as NPC1- FlyBase) mutations (Fluegel, 2006; Huang, 2005). Drosophila and all other insects are unable to synthesize sterol from simple precursors. In order to synthesize the molting hormone 20-hydroxyecdysone (20E) and to sustain the growth and reproduction of the fly, sterol has to be obtained from food. In Drosophila, npc1a is crucial for sterol homeostasis, as is mammalian NPC1. The fly mutants have a molting defect and homozygotes die as first-instar larvae due to a deficiency of the molting hormone 20E, the primary steroid hormone identified in insects to date. 20E plays crucial roles in insect oogenesis, embryogenesis and metamorphosis. npc1a mutants can be rescued by feeding them excess 20E or either of two of its precursors: cholesterol or 7-dehydrocholesterol. Thus, the ecdysteroid deficiency is evidently due to an inability to access sufficient sterol precursor, a somewhat surprising result given the massive accumulations of sterol in punctated structures that are seen in the mutants by filipin staining. The simplest explanation is that the accumulated sterol, stored in multi-lamellar and multivesicular compartments, is not available for 20E synthesis (Huang, 2007).

Based on the findings in npc1 mutant worms, flies and mice, a cholesterol shortage model of NPC disease has been proposed (Huang, 2005). The normal function of Npc1 protein may be to promote delivery of sufficient sterol to the ER and/or mitochondria, organelles in which specific steps of steroidogenesis occur. This paper examined the functions of Npc2 proteins in Drosophila. The results further support the cholesterol shortage model (Huang, 2007).

The Npc2 protein has been conserved throughout much of eukaryotic evolution. Only one npc2 gene is present in yeast, worm, mouse and human genomes. Drosophila, clearly a highly advanced organism, has a family of eight npc2-like genes, which have been named npc2a-h. The gene family was identified by BLAST searching with the sequence of human NPC2. Protein sequences of Npc2a-h (CG7291, CG3153, CG3934, CG12813, CG31410, CG6164, CG11314 and CG11315 range from 22% to 36% identical to human NPC2 (Huang, 2007).

Of the eight Npc2-like proteins, Npc2a (also referred to as NPC2 in FlyBase) has the highest sequence identity (36%) and similarity (53%) to human NPC2. Further protein sequence analysis within this protein family reveals that CG3934 (Npc2c), CG12813 (Npc2d) and CG31410 (Npc2e) form a subgroup clustered at cytogenetic locus 85F8 on chromosome III, while CG11314 (Npc2g) and CG11315 (Npc2h) form another subgroup clustered at locus 100A3 on chromosome III. Both groups of genes presumably arose from gene duplication events (Huang, 2007).

Crystal structure determination and mutational analyses have shown that Npc2 has three disulfide bonds and forms a hydrophobic core implicated in cholesterol binding (Friedland, 2003; Ko, 2003). All six disulfide bond-forming cysteine residues are absolutely conserved in Drosophila Npc2a-h proteins. At other positions shown to be functional in mouse Npc2, Npc2a-h proteins have some variation. For example, F66, V96 and Y100 (amino acid numbers correspond to positions in the mature Npc2 protein without the signaling peptide) of mouse Npc2 are located near the hydrophobic core and are involved in cholesterol binding (Ko, 2003). V96 is the same or highly similar in seven Drosophila Npc2 proteins except Npc2h, F66 is conserved or replaced by the similar amino acid Tyr (Y) in five Npc2 proteins (not in Npc2f, g and h), and Y100 is conserved or replaced by the similar Phe (F) in six Npc2 proteins (not in Npc2c and f). D72 and K75 of mouse Npc2 are not required for cholesterol binding but are necessary for normal Npc2 function. D72 is conserved or replaced by the related amino acid Glu (E) in four of the Drosophila Npc2 proteins (Npc2a, e, f and h), while K75 is conserved in only three Npc2 proteins (Npc2e, g and h). The variations of these key residues in Npc2 proteins may allow retention of cholesterol-binding ability while adding some capability to bind to sterols other than cholesterol. Evidence for functional conservation despite the changes in key residues is provided by the rescue of mammalian Npc2-mutant cells with an introduced yeast NPC2 gene (Berger, 2005), which also has changes in encoded key residues such as K75 and Y100 (Huang, 2007).

