Alternative titles; symbols
HGNC Approved Gene Symbol: NPC1
SNOMEDCT: 18927009; ICD10CM: E75.243;
Cytogenetic location: 18q11.2 Genomic coordinates (GRCh38) : 18:23,506,184-23,586,506 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q11.2 | Niemann-Pick disease, type C1 | 257220 | Autosomal recessive | 3 |
| Niemann-Pick disease, type D | 257220 | Autosomal recessive | 3 |
By positional cloning methods, Carstea et al. (1997) identified the putative gene responsible for Niemann-Pick disease type C1 (257220). The NPC1 gene encodes a 1,278-amino acid protein with sequence similarity to the morphogen receptor 'Patched' (601309), which is mutant in the basal cell nevus syndrome (BCNS; 109400), and to the putative sterol-sensing regions of SREBP cleavage-activating protein (601510) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (142910).
Loftus et al. (1997) used an integrated human-mouse positional candidate approach to identify the gene responsible for the phenotypes observed in a mouse model of NPC disease. Similar to the human protein, the predicted murine NPC1 protein had sequence homology to the putative transmembrane domains of 'Patched', the cholesterol-sensing regions of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the SREBP cleavage-activating protein, and the NPC1 orthologs identified in human, nematode, and yeast.
Morris et al. (1999) defined the genomic structure of NPC1 along with the 5-prime flanking sequence. The NPC1 gene spans more than 47 kb and contains 25 exons. All intron/exon boundaries follow the GT/AG rule. The 5-prime flanking sequence has a CpG island containing multiple Sp1 sites indicative of a promoter region. The CpG island is located in the 5-prime flanking sequence, exon 1, and the 5-prime end of intron 1. Morris et al. (1999) also identified multiple single-nucleotide polymorphisms in the coding and intronic sequences.
The locus corresponding to the mouse Npc phenotype (Pentchev et al., 1984), symbolized spm, was shown by Sakai et al. (1991) to be on mouse chromosome 18. Linkage studies by Carstea et al. (1993) localized the human NPC gene to chromosome 18. The mapping to chromosome 18 was extended by the demonstration by Kurimasa et al. (1993) of restoration of cholesterol metabolism in the homozygous spm mouse by transfer of a human chromosome 18. In the experiments, they used 3T3 cell lines derived from homozygous sphingomyelinosis mice. The gene was tentatively mapped to either 18pter-p11.3 or 18q21.3-qter, these being segments that were lost during subcloning, which resulted in reaccumulation of the intracellular cholesterol. The chromosome transfer was achieved in microcell hybrids. By linkage studies, Carstea et al. (1994) located the NPC gene to a region defined by DNA markers in the 18q11-q12 region.
Carstea et al. (1997) showed that transfection of NPC fibroblasts with wildtype NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking.
To elucidate structural features of the NPC1 gene product defective in Niemann-Pick type C disease, Watari et al. (1999) examined the ability of wildtype NPC1 and NPC1 mutants to correct the excessive lysosomal storage of low density lipoprotein-derived cholesterol in a model cell line displaying the NPC cholesterol-trafficking defect, i.e., CT60 Chinese hamster ovary cells. CT60 cells transfected with human wildtype NPC1 contained immunoreactive proteins of 170 and 190 kD localized to the lysosomal/endosomal compartment. Wildtype NPC1 protein corrected the NPC cholesterol-trafficking defect in the CT60 cells. Mutation of conserved cysteine residues in the NPC1 N terminus to serine residues resulted in proteins targeted to lysosomal membranes encircling cholesterol-laden cores, whereas deletion of the C-terminal 4 amino acid residues containing the leu-leu-gln-phe (LLNF) lysosome-targeting motif resulted in the expression of protein localized to the endoplasmic reticulum. None of these mutant NPC1 proteins corrected the NPC cholesterol-trafficking defect in CT60 cells. Watari et al. (1999) concluded that transport of the NPC1 protein to the cholesterol-laden lysosomal compartment is essential for expression of its biologic activity and that domains in the N terminus of the NPC1 protein are critical for mobilization of cholesterol from lysosomes.
