LRP8

Summary

LRP8 (LDL receptor related protein 8, HGNC:6700) is a protein-coding gene on chromosome 1p32.3, encoding Low-density lipoprotein receptor-related protein 8 (Q14114). Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands.

This gene encodes a member of the low density lipoprotein receptor (LDLR) family. Low density lipoprotein receptors are cell surface proteins that play roles in both signal transduction and receptor-mediated endocytosis of specific ligands for lysosomal degradation. The encoded protein plays a critical role in the migration of neurons during development by mediating Reelin signaling, and also functions as a receptor for the cholesterol transport protein apolipoprotein E. Expression of this gene may be a marker for major depressive disorder. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 7804 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Tourette syndrome (No Known Disease Relationship, GenCC)
• GWAS associations: 15
• Clinical variants (ClinVar): 149 total
• MANE Select transcript: NM_004631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6700
Approved symbol	LRP8
Name	LDL receptor related protein 8
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	APOER2, MCI1, LRP-8, HSZ75190
Ensembl gene	ENSG00000157193
Ensembl biotype	protein_coding
OMIM	602600
Entrez	7804

Gene structure

Transcript identifiers

Ensembl transcripts: 78 — 60 protein_coding, 8 nonsense_mediated_decay, 6 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000306052, ENST00000347547, ENST00000354412, ENST00000371454, ENST00000450469, ENST00000459674, ENST00000460214, ENST00000465675, ENST00000475501, ENST00000480045, ENST00000481431, ENST00000496580, ENST00000529670, ENST00000653169, ENST00000653217, ENST00000653810, ENST00000654634, ENST00000654834, ENST00000654947, ENST00000655704, ENST00000656486, ENST00000657047, ENST00000657895, ENST00000658277, ENST00000658404, ENST00000659993, ENST00000661359, ENST00000661457, ENST00000662198, ENST00000662604, ENST00000662802, ENST00000667377, ENST00000668071, ENST00000668448, ENST00000668991, ENST00000669432, ENST00000914968, ENST00000914969, ENST00000914970, ENST00000914971, ENST00000914972, ENST00000914973, ENST00000914974, ENST00000914975, ENST00000914976, ENST00000914977, ENST00000914978, ENST00000914979, ENST00000914980, ENST00000914981, ENST00000914982, ENST00000914983, ENST00000914984, ENST00000914985, ENST00000914986, ENST00000914987, ENST00000914988, ENST00000914989, ENST00000914990, ENST00000914991, ENST00000914992, ENST00000914993, ENST00000914994, ENST00000914995, ENST00000914996, ENST00000914997, ENST00000914998, ENST00000914999, ENST00000915000, ENST00000915001, ENST00000915002, ENST00000945255, ENST00000945256, ENST00000945257, ENST00000945258, ENST00000945259, ENST00000945260, ENST00000945261

RefSeq mRNA: 4 — MANE Select: NM_004631 NM_001018054, NM_004631, NM_017522, NM_033300

CCDS: CCDS30720, CCDS578, CCDS579, CCDS580

Canonical transcript exons

ENST00000306052 — 19 exons

Exon	Start	End
ENSE00001031081	53276692	53277078
ENSE00001455259	53242364	53247056
ENSE00003461529	53271028	53271153
ENSE00003489712	53280587	53280715
ENSE00003489729	53262068	53262207
ENSE00003500091	53271227	53271346
ENSE00003510050	53262446	53262564
ENSE00003513209	53249380	53249556
ENSE00003523443	53257240	53257464
ENSE00003524622	53250690	53250862
ENSE00003568292	53260464	53260605
ENSE00003585859	53326873	53326992
ENSE00003594882	53255117	53255185
ENSE00003609939	53266473	53266647
ENSE00003632064	53275631	53275753
ENSE00003642659	53258319	53258471
ENSE00003664024	53289567	53289689
ENSE00003784065	53264169	53264396
ENSE00003879526	53327789	53328070

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 98.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3527 / max 173.7470, expressed in 1551 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12404	6.9655	1540
12403	0.3872	203

