LRP3

Summary

LRP3 (LDL receptor related protein 3, HGNC:6695) is a protein-coding gene on chromosome 19q13.11, encoding Low-density lipoprotein receptor-related protein 3 (O75074). Probable receptor, which may be involved in the internalization of lipophilic molecules and/or signal transduction.

Involved in negative regulation of fat cell differentiation; positive regulation of osteoblast differentiation; and regulation of gene expression. Predicted to be located in membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 4037 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 168 total
• MANE Select transcript: NM_002333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6695
Approved symbol	LRP3
Name	LDL receptor related protein 3
Location	19q13.11
Locus type	gene with protein product
Status	Approved
Aliases	LRP-3, hLRp105
Ensembl gene	ENSG00000130881
Ensembl biotype	protein_coding
OMIM	603159
Entrez	4037

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000253193, ENST00000590275, ENST00000590278, ENST00000592484

RefSeq mRNA: 1 — MANE Select: NM_002333 NM_002333

CCDS: CCDS12430

Canonical transcript exons

ENST00000253193 — 7 exons

Exon	Start	End
ENSE00000695940	33205246	33206362
ENSE00001314394	33194330	33194858
ENSE00001619199	33206988	33208864
ENSE00003514354	33206601	33206733
ENSE00003555920	33202848	33202986
ENSE00003658281	33196730	33196777
ENSE00003705963	33204638	33204852

Expression profiles

Bgee: expression breadth ubiquitous, 142 present calls, max score 95.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.5238 / max 483.1125, expressed in 1608 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175081	10.4995	1551
175079	6.9018	1523
175078	0.6092	391
175080	0.5133	319

Top tissues by expression

144 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
putamen	UBERON:0001874	95.96	gold quality
nucleus accumbens	UBERON:0001882	95.84	gold quality
caudate nucleus	UBERON:0001873	95.67	gold quality
left ovary	UBERON:0002119	95.52	gold quality
superior frontal gyrus	UBERON:0002661	95.36	gold quality
temporal lobe	UBERON:0001871	95.21	gold quality
right frontal lobe	UBERON:0002810	95.17	gold quality
amygdala	UBERON:0001876	95.16	gold quality
primary visual cortex	UBERON:0002436	95.09	gold quality
prefrontal cortex	UBERON:0000451	95.06	gold quality
right ovary	UBERON:0002118	95.05	gold quality
frontal cortex	UBERON:0001870	94.97	gold quality
anterior cingulate cortex	UBERON:0009835	94.77	gold quality
ovary	UBERON:0000992	94.76	gold quality
Ammon’s horn	UBERON:0001954	94.49	gold quality
cortical plate	UBERON:0005343	94.45	gold quality
cerebral cortex	UBERON:0000956	94.44	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.83	gold quality
brain	UBERON:0000955	93.52	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.90	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.84	gold quality
cerebellum	UBERON:0002037	91.96	gold quality
cerebellar hemisphere	UBERON:0002245	91.90	gold quality
cerebellar cortex	UBERON:0002129	91.88	gold quality
hypothalamus	UBERON:0001898	91.64	gold quality
embryo	UBERON:0000922	91.21	gold quality
ganglionic eminence	UBERON:0004023	91.21	gold quality
stromal cell of endometrium	CL:0002255	91.17	gold quality
right lobe of liver	UBERON:0001114	91.08	gold quality
substantia nigra	UBERON:0002038	91.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.88

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ADIPOQ	Repression
ALPL	Activation
CDH11	Activation
DKK2	Activation
FABP4	Repression
ITGA10	Activation
LPL	Repression
PPARG	Repression
SPP1	Activation

miRNA regulators (miRDB)

58 targeting LRP3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-5787	99.22	67.86	2628

Literature-anchored findings (GeneRIF, showing 2)

• Low-density lipoprotein receptor-related protein 3 (-deficient cells showed impaired osteoblastic and enhanced adipocytic differentiation. (PMID:28340487)
• The apolipoprotein receptor LRP3 compromises APP levels. (PMID:34727970)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrp3	ENSDARG00000008485
mus_musculus	Lrp3	ENSMUSG00000001802
rattus_norvegicus	Lrp3	ENSRNOG00000011451
drosophila_melanogaster	arr	FBGN0000119

Paralogs (14): LRP6 (ENSG00000070018), LRP2 (ENSG00000081479), NID2 (ENSG00000087303), NID1 (ENSG00000116962), LRP1 (ENSG00000123384), LDLR (ENSG00000130164), LRP4 (ENSG00000134569), EGF (ENSG00000138798), LRP12 (ENSG00000147650), VLDLR (ENSG00000147852), LRP8 (ENSG00000157193), LRP5 (ENSG00000162337), LRP1B (ENSG00000168702), LRP10 (ENSG00000197324)

Protein

Protein identifiers

Low-density lipoprotein receptor-related protein 3 — O75074 (reviewed: O75074)

Alternative names: 105 kDa low-density lipoprotein receptor-related protein

All UniProt accessions (2): O75074, V9GYG8

UniProt curated annotations — full annotation on UniProt →

Function. Probable receptor, which may be involved in the internalization of lipophilic molecules and/or signal transduction. Its precise role is however unclear, since it does not bind to very low density lipoprotein (VLDL) or to LRPAP1 in vitro.