NPC1 is a member of a family of genes encoding membrane-bound proteins containing putative sterol-sensing domains. By use of a specific antipeptide antibody to human NPC1, Patel et al. (1999) investigated the cellular and subcellular localization and regulation of NPC1 in monkey brain. By light and electron microscopic immunocytochemistry, NPC1 was expressed predominantly in presynaptic astrocytic glial processes. At a subcellular level, NPC1 localized to vesicles with the morphologic characteristics of lysosomes and to sites near the plasma membrane. Analysis of the temporal and spatial pattern of neurodegeneration in the NPC mouse, a spontaneous mutant model of human NPC, by amino-cupric-silver staining, showed that the terminal fields of axons and dendrites are the earliest sites of degeneration that occur well before the appearance of a neurologic phenotype. Western blots of cultured human fibroblasts and monkey brain homogenates revealed NPC1 as a 165-kD protein. NPC1 levels in cultured fibroblasts were unchanged by incubation with low density lipoproteins or oxysterols but were increased 2- to 3-fold by the drugs progesterone and U-18666A, which block cholesterol transport out of lysosomes, and by the lysosomotropic agent NH(4)Cl. These studies show that NPC1 in brain is predominantly a glial protein present in astrocytic processes closely associated with nerve terminals, the earliest site of degeneration in NPC. Given the vesicular localization of NPC1 and its proposed role in mediating retroendocytic trafficking of cholesterol and other lysosomal cargo, these results suggested that disruption of NPC1-mediated vesicular trafficking in astrocytes may be linked to neuronal degeneration in NPC.
Zhang et al. (2001) followed the biosynthesis and trafficking of NPC1 with a functional green fluorescent protein-fused NPC1. Newly synthesized NPC1 was exported from the endoplasmic reticulum and required transit through the Golgi before it was targeted to late endosomes. NPC1-containing late endosomes then moved by a dynamic process involving tubulation and fission, followed by rapid retrograde and anterograde migration along microtubules. Cell fusion studies with normal and mutant NPC1 cells showed that exchange of contents between late endosomes and lysosomes depended upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement required an intact NPC1 sterol-sensing domain and was retarded by an elevated endosomal cholesterol content. Zhang et al. (2001) concluded that the neuropathology and cellular lysosomal lipid accumulation in NPC1 disease results, at least in part, from striking defects in late endosomal tubulovesicular trafficking.
Davies et al. (2000) demonstrated that the NPC1 protein has homology with the resistance-nodulation-division (RND) family of prokaryotic permeases and may normally function as a transmembrane (TM) efflux pump. Studies of acriflavine loading in normal and NCP1 fibroblasts indicated that NPC1 uses a proton motive force to remove accumulated acriflavine from the endosomal/lysosomal system. Expression of NPC1 in E. coli facilitated the transport of acriflavine across the plasma membrane, causing cytosolic accumulation, and resulted in transport of oleic acid but not cholesterol or cholesterol-oleate across the plasma membrane. Davies et al. (2000) concluded that their studies establish NPC1 as a eukaryotic member of the RND permease family.
Ioannou (2000) described the NPC1 gene product as a large polytopic glycoprotein with a cytoplasmic tail containing a dileucine endosome-targeting motif. The NPC1 protein sequence shares strong homology with NPC1-like-1, or NPC1L1, and the morphogen receptor Patched. In addition, a group of 5 NPC1 transmembrane domains share homology with the sterol-sensing domain of proteins involved in cellular cholesterol homeostasis. Subcellular localization studies have shown NPC1 to reside in late endosomes and to associate transiently with lysosomes and the trans-Golgi network. Analysis of its topologic arrangement in membranes suggests that NPC1 contains 13 transmembrane domains and 3 large, hydrophilic, luminal loops. A number of observations suggested that NPC1 may be related to a family of prokaryotic efflux pumps and thus may also act as a molecular pump.
Macrophages from mice with a heterozygous mutation in the Npc1 protein have a selective defect in cholesterol trafficking to the endoplasmic reticulum (ER) and are protected from cholesterol-induced apoptosis. Feng et al. (2003) tested the importance of intracellular cholesterol trafficking in atherosclerotic lesional macrophage death by comparing lesion morphology in 2 groups of mice: apoE -/- and either Npc1 +/+ or Npc1 +/-. Feng et al. (2003) presented data that provided in vivo evidence that intact intracellular cholesterol trafficking is important for macrophage apoptosis in advanced atherosclerotic lesions and that the ER-based model of cholesterol-induced cytotoxicity is physiologically relevant. By showing that lesional necrosis can be diminished by a subtle defect in intracellular trafficking, these findings suggested therapeutic strategies to stabilize atherosclerotic plaques. These data raised the interesting possibility that heterozygous Niemann-Pick C humans, who are reported to be 'normal,' actually had a lower incidence of acute ischemic events compared with individuals without this mutation.