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	98.15	gold quality
pigmented layer of retina	UBERON:0001782	97.48	gold quality
cortical plate	UBERON:0005343	93.05	gold quality
ventricular zone	UBERON:0003053	92.10	gold quality
right testis	UBERON:0004534	91.35	gold quality
left testis	UBERON:0004533	91.16	gold quality
right lobe of thyroid gland	UBERON:0001119	91.04	gold quality
pons	UBERON:0000988	90.98	gold quality
left lobe of thyroid gland	UBERON:0001120	90.75	gold quality
thyroid gland	UBERON:0002046	90.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.93	gold quality
embryo	UBERON:0000922	89.89	gold quality
testis	UBERON:0000473	89.80	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.01	gold quality
superior vestibular nucleus	UBERON:0007227	88.48	gold quality
parietal lobe	UBERON:0001872	88.47	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.30	gold quality
endothelial cell	CL:0000115	87.88	gold quality
occipital lobe	UBERON:0002021	87.87	gold quality
postcentral gyrus	UBERON:0002581	87.82	gold quality
ventral tegmental area	UBERON:0002691	87.42	gold quality
buccal mucosa cell	CL:0002336	87.26	silver quality
superior frontal gyrus	UBERON:0002661	87.11	gold quality
orbitofrontal cortex	UBERON:0004167	86.95	gold quality
Brodmann (1909) area 23	UBERON:0013554	86.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	86.76	gold quality
cerebellar hemisphere	UBERON:0002245	86.73	gold quality
cerebellar cortex	UBERON:0002129	86.65	gold quality
cerebellum	UBERON:0002037	86.50	gold quality
primary visual cortex	UBERON:0002436	86.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7381	no	278.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIC1

miRNA regulators (miRDB)

231 targeting LRP8, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029

Literature-anchored findings (GeneRIF, showing 40)

