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FLASH GENE
Symbol NPC1 contributors: mct/pgu - updated : 09-02-2017
HGNC name Niemann-Pick disease, type C1
HGNC id 7897
Corresponding disease
NPC1 Niemann-Pick disease type C1
NPD Niemann-Pick disease type D
Location 18q11.2      Physical location : 21.111.463 - 21.166.581
Synonym name Niemann-Pick C1 protein
Synonym symbol(s) NPC, NPCA1, FLJ98532
DNA
TYPE functioning gene
STRUCTURE 55.12 kb     25 Exon(s)
10 Kb 5' upstream gene genomic sequence study
MAPPING cloned Y linked N status confirmed
Map n
RNA
TRANSCRIPTS type messenger
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
25 - 4827 - 1278 - 2009 19563754
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveliver   lowly
 stomach   highly
Endocrineadrenal gland   highly
Lymphoid/Immunespleen   lowly
Nervousbrain   moderately
 nervecranial nerve  highly
Reproductivefemale systembreastmammary gland highly
Respiratorylung   lowly
 respiratory tracttrachea  highly
Visualeye   moderately
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Connectiveadiposewhite highly Homo sapiensAdult
Connectivebone  highly
Nervouscentral   
Nervousperipherous   
cells
SystemCellPubmedSpeciesStageRna symbol
Digestivehepatocyte
Nervousglia
Nervousneuron
not specificadipocyte Homo sapiensAdult
cell lineage
cell lines
fluid/secretion
at STAGE
physiological period pregnancy
Text placenta
PROTEIN
PHYSICAL PROPERTIES Hydrophilic
STRUCTURE
motifs/domains
  • a N terminal signal peptide typical for ER targeting and NPC1 domain containing eight cysteine residues critical for the mobilization of cholesterol from lysosomes
  • four conserved potential N-glycosylation sites and a leucine zipper motif
  • 13 predicted membrane-spanning helices
  • a sequence including sterol sensing domains (SSD), TM3 to TM7 and a dileucine motif LLNF in the C terminal region
  • three large luminal domains; first luminal domain NTD (240 AAs), designated NPC1(NTD)
  • other two large luminal domains are loops that span between transmembrane helices 2/3 and 8/9
  • a cytoplasmic tail
  • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to Drosophila patched (TM region)
    homolog to murine Npc1 (86.37 pc)
    intraspecies homolog to mediators of cholesterol homeostasis
    Homologene
    FAMILY
  • lipid transport facilitators family
  • patched family
  • CATEGORY regulatory , transport
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • late endosomes associating with lysosomes and Golgi
  • localized primarily to late endosomes and lysosomes, where it is involved in lipid sorting and vesicular trafficking, and is thought to act as an efflux pump for cholesterol from these compartments
  • within late endosomes and lysosomes, NPC1 and NPC2 proteins are required for the subsequent delivery of cholesterol to other intracellular compartments
  • basic FUNCTION
  • regulator of intracellular cholesterol trafficking,from late endosome/lysosome to caveolin 1 and 2 compartment such as the trans Golgi network and plasma membrane caveolae
  • putative transmembrane efflux pump
  • may be facilitate endocytic transport, lysosomal cholesterol efflux and fatty acid efflux
  • having functions in regulating lysosomal amine content
  • may facilitate the transport of cholesterol directly between two compartments, late endosomes/lysosomes and distinct regions of the endoplasmic reticulum
  • regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis
  • regulates the transport of cholesterol from late endosomes/lysosomes to other compartments responsible for maintaining intracellular cholesterol homeostasis
  • with NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo
  • functions independently of NPC2 in late endosome/lysosome retrograde fusion that leads to the creation of hybrid organelles
  • soluble NPC2 and membrane-bound NPC1 are cholesterol-binding lysosomal proteins required for export of lipoprotein-derived cholesterol from lysosomes
  • action for NPC1 and NPC2 in mediating cholesterol efflux
  • both NPC1 and NPC2 proteins participate in endosomal/lysosomal processing of both sphingolipids and cholesterol
  • function of NPC1, NPC2 within lysosomes are linked closely
  • importance of the interaction between NPC1 and NPC2 proteins to accomplish cholesterol delivery from lysosomes into the cytoplasm
  • required for cholesterol efflux from late endosomes and lysosomes
  • possible role of NPC1 in platelet function and formation
  • may play a role in adipocyte processes underlying obesity
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cellular trafficking transport
    PATHWAY
    metabolism
    signaling hormonal
    steroid
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with NPC2 (after lysosomal hydrolysis of LDL-cholesteryl esters, cholesterol binds NPC2, which transfers it to NPC1(NTD), reversing its orientation and allowing insertion of its isooctyl side chain into the outer lysosomal membranes)
  • NPC2 binding is necessary for NPC1 function
  • NPC1 second lumenal domain binds NPC2 in a cholesterol-dependent manner, a process that may facilitate directional transfer of cholesterol from NPC2 onto NPC N-terminal domain
  • CTSD and NPC1 interaction with a new lysosomal function of NPC1 as a regulator of CTSD processing and activity
  • NPC1 protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits MTOR signaling through its sterol transport function
  • role for NPC1 in tethering ER-endocytic organelle Membrane contact sites (MCS) where it interacts with the ER-localised sterol transport protein GRAMD1B to regulate cholesterol egress
  • cell & other
    REGULATION
    ASSOCIATED DISORDERS
    corresponding disease(s) NPC1 , NPD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    neuronal NPC1 deficiency is sufficient to mediate neurodegeneration
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    metabolismlysosome 
    small molecules that remodel the protein-folding environment in the ER may be therapeutically beneficial for some Niemann–Pick C patients
    metabolismlysosome 
    utility of proteostasis regulators to remodel the protein-folding environment in the ER to recover function in the setting of disease-causing missense alleles
    ANIMAL & CELL MODELS
  • global deletion of Npc1 in adult mice leads to progressive weight loss, impaired motor function and early death in a time course similar to that resulting from germline deletion