Lloyd-Evans et al. (2008) found that lysosomal sphingosine storage and reduced lysosomal calcium levels were early events in development of the NPC phenotype in normal human cells exposed to the NPC-inducing drug U18666A. In this model, accumulation of cholesterol, sphingomyelin, and glycerosphingolipid was a secondary event. Pharmacologic elevation of cytosolic calcium or reduction of sphingosine content reversed the NPC phenotype in several cellular models of NPC, and sphingosine alone induced the abnormal calcium phenotype in a concentration-dependent manner. Treatment of Npc1 -/- mice with curcumin, a weak SERCA (see 108730) antagonist that elevates cytosolic calcium levels, increased life expectancy by 35% and slowed the rate of disease progression by 3 weeks. Lloyd-Evans et al. (2008) concluded that NPC1 is involved in sphingosine efflux from lysosomes, and that lysosomal sphingosine accumulation in NPC alters intracellular calcium concentration and causes abnormal endocytic trafficking.
Castellano et al. (2017) identified cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTOR complex 1 (mTORC1; see 601231) recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein SLC38A9 (616203) is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the NPC1 protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Castellano et al. (2017) concluded that, thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex.
Role of NPC1 in Ebola Virus Infection
Infections by the Ebola and Marburg filoviruses cause a rapidly fatal hemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes, and catalyzes fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are likely required for viral membrane fusion. Using a replication-competent vesicular stomatitis virus bearing Ebola virus GP (rVSV-GP-EboV) for a genomewide haploid genetic screen in human cells, followed by selection of rVSV-GP-EboV-resistant cells, Carette et al. (2011) confirmed a role for cathepsin B (CTSB; 116810) and identified roles for NPC1 and all 6 subunits of the HOPS complex, VPS11 (608549), VPS16 (608550), VPS18 (608551), VPS33A (610034), VPS39 (612188), and VPS41 (605485), in Ebola virus entry. Subcloned cells lacking VPS11, VPS33A, or NPC1 displayed marked resistance to rVSV-GP-EboV or Marburg virus-GP, and susceptibility could be restored by expression of the corresponding cDNAs. Infection of primary fibroblast from patients with NPC1 mutations, but not those from patients with NPC2 (601015) mutations, resulted in poor or no infection, but infection could be restored by expression of wildtype NPC1. Small molecules that induce a cellular phenotype similar to NPC1 deficiency, such as U18666A and imipramine, potently inhibited infection by rVSV-GP-EboV, even after a short exposure to the molecules. Immunofluorescence microscopy demonstrated that wildtype cells treated with U18666A or cells lacking NPC1, VPS11, or VPS33A had an altered distribution of virus within cells. Fibroblasts from patients with NPC1 mutations, human monocytes and endothelial cells and green monkey kidneys cells treated with U18666A, or human endothelial cells in which NPC1 had been knocked down exhibited reduced infection with authentic Ebola or Marburg virus. Npc1 +/- mice were largely protected from mouse-adapted Ebola or Marburg virus, whereas wildtype mice rapidly succumbed to infection. Carette et al. (2011) concluded that most of the genes involved in filovirus entry are involved in lysosome function, indicating that filoviruses exploit this organelle differently than other viruses. In this model, NPC1 appeared to be involved in release of virus into the cytoplasm.
Cote et al. (2011) identified a novel inhibitor of Ebola virus that targeted NPC1 and interfered with binding of viral GP to NPC1. They concluded that endosomal cathepsin proteases remove heavily glycosylated GP domains to expose the N-terminal domain of the GP1 subunit, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit.
Wang et al. (2016) determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 angstroms. NPC1-C utilized 2 protruding loops to engage a hydrophobic cavity on the head of GPcl. Upon enzymatic cleavage and NPC1-C binding, a conformational change in GPcl further affected the state of the internal fusion loop, triggering membrane fusion. Wang et al. (2016) concluded that their data provide structural insights into filovirus entry in the late endosome.
In 9 unrelated families with Niemann-Pick disease type C1 (NPC1; 257220), Carstea et al. (1997) identified 8 distinct mutations in the NPC1 gene (e.g., 607623.0001).
In a study of cDNA and genomic DNA isolated from the fibroblasts of 11 patients with NPC1, 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and 1 Caucasian, Yamamoto et al. (1999) found 14 novel mutations, including small deletions and point mutations. Of the 14 mutations, the 1553G-A transition (257220.0005), which caused a splicing error of exon 9, appeared to be relatively common in Japanese patients because 2 patients were homozygous and 1 patient was compound heterozygous for this mutation.