• transmembrane domain and PXXP motif excludes it from carrying out clathrin-mediated endocytosis (PMID:12621059)
• Sequential proteolytic processing of murine ApoER2 results in the release of its intracellular domain by the protease gamma-secretase. The prior cleavage of its extracellular domain is determined by the glycosylation state of the receptor. (PMID:12871934)
• Data show that the apolipoprotein E receptor 2 binding domain of apolipoprotein E is in the 1-165 amino terminal region, whereas the carboxy terminal 230-299 region of apoE is required for efficient initial association with phospholipids. (PMID:12950167)
• The effects of apoE on receptor proteolysis were mediated by the ligand binding domain of the receptor. We suggest that signaling promoted by these receptors depends in part on these regulated proteolytic events. (PMID:15950758)
• Complete molecular structure examined by nuclear magnetic resonance. (PMID:16034672)
• ApoEr2 can form a multiprotein complex with NMDA receptor subunits and PSD95 (PMID:16332682)
• Reelin signals by binding to two transmembrane receptors, apolipoprotein E receptor 2 (Apoer2) and very-low-density lipoprotein receptor. (PMID:16481437)
• In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth. (PMID:16642433)
• The effect of Dab1 on APP and apoEr2 processing in transfected cells and primary neurons is reported. (PMID:16951405)
• The presence of three splice variants of ApoER2 on platelets was confirmed by immuno-blotting, with ApoER2Delta4-5 being the most abundantly expressed splice variant. (PMID:17470198)
• However, this polymorphism increased the risk of AD conferred by the MAPK8IP1 G allele. (PMID:17614163)
• A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. (PMID:17847002)
• the activity of PCSK9 and its binding affinity on VLDLR and ApoER2 does not depend on the presence of LDLR. (PMID:18039658)
• Fyn, due in part to its effects on Dab1, regulates the phosphorylation, trafficking, and processing of APP and apoEr2. (PMID:18089558)
• protein C and APC may directly promote cell signaling in other cells by binding to ApoER2 and/or GPIbalpha (PMID:18489431)
• Study showed no evidence for association of genetic variants in the LRP8 gene with familial and sporadic myocardial infarction. (PMID:18592168)
• ligation of ApoER2 by APC signals via Dab1 phosphorylation and subsequent activation of PI3K and Akt and inactivation of GSK3beta, thereby contributing to APC’s beneficial effects on cells. (PMID:19116273)
• Our data suggest that LRP8 R952Q variant may have an additive effect to APOE epsilon2/epsilon3/epsilon4 genotype in determining ApoE concentrations and risk of MI in an Italian population (PMID:19439088)
• apolipoprotein E receptor 2 (ApoER2, LRP8), a member of the LDL receptor family, is a platelet receptor for FXI. (PMID:19661487)
• ApoEr2 regulates cell movement, and both X11alpha and Reelin enhance this effect. (PMID:19720620)
• Differential functions of ApoER2 and very low density lipoprotein receptor in Reelin signaling depend on differential sorting of the receptors. (PMID:19948739)
• There were seven polymorphisms in apoE receptor 2 in Japanese sporadic Alzheimer disease patients, but no association of these polymorphisms with Alzheimers. (PMID:20208369)
• the expression of ApoER2 may serve as a trait marker for major depressive disorder. (PMID:20493228)
• Deficient sLRP-amyloid-beta binding might precede and correlate later in disease with an increase in the tau/Abeta42 CSF ratio and global cognitive decline in mild cognitive impairment individuals converting into Alzheimer’s disease. (PMID:21157031)
• LRP8 gene polymorphisms influence plasma cholesterol levels as well as size and composition of LDL particles (PMID:21316997)
• ApoEr2 plays important roles in structure and function of CNS synapses and dendritic spines (PMID:21347244)
• In later stages of cerebral cortical development, ApoER2 is expressed earlier than VLDLR in migrating neurons. (PMID:21601501)
• activation of VLDLR and apoER2 by reelin and apoE induces ABCA1 expression and cholesterol efflux via a Dab1-PI3K-PKCzeta-Sp1 signaling cascade. (PMID:22170052)
• genetic variant R952Q of LRP8 is associated with increased plasma TG levels in patients who are overweight and have premature CAD/MI and history of smoking. (PMID:22404453)
• Variation in genes encoding proteins at the gateway of Reelin signaling: ligands RELN and APOE, their common receptors APOER2 and VLDLR, and adaptor DAB1, was examined. (PMID:22419519)
• results identify LRP8 as a novel positive factor of canonical Wnt signaling pathway (PMID:22589174)
• In a Chinese unrelated Han population, variants within the LRP8 gene do not convey the risk of developing Parkinson’s disease. (PMID:22889673)
• TCCGC haplotype at the 3’-terminal block of the LRP8 gene confers a protective role in the development of familial and early-onset coronary artery disease and/or myocardial infarction. (PMID:23524007)
• By incorporating the information from bioinformatics and RNA expression analyses, we identified at least two of the most promising risk genes for alcohol dependence: APOER2 and UBAP2 (PMID:23739027)
• ectopic expression of HIC1 in U2OS and MDA-MB-231 cell lines decreases expression of the ApoER2 and VLDLR genes, encoding two canonical tyrosine kinase receptors for Reelin. (PMID:24076391)
• Data suggest that PS1/gamma-secretase-dependent processing of the reelin receptor ApoER2 inhibits reelin expression and may regulate its signaling. (PMID:24344333)
• results of this study demonstrated the presence of reelin, its receptors VLDLR and ApoER2 as well as Dab1 in the ENS and might indicate a novel role of the reelin system in regulating neuronal plasticity and pre-synaptic functions in the ENS. (PMID:24844606)
• A novel TACGC risk haplotype in the LRP8 gene that is present in patients with CAD and MI but not in normal controls. (PMID:24867879)
• LRP8 is a risk gene for psychosis. (PMID:26637325)
• ApoER2 contributes cooperatively with endothelial cell protein C receptor and protease activated receptor 1 to APC-initiated endothelial antiapoptotic and barrier protective signaling. (PMID:26800564)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrp8	ENSDARG00000070074
mus_musculus	Lrp8	ENSMUSG00000028613
rattus_norvegicus	Lrp8	ENSRNOG00000013064
drosophila_melanogaster	arr	FBGN0000119

Paralogs (14): LRP6 (ENSG00000070018), LRP2 (ENSG00000081479), NID2 (ENSG00000087303), NID1 (ENSG00000116962), LRP1 (ENSG00000123384), LDLR (ENSG00000130164), LRP3 (ENSG00000130881), LRP4 (ENSG00000134569), EGF (ENSG00000138798), LRP12 (ENSG00000147650), VLDLR (ENSG00000147852), LRP5 (ENSG00000162337), LRP1B (ENSG00000168702), LRP10 (ENSG00000197324)

Protein

Protein identifiers

Low-density lipoprotein receptor-related protein 8 — Q14114 (reviewed: Q14114)