The npc2-like gene family is present in other sequenced Drosophila genomes, such as D. yakuba, D. pseudoobscura and D. virilis, as well as genomes from other insect species, including Anopheles gambiae (at least eight npc2-like genes), Bombyx mori (at least three npc2-like genes) and Tribolium casteneum (at least three npc2-like genes). Together these data suggest possible multiple rounds of gene duplication events within Class Insecta (Huang, 2007).

The gene structures of Drosophila melanogaster npc2a-h reveal a pattern of evolution in the generation of introns within the coding region. Three genes (npc2a, g and h) have no intron. Two genes, npc2b and d, each have one intron in the same position. Two others, npc2c and e, have two introns in the same positions. The eighth gene, npc2f, has three introns. Interestingly, the intron positions in the Drosophila npc2-like gene family are almost identical to the intron positions of the vertebrate npc2 genes, including those from human, mouse, rat, chimpanzee, cow and zebrafish. By contrast, the intron position in ncr-2, the Caenorhabditis elegans homolog of npc2, is different. Together, the chromosomal clustering of npc2 genes and the similarity of intron positions support the concept that the generation of the npc2 gene family was a result of multiround gene duplication events (Huang, 2007).

To address the potential roles of different NPC2-like proteins, the temporal and spatial expression patterns of the npc2a-h genes during embryonic stages was determined using whole-mount in situ hybridization. The data revealed that npc2a has the broadest expression pattern, whereas other npc2 genes are either not detectably expressed or expressed in restricted locations. The npc2a gene provides a substantial maternal contribution of RNA, and is also ubiquitously expressed at all stages examined. High levels of npc2a expression were found in midgut, salivary gland and ventral nerve cord. npc2b is expressed at the highest levels in the trachea and hypopharynx. npc2g is specifically expressed in head mesoderm and fat body. npc2d and npc2h transcripts could be detected only in salivary gland, while npc2e is expressed in hindgut. The expression of npc2c and npc2f was not detected by in situ hybridization at any time during embryogenesis (Huang, 2007).

Since npc1a is highly expressed in the ring gland, and ring gland expression of npc1a is important for ecdysteroid biosynthesis, the expression of npc2a-h in ring glands was examined. Brains and imaginal discs from wandering third-instar larvae were also examined. In contrast to npc1a, none of the npc2a-h genes was highly expressed in ring glands. Moderate levels of gene expression were detected in larval ring ring gland , brain and imaginal discs for several npc2 genes, including npc2a and npc2b (Huang, 2007).

Because npc2a has the broadest expression pattern among the eight genes studied, and the highest protein sequence similarity to vertebrate Npc2, focus was initially placed on characterizing npc2a function using mutant phenotypic analysis. Through P element imprecise excision three deletion alleles (npc2a²³⁹, npc2a²⁷¹ and npc2a³⁷⁶ were generated. The whole coding region of npc2a was completely deleted in each of the three alleles, yet homozygous mutant animals were viable and adults were fertile. Each allele was tested in trans to several different genetic deficiencies that remove the gene, and these genetic combinations were also viable and fertile. Whole-mount in situ hybridization with an npc2a antisense probe did not detect any RNA signal in homozygous npc2a mutant embryos, indicating that they are bona fide npc2a mutants (Huang, 2007).

The sterol distribution was next examined in npc2a mutants using filipin staining. Filipin, which stains non-esterified sterols, is often used to study sterol accumulation in NPC1 and NPC2 mutant mammalian cells. Filipin has been successfully used to determine the sterol distribution in Drosophila npc1a mutants and it was found that homozygous mutants have an abnormal sterol distribution similar to that found in mammalian NPC mutants. This is most easily seen by light microscopy as a punctate pattern of filipin-stained particles, and with electron microscopy as multi-lamellar structures (Huang, 2007).

In npc2a/npc2a mutant tissues, including salivary gland, midgut, malpighian tubules, imaginal discs, brains, trachea and oogenesis, a punctate pattern of filipin fluorescence was found. Most tissues had many such spots of accumulated sterol, except trachea, where fewer puncta were found. The filipin staining phenotype was similar to that of Drosophila npc1a mutant tissues and mammalian NPC mutant cells, indicating a conserved role for Drosophila npc2a in regulating efficient intracellular sterol trafficking. The sterol distribution abnormality in npc2a/npc2a mutants could be fully rescued by ubiquitous expression of a UAST-npc2a transgene, indicating that this phenotype is indeed due to npc2a mutation (Huang, 2007).