By SSCP analysis in 13 apparently unrelated families with NPC, Greer et al. (1999) identified 13 mutations, accounting for 19 of the 26 alleles. These mutations included 8 different missense mutations (including 1 that Greer et al. (1998) had reported), 3 small deletions that generated premature stop codons, and 2 intronic mutations predicted to alter splicing. The missense mutations were present in predicted transmembrane domains in 2 instances. The clustering of these and other reported NPC1 mutations in the C-terminal third of the protein indicated that screening of these exons, by means of the SSCP analysis reported by Greer et al. (1999), will detect most mutations. The C-terminal half of the NPC1 protein shares amino acid similarity with the transmembrane domains of the morphogen receptor 'Patched,' with the largest stretch of unrelated sequence lying between 2 putative transmembrane spans. Seven of a total of 13 NPC1 missense mutations were concentrated in a single NPC1-specific domain, suggesting that integrity of this region is particularly crucial for normal functioning of the protein.
Sun et al. (2001) performed mutation analysis of the NPC1 gene in NPC variant and 'classic' NPC cell samples and found a high incidence of specific mutations within the cysteine-rich region of NPC1 in variants. In 5 of the 12 variant cell samples, no apparent defect in NPC1 could be found, but they were otherwise indistinguishable from other variant cells. Meiner et al. (2001) identified 8 novel mutations in the NPC1 gene.
Bauer et al. (2002) described the complete genomic sequence of 57,052 kb corresponding to the transcribed region of NPC1 including several exonic and intronic single-nucleotide polymorphisms (SNPs). Through sequencing of cDNA and genomic DNA, they identified 13 different mutations in NPC1 in 12 patients affected by type C Niemann-Pick disease. Ten unique mutations in 24 disease alleles were observed in compound heterozygous patients. Of the 3 missense mutations, 2 identified more than once were observed in a total of 4 patients homozygous for the respective mutation along with homozygosity for the underlying haplotype. The haplotype 2572G-2793T was found in 17 of 24 NPC1 alleles (71%), whereas this haplotype accounted for only 41% in controls, suggesting the possibility of an influence of the haplotypic background on expression of missense mutations in NPC1.
Kaminski et al. (2002) analyzed the NPC1 gene in 5 German patients with NPC1-related families. They identified a total of 5 novel mutations in the coding region of NPC1.
Blom et al. (2003) identified the mutations in an NPC1 patient as cys113 to arg (C113R; 607623.0022) and del 3611-3614 (607623.0023). The level of NPC1 protein in the patient's fibroblasts was similar to that in control cells, but the protein was partially mislocalized from late endocytic organelles diffusely to the cell periphery. In contrast, NPC2 (601015) was upregulated and accumulated in cholesterol-storing late endocytic organelles. The authors suggested that NPC1 may govern the endocytic transport of NPC2. In Finnish and Swedish population samples, alleles carrying C113R or del3611-3614 were not identified, whereas 5% of alleles carried a benign polymorphism.
To obtain more information on the functional domains of the NPC1 protein, Millat et al. (2001) studied the mutational spectrum and the level of immunoreactive protein in skin fibroblasts from 30 unrelated patients with Niemann-Pick C1 disease. In 9 of these, there was a mild alteration of cellular cholesterol transport (the 'variant' biochemical phenotype). The mutations showed a wide distribution to nearly all NPC1 domains, with a cluster (11 of 32 mutations) in a conserved NPC1 cysteine-rich luminal loop. Homozygous mutations in 14 patients and a phenotypically defined allele, combined with a new mutation, in a further 10 patients allowed genotype/phenotype correlations. Codon mutations causing premature termination, 3 missense mutations in the sterol-sensing domain (SSD), and a missense mutation in the cysteine-rich luminal loop all occurred in patients with infantile neurologic onset and 'classic' (i.e., severe) cholesterol-trafficking alterations. By Western blot analysis, NPC1 protein was undetectable in the SSD missense mutations and essentially absent in the missense allele in the cysteine-rich luminal loop. In the remaining missense mutations studied, corresponding to other disease presentations (including 2 adults with nonneurologic disease), NPC1 protein was present in significant amounts of normal size, without clear-cut correlation with either the clinical phenotype or the 'classic'/'variant' biochemical phenotype since mutations in the cysteine-rich luminal loop resulted in a wide array of clinical and biochemical phenotypes. Remarkably, all 5 mutant alleles, including the recurrent P1007A (607623.0012), definitively correlated with the 'variant' phenotype and clustered within this loop, providing new insight on the functional complexity of the latter domain.