Subunit / interactions. Binds GGA1 and GGA2.

Subcellular location. Membrane. Coated pit.

Tissue specificity. Widely expressed. Highly expressed in skeletal muscle and ovary. Expressed at intermediate level in heart, brain, liver, pancreas, prostate and small intestine. Weakly expressed in testis, colon and leukocyte.

Similarity. Belongs to the LDLR family.

RefSeq proteins (1): NP_002324* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000859	CUB_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR023415	LDLR_class-A_CS	Conserved_site
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR050685	LDLR	Family

Pfam: PF00057, PF00431

UniProt features (37 total): disulfide bond 15, domain 6, compositionally biased region 3, glycosylation site 3, topological domain 2, sequence variant 2, sequence conflict 2, signal peptide 1, chain 1, region of interest 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75074-F1	68.25	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (15): 43–72, 99–120, 166–178, 173–191, 185–200, 212–227, 219–240, 234–249, 254–282, 416–430, 423–443, 437–452, 455–467, 462–480, 474–489

Glycosylation sites (3): 71, 199, 359

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 148 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_255, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, MODULE_317, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_VESICLE_MEDIATED_TRANSPORT, MODULE_16, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_UP, FREAC3_01, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_FAT_CELL_DIFFERENTIATION, GOBP_OSSIFICATION, MODULE_88

GO Biological Process (8): receptor-mediated endocytosis (GO:0006898), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), negative regulation of fat cell differentiation (GO:0045599), positive regulation of osteoblast differentiation (GO:0045669), transport across blood-brain barrier (GO:0150104), endocytosis (GO:0006897), vesicle-mediated transport (GO:0016192)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), clathrin-coated pit (GO:0005905), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gene expression	2
regulation of gene expression	2
membrane	2
endocytosis	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
osteoblast differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
vascular transport	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
transport	1
cellular process	1
binding	1
cell periphery	1
endomembrane system	1
cellular anatomical structure	1

Protein interactions and networks

STRING

532 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRP3	LRPAP1	P30533	733
LRP3	LRP11	Q86VZ4	546
LRP3	LDLRAD2	Q5SZI1	508
LRP3	APOE	P02649	493
LRP3	CNST	Q6PJW8	457
LRP3	DOC2B	Q14184	436
LRP3	LRP2	P98164	409
LRP3	APLP1	P51693	407
LRP3	EGF	P01133	407
LRP3	NOXA1	Q86UR1	395
LRP3	FKRP	Q9H9S5	395
LRP3	GGA2	Q9UJY4	386
LRP3	VWA5B2	Q8N398	383
LRP3	LRP5	O75197	375
LRP3	LRP6	O75581	367

IntAct

8 interactions, top by confidence:

A	B	Type	Score
MTNR1A	LRP3	psi-mi:“MI:0915”(physical association)	0.370
LRP3	GGA2	psi-mi:“MI:0915”(physical association)	0.370
GGA1	LRP3	psi-mi:“MI:0915”(physical association)	0.370
LRP3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SLC15A3	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SLC44A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350
SLC9A3	ESYT3	psi-mi:“MI:0914”(association)	0.350

BioGRID (51): LRP3 (Two-hybrid), DNPEP (Affinity Capture-MS), KCNT2 (Affinity Capture-MS), SYNE2 (Affinity Capture-MS), ZNF100 (Affinity Capture-MS), ZNF324B (Affinity Capture-MS), ITCH (Affinity Capture-MS), FAM189B (Affinity Capture-MS), MANEA (Affinity Capture-MS), SARAF (Affinity Capture-MS), POM121 (Affinity Capture-MS), GRAMD1A (Affinity Capture-MS), LRP12 (Affinity Capture-MS), LMBR1 (Affinity Capture-MS), TRPM3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTW7, A0A1D5NSK0, A0A1L8HYT7, A0A286YEC0, D3ZT86, D3ZWJ9, D4A929, F8W3R9, G7PWZ3, I6M4H4, O08852, O43157, O43278, O75074, O88204, P17813, P49000, P59383, Q04912, Q17R55, Q499Z3, Q4R3B7, Q4TUC0, Q5ND34, Q62190, Q63961, Q6AXX1, Q76MJ5, Q7TN88, Q7TQH7, Q7Z442, Q7Z4F1, Q80W87, Q80YN4, Q866Y3, Q86VZ4, Q8BHW9, Q8BMN4, Q8BYI8, Q8BZT7