Alternative names: Apolipoprotein E receptor 2

All UniProt accessions (23): Q14114, A0A590UJ30, A0A590UJ39, A0A590UJ57, A0A590UJ98, A0A590UJF9, A0A590UJH5, A0A590UJJ8, A0A590UJJ9, A0A590UJQ4, A0A590UJT0, A0A590UJV3, A0A590UK45, A0A590UK53, A0A590UK84, A0A590UK97, A0A590UKB1, A0A590UKB5, E9PKG2, E9PP15, H0YCA4, H0YEA5, H0YEV6

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor for Reelin (RELN) and apolipoprotein E (apoE)-containing ligands. LRP8 participates in transmitting the extracellular Reelin signal to intracellular signaling processes, by binding to DAB1 on its cytoplasmic tail. Reelin acts via both the VLDL receptor (VLDLR) and LRP8 to regulate DAB1 tyrosine phosphorylation and microtubule function in neurons. LRP8 has higher affinity for Reelin than VLDLR. LRP8 is thus a key component of the Reelin pathway which governs neuronal layering of the forebrain during embryonic brain development. Binds the endoplasmic reticulum resident receptor-associated protein (RAP). Binds dimers of beta 2-glycoprotein I and may be involved in the suppression of platelet aggregation in the vasculature. Highly expressed in the initial segment of the epididymis, where it affects the functional expression of clusterin and phospholipid hydroperoxide glutathione peroxidase (PHGPx), two proteins required for sperm maturation. May also function as an endocytic receptor. Not required for endocytic uptake of SEPP1 in the kidney which is mediated by LRP2. Together with its ligand, apolipoprotein E (apoE), may indirectly play a role in the suppression of the innate immune response by controlling the survival of myeloid-derived suppressor cells. (Microbial infection) Acts as a receptor for Semliki Forest virus. (Microbial infection) Acts as a receptor for tick-borne encephalitis virus by mediating viral cell attachment and internalization.

Subunit / interactions. Homooligomer. Interacts with VLDLR. Reelin associates with two or more receptor molecules. Interacts with DAB1 and JNK-interacting proteins. Interacts with SNX17. Interacts with PCSK9. Interacts with MDK; this interaction is calcium dependent. Interacts with CLU. (Microbial infection) Interacts with Semliki Forest virus E2-E1 heterodimer; this interaction mediates viral entry to host cell. (Microbial infection) Interacts (via class A repeats) with Eastern equine encephalitis virus spike glycoprotein E2; this interaction mediates viral entry into host cell. (Microbial infection) Interacts with tick-borne encephalitis virus envelope protein E; this interaction mediates viral entry to host cell.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Expressed mainly in brain and placenta. Also expressed in platelets and megakaryocytic cells. Not expressed in the liver.

Post-translational modifications. O-glycosylated. Some alternatively spliced isoforms lack the O-linked sugar domain. Undergoes sequential, furin and gamma-secretase dependent, proteolytic processing, resulting in the extracellular release of the entire ligand-binding domain as a soluble polypeptide and in the intracellular domain (ICD) release into the cytoplasm. The gamma-secretase-dependent proteolytical processing occurs after the bulk of the extracellular domain has been shed, in a furin-dependent manner, in alternatively spliced isoforms carrying the furin cleavage site. Hypoglycosylation (mainly hypo-O-glycosylation) leads to increased extracellular cleavage, which in turn results in accelerating release of the intracellular domain (ICD) by the gamma-secretase. The resulting receptor fragment is able to inhibit Reelin signaling and in particular the Reelin-induced DAB1 phosphorylation. Tyrosine phosphorylated upon apoE binding. Ubiquitinated by MYLIP leading to degradation.

Disease relevance. Myocardial infarction 1 (MCI1) [MIM:608446] A condition defined by the irreversible necrosis of heart muscle secondary to prolonged ischemia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The cytoplasmic domain is involved in the binding of DAB1 and in the recruitment of JNK-interacting proteins. Isoforms, which lack part of the cytoplasmic domain, are unable to recruit members of the family of JNK interacting proteins (JIP) to the cytoplasmic tail.

Miscellaneous. Natural isoforms of apoE (E2, E3, E4) have similar affinities for LRP8. Contains an insert in the extracellular part which carries a furin cleavage site.