In a group of 13 unrelated NPC1 patients, among whom 12 were of Portuguese extraction, Ribeiro et al. (2001) observed an unusually large proportion of families presenting mild alterations of intracellular cholesterol transport, the so-called variant biochemical phenotype, without strict correlation between the biochemical phenotype and the clinical expression of the disorder. Ten novel mutations were identified. A correlation with the biochemical phenotype was found: splicing mutations, I1061T (607623.0010), and A1035V (607623.0016) corresponded to 'classic' alleles, while 3 missense mutations, C177Y (607623.0018), R978C (607623.0020), and P1007A (607623.0012), could be defined as 'variant' alleles. All 'variant' mutations described to that time appeared to be clustered within the cysteine-rich luminal loop between TM 8 and 9, with the remarkable exception of C177Y. The latter mutant allele, at variance with P1007A, was correlated to a decreased level of NPC1 protein and a severe course of the disease, and disclosed a new location for 'variant' mutations, the luminal loop located in the N-terminal region of the protein.
Park et al. (2003) described mutation analysis on samples from 143 unrelated NPC patients using a conformation-sensitive gel electrophoresis and DNA sequencing of the NPC1 and NPC2 genes, respectively. Mutations were identified in one or the other gene on 251 of 286 (88%) disease alleles, including 121 different mutations (114 in NPC1 and 7 in NPC2), 58 of which had not been previously reported. The most common NPC1 mutation, I1061T (607623.0010), was detected in 18% of NPC alleles. The region between amino acids 1038 and 1253, which shared 35% identity with Patched (601309), appeared to be a hotspot for mutations. Additionally, a high percentage of mutations were located at amino acids identical to the NPC1 homolog, NPC1L1 (608010). Biochemical complementation analysis in cases negative for mutations revealed a high percentage of equivocal results where the complementation group appeared to be non-NPC1 and non-NPC2. This raised the possibility of 1 or more additional NPC complementation groups or nonspecificity of the biochemical testing for NPC.
Fernandez-Valero et al. (2005) analyzed the NPC1 and NPC2 genes in 40 unrelated Spanish patients with Niemann-Pick type C and identified 38 different mutations in the NPC1 gene. Data from homozygous patients indicated that the Q775P mutation correlated with a severe infantile neurologic form and the C177Y mutation with a late infantile clinical phenotype.
Loftus et al. (1997) described 2 spontaneous mouse mutant strains with a phenotype similar to that observed in human Niemann-Pick disease type C. Using high-resolution linkage mapping and candidate gene analysis, Loftus et al. (1997) found that a retroposon insertion in the mouse Npc1 gene was responsible for BALB/c mouse model of the disease (Npc1 -/-).
Loftus et al. (2002) constructed transgenic mice in which the wildtype NPC1 protein was expressed primarily in the CNS, using the prion promoter. When the transgene was introduced into Npc1 -/- animals, neurodegeneration was prevented, a 'normal' life span occurred, and the sterility of Npc1 -/- mice was corrected. The rescue did not provide complete neurologic correction in the CNS, as GM2 and GM3 gangliosides were observed to accumulate in some neurons and glia of transgenic animals. Two of 3 transgenic lines demonstrated some low-level ectopic expression resulting in correction of visceral phenotypes in liver and spleen. The third transgenic line continued to have moderate histiocytosis in liver and spleen, yet had no detectable neurodegeneration. Loftus et al. (2002) concluded that it is primarily the lack of NPC1 in the CNS, and not the secondary effects of the visceral involvement, that causes the neurologic decline in NPC disease. In addition, the expression levels of Npc1 found in the CNS of transgenic animals were much greater than in normal littermates, demonstrating that overexpression of NPC1 is not harmful and may be useful in genetic therapy.
The NPC1 and NPC2 (601015) proteins are required for the egress of lipids from the lysosome. To gain insight into the normal function of NPC2 and to investigate its interactions, if any, with NPC1, Sleat et al. (2004) generated a murine Npc2 hypomorph that expressed 0 to 4% residual protein in different tissues and examined its phenotype in the presence and absence of Npc1. The phenotypes of Npc1 and Npc2 single mutants and an Npc1/Npc2 double mutant were similar or identical in terms of disease onset and progression, pathology, neuronal storage, and biochemistry of lipid accumulation. These findings provided genetic evidence that the NPC1 and NPC2 proteins function in concert to facilitate the intracellular transport of lipids from the lysosome to other cellular sites.
