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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000271 25 - 4827 NP_000262 - 1278 - 2009 19563754

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       lowly   stomach       highly Endocrine adrenal gland       highly Lymphoid/Immune spleen       lowly Nervous brain       moderately   nerve cranial nerve     highly Reproductive female system breast mammary gland   highly Respiratory lung       lowly   respiratory tract trachea     highly Visual eye       moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective adipose white   highly Homo sapiens Adult Connective bone     highly Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Digestive hepatocyte Nervous glia Nervous neuron not specific adipocyte Homo sapiens Adult

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)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional       loss of function neuronal NPC1 deficiency is sufficient to mediate neurodegeneration

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed metabolism lysosome   small molecules that remodel the protein-folding environment in the ER may be therapeutically beneficial for some Niemann–Pick C patients metabolism lysosome   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