Similarity. Belongs to the LDLR family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q14114-1	1, ApoER2 922	yes
Q14114-2	2, ApoER2 906
Q14114-3	3
Q14114-4	4, ApoER2delta4-7
Q14114-5	5

RefSeq proteins (4): NP_001018064, NP_004622, NP_059992, NP_150643 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000033	LDLR_classB_rpt	Repeat
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR011042	6-blade_b-propeller_TolB-like	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR049883	NOTCH1_EGF-like	Domain
IPR051221	LDLR-related	Family

Pfam: PF00057, PF00058, PF07645, PF14670

UniProt features (151 total): strand 45, disulfide bond 27, turn 13, helix 11, domain 9, sequence variant 9, binding site 6, glycosylation site 6, repeat 5, splice variant 5, sequence conflict 5, compositionally biased region 3, region of interest 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7UCX	X-RAY DIFFRACTION	1.72
5B4Y	X-RAY DIFFRACTION	1.9
3A7Q	X-RAY DIFFRACTION	2.6
5B4X	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14114-F1	73.28	0.33

Antibody-complex structures (SAbDab): 1 — 7UCX

Functional residue map

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

Ligand- & substrate-binding residues (6): 64; 67; 69; 71; 77; 78

Disulfide bonds (27): 47–59, 54–72, 66–81, 86–98, 93–111, 105–122, 127–141, 134–154, 148–163, 167–179, 174–192, 186–201, 206–221, 213–234, 228–245, 259–272, 267–285, 279–294, 299–311, 306–324 …

Glycosylation sites (6): 176, 441, 518, 538, 772, 807

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-432142	Platelet sensitization by LDL
R-HSA-975634	Retinoid metabolism and transport
R-HSA-109582	Hemostasis
R-HSA-1430728	Metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-418346	Platelet homeostasis
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-9709957	Sensory Perception

MSigDB gene sets: 474 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, HARRIS_HYPOXIA, GOBP_RESPONSE_TO_PEPTIDE, LFA1_Q6, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOCC_CELL_SURFACE, GOBP_LAYER_FORMATION_IN_CEREBRAL_CORTEX

GO Biological Process (24): retinoid metabolic process (GO:0001523), proteolysis (GO:0006508), lipid metabolic process (GO:0006629), endocytosis (GO:0006897), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), response to xenobiotic stimulus (GO:0009410), cytokine-mediated signaling pathway (GO:0019221), ventral spinal cord development (GO:0021517), ammon gyrus development (GO:0021541), layer formation in cerebral cortex (GO:0021819), reelin-mediated signaling pathway (GO:0038026), regulation of apoptotic process (GO:0042981), regulation of innate immune response (GO:0045088), dendrite morphogenesis (GO:0048813), modulation of chemical synaptic transmission (GO:0050804), positive regulation of dendritic spine morphogenesis (GO:0061003), cellular response to growth factor stimulus (GO:0071363), cellular response to cholesterol (GO:0071397), positive regulation of dendrite development (GO:1900006), hippocampus development (GO:0021766), cerebral cortex development (GO:0021987), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of neuron migration (GO:2001222)

GO Molecular Function (13): amyloid-beta binding (GO:0001540), transmembrane signaling receptor activity (GO:0004888), low-density lipoprotein particle receptor activity (GO:0005041), calcium ion binding (GO:0005509), high-density lipoprotein particle binding (GO:0008035), kinesin binding (GO:0019894), very-low-density lipoprotein particle receptor activity (GO:0030229), apolipoprotein binding (GO:0034185), cargo receptor activity (GO:0038024), reelin receptor activity (GO:0038025), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (15): obsolete extracellular space (GO:0005615), microtubule associated complex (GO:0005875), plasma membrane (GO:0005886), caveola (GO:0005901), cell surface (GO:0009986), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), signaling receptor complex (GO:0043235), Schaffer collateral - CA1 synapse (GO:0098685), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), extracellular region (GO:0005576), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Platelet homeostasis	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Metabolism	1
Sensory Perception	1
Hemostasis	1
Metabolism of vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
vesicle-mediated transport	2
cell surface receptor signaling pathway	2
anatomical structure development	2
dendrite development	2
positive regulation of neuron projection development	2
lipoprotein particle receptor activity	2
protein binding	2
protein-containing complex	2
neuron projection	2
synapse	2
diterpenoid metabolic process	1
protein metabolic process	1
primary metabolic process	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
response to chemical	1
cellular response to cytokine stimulus	1
spinal cord development	1
hippocampus development	1
cerebral cortex radial glia-guided migration	1
anatomical structure formation involved in morphogenesis	1
apoptotic process	1
regulation of programmed cell death	1
regulation of response to biotic stimulus	1
regulation of defense response	1
regulation of response to external stimulus	1
innate immune response	1
regulation of immune response	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1