Langmade et al. (2006) noted that the failure to properly traffic lipoprotein cholesterol in NPC1 results in impaired oxysterol and steroid synthesis. The authors found that treatment of Npc1 -/- mice with the neurosteroid allopregnanolone and a synthetic oxysterol ligand delayed the onset of neurologic symptoms and prolonged life span, suggesting that the treatment bypassed the cholesterol trafficking defect. The therapy preserved Purkinje cells, suppressed cerebellar expression of microglial-associated genes, and reduced infiltration of microglia in cerebellar tissue. Transfection assays correlated the efficacy of treatment with activation of murine PXR (NR1I2; 603065) in vivo.
To determine the extent to which tau (MAPT; 157140) affects NPC pathogenesis, Pacheco et al. (2009) generated Mapt/Npc1 double-knockout mice and found markedly smaller litters, an enhanced NPC phenotype, and death occurring significantly earlier than in Npc1-null mice. Following knockdown of MAPT in NPC1-deficient human fibroblasts, the authors found decreased induction and flux through the autophagic pathway. Pacheco et al. (2009) concluded that MAPT deletion exacerbates the NPC phenotype through a mechanism independent of tau protein aggregation, and they proposed a critical role for tau in the regulation of autophagy in NPC1-deficient cells.
Elrick et al. (2010) generated Npc1 conditional null mutant mice. Deletion of Npc1 in mature cerebellar Purkinje cells led to an age-dependent impairment in motor tasks, including rotarod and balance beam performance. These mice did not show the early death or weight loss characteristic of global Npc1-null mice, suggesting that Purkinje cell degeneration may not underlie these phenotypes. Histologic examination revealed the progressive loss of Purkinje cells in an anterior-to-posterior gradient. This cell-autonomous neurodegeneration occurred in a spatiotemporal pattern similar to that of global knockout mice. A subpopulation of Purkinje cells in the posterior cerebellum exhibited marked resistance to cell death despite Npc1 deletion. Purkinje cells in both vulnerable and resistant subpopulations displayed no electrophysiologic abnormalities prior to degeneration. The authors concluded that Npc1 deficiency leads to cell-autonomous selective neurodegeneration and suggested that the ataxic symptoms of NPC disease may arise from Purkinje cell death rather than cellular dysfunction.
In a patient with Niemann-Pick disease type C1 (NPC1; 257220), Carstea et al. (1997) identified a 2783A-C transversion of the NPC1 gene that resulted in a gln928-to-pro amino acid substitution. The patient was a compound heterozygote.
In a patient with Niemann-Pick disease (NPC1; 257220), Carstea et al. (1997) observed homozygosity for a 3107C-T transition of the NPC1 gene that resulted in a thr1036-to-met amino acid substitution. The same mutation was found as one allele in a compound heterozygote. This patient was apparently unrelated to the first.
In each of 2 unrelated patients with Niemann-Pick disease (NPC1; 257220), Carstea et al. (1997) found compound heterozygosity at the NPC1 locus with one of the mutations being a 3467A-G transition, resulting in an asn1156-to-ser amino acid substitution in the NPC1 protein. The authors noted that asn1156 is conserved in human, mouse, C. elegans, and S. cerevisiae orthologs of NPC1.
Greer et al. (1997) mapped the Nova Scotian type of Niemann-Pick disease, also called type D (see 257220), to a 13-cM chromosome segment between D18S40 and D18S66. A gene isolated from this region, NPC1, had been found to be mutated in most patients with Niemann-Pick disease type C. Greer et al. (1998) identified a point mutation within the NPC1 gene (3097G-T, G992W) that showed complete linkage disequilibrium with the Nova Scotian form, confirming that type D is an allelic variant of NPC1.
Among 3 Japanese patients with the late infantile form of type C Niemann-Pick disease (NPC1; 257220), Yamamoto et al. (1999) found homozygosity for a G-to-A transition at nucleotide 1553, which resulted in a 227-bp deletion, representing all of exon 9 (nucleotides 1327 to 1553), and an arg518-to-gln (R518Q) amino acid substitution. The mutation was predicted to cause a 75-amino acid deletion and a frameshift to create a premature termination at codon 499 in exon 10.