The structure of mutant npc2a/npc2a cells was examined using electron microscopy. Large multi-lamellar body and multi-vesicular body structures were found in npc2a mutant Malpighian tubules, just as in homozygous npc1a mutants. The multi-lamellar structures were often clustered together to form large inclusions with or without electron-dense materials within. The similarities in cellular phenotypes and ultrastructural defects of npc1a and npc2a mutants further suggest the conserved roles of NPC genes in regulating intracellular sterol trafficking from Drosophila to mammals. As the homozygous mutants survive to adulthood, while npc1a/npc1a flies do not, there must be important differences between npc1 and npc2a phenotypes, and accumulation of sterol is not, by itself, adequate to cause death (Huang, 2007).

The apparently similar defects in sterol distribution in Drosophila npc1a and npc2a mutants raise the question: why do npc1a mutants die as first-instar larvae, while npc2a mutants are viable and ultimately fertile? It was suggested that the first-instar larval lethality of npc1a is due to ecdysteroid deficiency, although this was inferred rather than measured directly (Huang, 2005). The difference in phenotypes between npc1a and npc2a homozygotes could reflect different ecdysteroid levels (Huang, 2007).

Ecdysteroid levels were directly measured during the first-instar stages (38 hours after egg laying) of wild-type, npc1a/npc1a and npc2a/npc2a larvae. Compared to wild type, the npc1a mutant had low ecdysteroid titers (16.7±0.9 pg/100 mutant larvae versus 87.7±4.4 pg/100 wild-type larvae). The npc2a/npc2a mutant larvae had somewhat lower than normal ecdysteroid levels (53.3±3.6 pg/100 mutant larvae versus 73.8±4.1 pg/100 wild-type larvae). These results could explain why npc1a mutants die as first-instar larvae, i.e., cannot molt, while npc2a mutants are viable and are fertile as adults. Furthermore, the data support the previous hypothesis that the first-instar lethality of npc1a/npc1a mutants is due to ecdysteroid deficiency (Huang, 2007).

Drosophila npc2a and npc2b play redundant roles in regulating sterol homeostasis and 20E biosynthesis. The mutant phenotypes of npc2a; npc2b double-homozygous mutants support the proposed cholesterol-shortage model. Moreover, the apoptotic neurodegeneration observed in the fly mutants suggests a further similarity to mammalian NPC disease, and opens up the possibility of applying model organism genetics to understanding the disease process more completely and perhaps devising treatments (Huang, 2007).

A single gene encoding the cholesterol-binding protein Npc2 is present in many eukaryotic species, with the notable exception that a family of Npc2-like proteins arose within insects or their ancestors. The gene structure analysis of the Drosophila npc2-like gene family clearly indicates that the npc2-like genes were formed by multiple rounds of gene duplication. Why do insects have so many Npc2-like proteins and what are their roles (Huang, 2007)?

In general, gene duplication allows the evolution of new gene functions. In that case, one copy can retain the original function of its ancestor and the other can gain new biological functions through further mutation. The prominent sterol accumulation phenotype in many tissues of the npc2a mutant, the broad expression of npc2a, and the high degree of sequence identity between Npc2a and human NPC2 compared with the other seven Npc2-like proteins, all suggest that npc2a functions similarly to vertebrate npc2. From that perspective, the mystery is about the roles of Npc2b-h. Thise study of npc2b demonstrates that npc2b is especially highly transcribed in trachea, and in that tissue it is partially redundant to npc2a with respect to sterol homeostasis. This is an incomplete answer to the origin of the gene duplications, because it is not clear why two genes are required. Other npc2 genes (npc2c-h) may also function partially redundantly with npc2a because npc2a; npc2b double mutants have a weaker phenotype than npc1a mutants (larval/pupal lethal versus first-instar lethal). Since insects are cholesterol auxotrophs and need external sterol sources for growth, it is possible that some of the Npc2-like proteins may be involved in sterol uptake. The pattern of introns in the Drosophila npc2 gene family provides additional insight into their evolution by suggesting a possible sequence of gene duplication events. The intron-less npc2 genes (npc2a, g, h) may have come first, since the vertebrate genes also lack introns. Next to arise would be npc2 genes like npc2b and d that have a single intron in position 1. An additional intron appears at position 2 in npc2c and e, and the most elaborate gene, npc2f, has a third intron in position 3. Alternatively, the ancient gene may have had three introns, and the other genes have been generated by successive loss of introns. Since the intron positions in vertebrate NPC2 genes are almost identical to those in Drosophila npc2 genes, one can speculate that they were generated in the same order through evolution (Huang, 2007).