Diamond homologs: A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O75581, O88204, O88307, O88572, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153, P98154, P98155, P98156, P98157, P98158, P98160, P98163, P98164, P98165, P98166, P98167, Q04833, Q06561, Q07954, Q0IIH7, Q14114, Q28832, Q29RU4, Q5HZW5, Q5R662

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

168 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	144
Likely benign	6
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

972 predictions. Top by Δscore:

Variant	Effect	Δscore
19:33194857:GG:G	donor_gain	1.0000
19:33194858:GG:G	donor_gain	1.0000
19:33196775:TAGG:T	donor_loss	1.0000
19:33196778:G:GA	donor_loss	1.0000
19:33196778:G:GG	donor_gain	1.0000
19:33196779:T:A	donor_loss	1.0000
19:33196782:G:GG	donor_gain	1.0000
19:33206731:CAGG:C	donor_loss	1.0000
19:33206732:AGG:A	donor_loss	1.0000
19:33206734:G:GA	donor_loss	1.0000
19:33206735:T:A	donor_loss	1.0000
19:33194755:G:GT	donor_gain	0.9900
19:33194858:GGT:G	donor_loss	0.9900
19:33194859:G:C	donor_loss	0.9900
19:33194859:G:GG	donor_gain	0.9900
19:33194860:T:G	donor_loss	0.9900
19:33196728:A:AG	acceptor_gain	0.9900
19:33196729:G:GA	acceptor_gain	0.9900
19:33196776:AG:A	donor_gain	0.9900
19:33196777:GG:G	donor_gain	0.9900
19:33204720:G:GT	donor_gain	0.9900
19:33206355:G:GT	donor_gain	0.9900
19:33206598:TAGGG:T	acceptor_loss	0.9900
19:33206599:A:T	acceptor_loss	0.9900
19:33206734:G:GG	donor_gain	0.9900
19:33206982:CCACA:C	acceptor_loss	0.9900
19:33206985:CAGGC:C	acceptor_loss	0.9900
19:33206987:G:GT	acceptor_loss	0.9900
19:33196728:AGT:A	acceptor_gain	0.9800
19:33196729:GT:G	acceptor_gain	0.9800

AlphaMissense

4968 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:33202901:A:C	S59R	1.000
19:33202903:C:A	S59R	1.000
19:33202903:C:G	S59R	1.000
19:33202912:G:C	W62C	1.000
19:33202912:G:T	W62C	1.000
19:33202946:T:A	W74R	1.000
19:33202946:T:C	W74R	1.000
19:33202948:G:C	W74C	1.000
19:33202948:G:T	W74C	1.000
19:33202953:T:A	I76N	1.000
19:33202953:T:C	I76T	1.000
19:33202983:T:A	I86N	1.000
19:33204831:T:C	F152L	1.000
19:33204832:T:C	F152S	1.000
19:33204832:T:G	F152C	1.000
19:33204833:C:A	F152L	1.000
19:33204833:C:G	F152L	1.000
19:33204838:T:C	L154P	1.000
19:33205564:T:C	F265S	1.000
19:33205564:T:G	F265C	1.000
19:33205620:T:A	W284R	1.000
19:33205620:T:C	W284R	1.000
19:33205622:G:C	W284C	1.000
19:33205622:G:T	W284C	1.000
19:33205687:A:T	D306V	1.000
19:33205809:T:G	Y347D	1.000
19:33205839:G:T	G357C	1.000
19:33205842:T:C	F358L	1.000
19:33205843:T:C	F358S	1.000
19:33205843:T:G	F358C	1.000

dbSNP variants (sampled 300 via entrez): RS1000156542 (19:33194099 G>A), RS1000444849 (19:33194156 G>GGGGCT), RS1000762772 (19:33204045 C>A,G,T), RS1001031893 (19:33195543 T>C), RS1001041791 (19:33195105 G>T), RS1001042719 (19:33201466 C>T), RS1001340585 (19:33198844 C>A), RS1001447432 (19:33208267 A>T), RS1001463107 (19:33195930 A>C), RS1001476796 (19:33208483 C>A), RS1001557903 (19:33194874 G>T), RS1001586810 (19:33204192 A>C), RS1001622358 (19:33207756 G>C,T), RS1001719408 (19:33198846 C>T), RS1001738293 (19:33207672 C>A,T)

Disease associations

OMIM: gene MIM:603159 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007993_1	Asthma (adult onset)	1.000000e-06
GCST007995_9	Asthma (childhood onset)	6.000000e-09
GCST009798_7	Asthma	1.000000e-23

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1002011	adult onset asthma

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Temozolomide	increases expression	1
Zoledronic Acid	decreases expression	1
Fulvestrant	increases methylation	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Malathion	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases expression, increases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.