Yamamoto et al. (1999) found compound heterozygosity for mutations in the NPC1 gene in a Japanese patient with the adult form of Niemann-Pick disease type C1 (NPC1; 257220), which began at 25 years of age and was characterized by dementia, ataxia, dystonia, epilepsy, and vertical supranuclear ophthalmoplegia, as well as splenomegaly. Death occurred at 42 years of age. One of the mutations was a G-to-A transition at nucleotide 2665, resulting in a val889-to-met amino acid substitution. The other mutation was a splicing error, a deletion of A at the -2 position in an acceptor splice site (3043-2delA; 607623.0007), which the authors termed intron 54B, leading to a 54-bp deletion and an in-frame deletion of 18 amino acids.
For discussion of the splice site mutation in the NPC1 gene (3043-2delA) that was found in compound heterozygous state in a patient with the adult form of Niemann-Pick disease type C1 (NPC1; 257220) by Yamamoto et al. (1999), see 607623.0006.
Yamamoto et al. (1999) demonstrated compound heterozygosity for mutations in the NPC1 gene in a patient who had onset of neurologic signs of juvenile Niemann-Pick disease type C (NPC1; 257220) at the age of 15 years. Manifestations consisted of dystonia, ataxia, and vertical supranuclear ophthalmoplegia, as well as mild splenomegaly. Two missense mutations were found: a 3263A-G transition leading to a tyr1088-to-cys amino acid substitution, and a 3639G-C transversion leading to a leu1213-to-phe amino acid substitution.
For discussion of the leu1213-to-phe (L1213F) mutation in the NPC1 gene that was found in compound heterozygous state in patient with neurologic signs of juvenile Niemann-Pick disease type C (NPC1; 257220) by Yamamoto et al. (1999), see 607623.0008.
In an initial study of 25 patients with type C1 Niemann-Pick disease (NPC1; 257220), Millat et al. (1999) identified a T-to-C transition at nucleotide 3182 of the NPC1 gene that led to an ile1061-to-thr substitution (I1061T) in 3 patients. The mutation, located in exon 21, affected a putative transmembrane domain of the protein. PCR-based tests with genomic DNA were used to survey 115 unrelated patients from around the world with all known clinical and biochemical phenotypes of the disease. The I1061T allele constituted 33 (14.3%) of the 230 disease-causing alleles and was never found in controls. The mutation was particularly frequent in patients with NPC from western Europe, especially France (11 of 62 alleles) and the U.K. (9 of 32 alleles), and in Hispanic patients whose roots were in the upper Rio Grande valley of the U.S. Millat et al. (1999) concluded that the I1061T mutation originated in Europe and that the high frequency in northern Rio Grande Hispanics resulted from a founder effect. All 7 unrelated patients who were homozygous for the mutation and their 7 affected sibs had a juvenile-onset neurologic disease and severe alterations of intracellular LDL-cholesterol processing. The mutation was not found (0 of 40 alleles) in patients with the severe infantile neurologic form of the disease.
Using human fibroblasts homozygous for the I1061T mutation, Gelsthorpe et al. (2008) found that mutant NPC1 did not become fully glycosylated and had a half-life of 6.5 hours compared with 42 hours for wildtype NPC1. Treatment with chemical chaperones, growth at a cooler temperature, and proteasome inhibition increased mutant protein levels, suggesting it is targeted for ER-associated degradation (ERAD) due to protein misfolding. Overexpression of I1061T mutant NPC1 in NPC1-deficient cells resulted in endosomal localization of the mutant protein and complementation of the NPC mutant phenotype, likely due to a small proportion of the mutant protein that was able to fold correctly and escape ERAD.
In 2 sibs with variant Niemann-Pick disease type C1 (NPC1; 257220), Sun et al. (2001) found compound heterozygosity for 2 missense mutations in the NPC1 gene: arg958 to gln and pro1007 to ala (P1007A; 607623.0012).
For discussion of the pro1007-to-ala (P1007A) mutation in the NPC1 gene that was found in compound heterozygous state in patients with variant Niemann-Pick disease type C1 (NPC1; 257220) by Sun et al. (2001), see 607623.0011.
In 3 families with variant Niemann-Pick disease type C1, Millat et al. (2001) found compound heterozygosity for the 2 most common alleles of the NPC1 gene, I1061T (607623.0010) and P1007A. Compound heterozygosity of these 2 alleles resulted in the juvenile onset of symptoms and a significantly slower progression of the disease than in homozygous I1061T patients. P1007A combined with the nonsense mutation in 1 patient studied by Millat et al. (2001) resulted in the late-infantile neurologic form.