As a classical lysosomal storage disease, NPC disease is characterized by the accumulation of large amounts of free cholesterol and other lipids in lysosome-like compartments. The search for the causes of this pathology focused mainly on potential cytotoxic effects caused by the accumulation of cholesterol and other lipids (Patterson, 2004). However, cholesterol-lowering drug treatments did not alleviate NPC disease progression and sometimes made it worse, arguing strongly against the original sterol-excess theory of the disease. To elucidate the molecular and cell biology of NPC protein functions, and shed light on the causes of NPC pathology, NPC models have been established in yeast, worms, flies and mice (Huang, 2007).

These studies of Drosophila npc2 genes are consistent with the sterol-shortage model (Huang, 2005). In this model, sterols are trapped in aberrant organelles in NPC mutant cells, and therefore insufficient amounts of sterol reach the ER or mitochondria. In mammals, the lack of sufficient sterol in the ER triggers a homeostatic activation of transcription of genes that encode machinery for the synthesis and import of sterol, thus setting in motion a sustaining cycle of excess sterol, leading to more excess sterol. In flies and mice, the failure to bring sufficient sterol substrate to the ER/mitochondria could deprive cells of the ability to synthesize adequate steroid hormone. The consequences are different between mammals and flies, because the actions of steroids are quite different. In flies the principal steroid hormone is 20E, the molting hormone, so the defect is a failure to molt. In mammals the cerebellar Purkinje neurons are known to produce multiple neurosteroids, although their functions are far from clear. Npc1/Npc1 mutant mice are deficient in neurosteroids, and administration of supplementary allopregnanolone reduces the symptoms of NPC disease (Griffin, 2004). Thus, both fly and mouse NPC mutants are steroid hormone deficient and both mutants can be rescued by exogenous steroid hormone treatment, suggesting strongly that cholesterol and the consequent steroid shortages play a central role in NPC disease (Huang, 2007).

These studies reveal a new layer of ecdysteroid biosynthesis regulation, i.e. sterol substrate availability. The regulation of ecdysteroid biosynthesis and the downstream events that mediate ecdysteroid hormone action have been studied continuously for several decades using genetic and biochemical approaches. To date, many genes that affect 20E biosynthesis have been identified and characterized, and these can be grouped into four functional classes. The first class of genes includes upstream factors such as prothoracicotropic hormone (PTTH) that control whether the prothoracic gland should synthesize ecdysone or not. A PTTH mutant has not been isolated in Drosophila, but studies in other insects have clearly demonstrated the essential function of PTTH in ecdysteroid biosynthesis (Gilbert, 2002). The larval arrest phenotypes resulting from ablating Drosophila neurons that produce PTTH are consistent with a role in governing ecdysteroid biosynthesis. The second class of genes consists of the yet-to-be-identified PTTH receptor and the Ras signaling cascade that transduces the PTTH signal. Ras appears to act through its downstream effector Raf to control ecdysteroid biosynthesis (Caldwell, 2005). The third class of genes includes nuclear transcription factors and regulators, such as ftz-f1, ecd, woc and mld. The targets of these proteins are not well defined but may include the fourth class of genes, the Halloween genes (e.g. dib, sad, phm, shd, spo and spo2) that encode p450 enzymes that mediate the conversion of cholesterol to 20E through multi-step reactions in the ER and mitochondria (Huang, 2007).

The present study, together with study of Drosophila npc1a, defines a fifth class of genes functioning to ensure a sufficient supply of sterol substrates for 20E biosynthesis. This class of mutants has intact 20E biosynthetic enzymes, as shown indirectly by feeding and rescue experiments, but has insufficient sterol substrate for 20E production. Therefore, the ecdysteroid-deficient mutant phenotype can be suppressed by excess cholesterol or 7-dehydrocholesterol, as in npc1a or npc2 (a and b) mutants. Other members of this gene class may include some START domain-containing proteins as well as PBR, which are implicated in transporting sterol into mitochondria for steroid biosynthesis in mammals (Huang, 2007).