In a patient with atypically mild manifestations of Niemann-Pick disease (NPC1; 257220), Millat et al. (2001) found homozygosity for a gly992-to-arg (G992R) missense mutation in the cysteine-rich luminal loop between transmembrane loops 8 and 9 of the NPC1 protein. The patient was an adult with splenomegaly and no neurologic symptoms. Compound heterozygosity of the V378A missense mutation (607623.0014) with the most frequent mutation, I1061T (607623.0010), was found by Millat et al. (2001) in another adult with similar mild manifestations, mainly splenomegaly and no neurologic symptoms.
Josephs et al. (2004) reported a 75-year-old woman who was heterozygous for the G992R mutation, resulting from a 2974G-C transversion in exon 20. She presented with a 10-year history of tremor, initially a side-to-side head tremor, which later progressed to her upper extremities. The tremor was worse at rest and worsened with mental activity, and she was initially diagnosed with Parkinson disease (168600). The patient had 3 brothers who were affected by a severe childhood-onset neurologic disorder characterized by spastic dysarthria, tremor, paresis of vertical eye movements, disturbance of gait, and splenomegaly (Willvonseder et al., 1973). Josephs et al. (2004) concluded that their patient was a manifesting carrier of Niemann-Pick disease type C and that her brothers likely carried 2 mutations in the NPC1 gene.
For discussion of the val378-to-ala (V378A) mutation in the NPC1 gene that was found in compound heterozygous state in a patient with Niemann-Pick disease type C1 (NPC1; 257220) by Millat et al. (2001), see 607623.0013.
Millat et al. (2001) found that homozygosity for a val950-to-met (V950M) mutation in the NPC1 gene correlated with adult onset of neurologic symptoms of Niemann-Pick disease type C1 (NPC1; 257220).
Among 12 unrelated Portuguese patients with type C Niemann-Pick disease (NPC1; 257220), Ribeiro et al. (2001) identified 2 with a 3104C-T change in exon 21 of the NPC1 gene, resulting in an ala1035-to-val substitution. The mutation occurred in homozygous state in 1 patient and in combination with a splicing mutation, IVS23+1G-A (607623.0017), in the other.
For discussion of the splice site mutation in the NPC1 gene (IVS23+1G-A) that was found in compound heterozygous state in patients with type C Niemann-Pick disease (NPC1; 257220) by Ribeiro et al. (2001), see 607623.0016.
Among 12 unrelated Portuguese patients with type C Niemann-Pick disease (NPC1; 257220), Ribeiro et al. (2001) identified 2 with a 530G-A change in exon 5 of the NPC1 gene, resulting in a cys177-to-tyr substitution. The mutation occurred in homozygous state in 1 patient and in combination with a splicing mutation, IVS16-82G-A (607623.0019), in the other.
For discussion of the splice site mutation in the NPC1 gene (IVS16-82G-A) that was found in compound heterozygous state in patients with type C Niemann-Pick disease (NPC1; 257220) by Ribeiro et al. (2001), see 607623.0018.
Among 12 unrelated Portuguese patients with type C Niemann-Pick disease (NPC1; 257220), Ribeiro et al. (2001) identified 1 with a 2932C-T change in exon 20 of the NPC1 gene, resulting in an arg978-to-cys substitution. The mutation occurred in compound heterozygous state with a 1-bp deletion (T) at nucleotide 3662 in exon 24 (607623.0021).
For discussion of the 1-bp deletion in the NPC1 gene (3662delT) that was found in compound heterozygous state in a patient with type C Niemann-Pick disease (NPC1; 257220) by Ribeiro et al. (2001), see 607623.0020.
In a Finnish patient with Niemann-Pick disease type C1 (NPC1; 257220), Blom et al. (2003) identified compound heterozygous mutations in the NPC1 gene: a T-to-C transition at nucleotide 337 resulting in a cys113-to-arg (C113R) substitution, and a 4-bp deletion (607623.0023). The level of NPC1 protein in the patient's fibroblasts was similar to that in control cells, but the protein was partially mislocalized from late endocytic organelles diffusely to the cell periphery. Overexpression of individual NPC1 mutations revealed that the C113R mutant protein localized to the endoplasmic reticulum, Rab7 (602298)-negative endosomes, and the cell surface.
In a Finnish patient with Niemann-Pick disease type C1 (NPC1; 257220), Blom et al. (2003) identified a 4-bp deletion in the NPC1 gene, TTAC (nucleotides 3611-3614), that truncated the NPC1 sequence in the predicted twelfth membrane span and as a result of frameshift led to the incorporation of 36 novel amino acids. Overexpression of individual NPC1 mutations revealed that del3611-3614 produced an unstable protein.
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