Search PubMed for articles about Drosophila Niemann-Pick proteins

Berger, A. C., Vanderford, T. H., Gernert, K. M., Nichols, J. W., Faundez, V. and Corbett, A. H. (2005). Saccharomyces cerevisiae Npc2p is a functionally conserved homologue of the human Niemann-Pick disease type C 2 protein, hNPC2. Eukaryotic Cell 4: 1851-1862. PubMed ID: 16278452

Caldwell, P. E., Walkiewicz, M. and Stern, M. (2005). Ras activity in the Drosophila prothoracic gland regulates body size and developmental rate via ecdysone release. Curr. Biol. 15: 1785-1795. PubMed ID: 16182526

Carstea, E. D., et al. (1997). Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277: 228-231. PubMed ID: 9211849

Cheruku, S. R., Xu, Z., Dutia, R., Lobel, P. and Storch, J. (2006). Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport. J. Biol. Chem. 281: 31594-31604. PubMed ID: 16606609

Fluegel, M. L., Parker, T. J. and Pallanck, L. J. (2006). Mutations of a Drosophila NPC1 gene confer sterol and ecdysone metabolic defects. Genetics 172: 185-196. PubMed ID: 16079224

Friedland, N., Liou, H. L., Lobel, P. and Stock, A. M. (2003). Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease. Proc. Natl. Acad. Sci. USA 100: 2512-2517. PubMed ID: 12591954

Gilbert, L. I., Rybczynski, R. and Warren, J. T. (2002). Control and biochemical nature of the ecdysteroidogenic pathway. Annu. Rev. Entomol. 47: 883-916. PubMed ID: 11729094

Griffin, L. D., Gong, W., Verot, L. and Mellon, S. H. (2004). Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat. Med. 10: 704-711. PubMed ID: 15208706

Higaki, K., Almanzar-Paramio, D. and Sturley, S. L. (2004). Metazoan and microbial models of Niemann-Pick Type C disease. Biochim. Biophys. Acta 1685: 38-47. PubMed ID: 15465425

Huang, X., Suyama, K., Buchanan, J., Zhu, A. J. and Scott, M. P. (2005). A Drosophila model of the Niemann-Pick type C lysosome storage disease: dnpc1a is required for molting and sterol homeostasis. Development 132: 5115-5124. PubMed ID: 16221727

Huang, X., Warren, J. T., Buchanan, J., Gilbert, L. I. and Scott, M. P. (2007). Drosophila Niemann-Pick type C-2 genes control sterol homeostasis and steroid biosynthesis: a model of human neurodegenerative disease. Development 134(20): 3733-42. PubMed ID: 17804599

Ko, D. C., Binkley, J., Sidow, A. and Scott, M. P. (2003). The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels. Proc. Natl. Acad. Sci. 100: 2518-2525. PubMed ID: 12591949

Langmade, S. J., Gale, S. E., Frolov, A., Mohri, I., Suzuki, K., Mellon, S. H., Walkley, S. U., Covey, D. F., Schaffer, J. E. and Ory, D. S. (2006). Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc. Natl. Acad. Sci. 103: 13807-13812. PubMed ID: 16940355

Li, J., Brown, G., Ailion, M., Lee, S. and Thomas, J. H. (2004). NCR-1 and NCR-2, the C. elegans homologs of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways. Development 131: 5741-5752. PubMed ID: 15509773

Loftus, S. K., et al. (1997). Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277: 232-235. PubMed ID: 9211850

Malathi, K., et al. (2004). Mutagenesis of the putative sterol-sensing domain of yeast Niemann Pick C-related protein reveals a primordial role in subcellular sphingolipid distribution. J. Cell Biol. 164: 547-556. PubMed ID: 14970192

Patterson, M. C. (2003). A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C. Neurologist 9: 301-310. PubMed ID: 14629784

Patterson, M. C. and Platt, F. (2004). Therapy of Niemann-Pick disease, type C. Biochim. Biophys. Acta 1685: 77-82. PubMed ID: 15465428

date revised: 2 February 2008

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