Protein interactions and networks

STRING

1510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRP8	APOE	P02649	997
LRP8	RELN	P78509	954
LRP8	VLDLR	P98155	940
LRP8	SPON1	Q9HCB6	910
LRP8	APOH	P02749	908
LRP8	CLU	P10909	893
LRP8	APBB1	O00213	862
LRP8	SELENOP	P49908	837
LRP8	THBS1	P07996	836
LRP8	APP	P05067	831
LRP8	SNX17	Q15036	808
LRP8	YWHAQ	P27348	800
LRP8	DLG4	P78352	730
LRP8	MAPT	P10636	713
LRP8	DAB1	O75553	674

IntAct

29 interactions, top by confidence:

A	B	Type	Score
Reln	LRP8	psi-mi:“MI:0407”(direct interaction)	0.770
Reln	LRP8	psi-mi:“MI:0915”(physical association)	0.770
LRP8	Reln	psi-mi:“MI:0915”(physical association)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
LRP8	APC	psi-mi:“MI:0407”(direct interaction)	0.560
LRPAP1	LRP8	psi-mi:“MI:0915”(physical association)	0.560
LRPAP1	LRP4	psi-mi:“MI:0914”(association)	0.530
KDR	LRP8	psi-mi:“MI:0915”(physical association)	0.470
KDR	LRP8	psi-mi:“MI:2364”(proximity)	0.470
LRP8	KRT8	psi-mi:“MI:0915”(physical association)	0.400
LRP8	APOE	psi-mi:“MI:0915”(physical association)	0.400
Pten	MPZL1	psi-mi:“MI:0914”(association)	0.350
LRP8	TYK2	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
TMEM17	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
TGOLN2	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
LRP8	SS18	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (143): LRP8 (Affinity Capture-RNA), LRP8 (Affinity Capture-RNA), LRP8 (Proximity Label-MS), ALB (Affinity Capture-MS), PRCC (Affinity Capture-MS), RAD51 (Affinity Capture-MS), TYK2 (Affinity Capture-MS), USP11 (Affinity Capture-MS), PPP1R9A (Affinity Capture-MS), DOCK6 (Affinity Capture-MS), CAMSAP3 (Affinity Capture-MS), CRTC3 (Affinity Capture-MS), PRKRIP1 (Affinity Capture-MS), ARHGAP39 (Affinity Capture-MS), GHDC (Affinity Capture-MS)

ESM2 similar proteins: A2VCU8, A6QR11, E1BMV3, O00339, O08746, O15232, O35674, O35701, O42401, O43184, O89029, O95460, P01130, P18337, P19336, P20063, P21743, P21941, P23142, P24591, P47876, P51942, P57110, P58335, P98110, Q08879, Q13219, Q14114, Q14393, Q4VC17, Q501P1, Q53RD9, Q61220, Q61581, Q61824, Q62179, Q62918, Q6AZ60, Q6DFX2, Q6Q484

Diamond homologs: A1Z877, O08523, O75443, O75581, O88572, P01131, P20063, P35950, P35951, P35952, Q14114, Q28832, Q5ZQU0, Q6X0I2, Q70E20, Q8TER0, Q91VN0, Q98931, Q99087, Q9JI18, Q9NZR2, Q9YH85, A2AR95, A2ARV4, A4IHY6, C0HL13, E9Q6D8, G3V928, O75074, O75197, O88204, O88307, P0DSP1, P13671, P35953, P56677, P61134, P61135, P86091, P98153

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
HIC1	“down-regulates quantity by repression”	LRP8	“transcriptional regulation”
MYLIP	“down-regulates quantity by destabilization”	LRP8	ubiquitination
FYN	“up-regulates quantity”	LRP8	phosphorylation
SRSF11	“up-regulates quantity by stabilization”	LRP8	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	105
Likely benign	13
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

3977 predictions. Top by Δscore:

Variant	Effect	Δscore
1:53247053:CTCG:C	acceptor_gain	1.0000
1:53247055:CG:C	acceptor_gain	1.0000
1:53255183:CAT:C	acceptor_gain	1.0000
1:53255186:C:CC	acceptor_gain	1.0000
1:53257239:CAGTG:C	donor_gain	1.0000
1:53257311:A:C	donor_gain	1.0000
1:53257312:C:CC	donor_gain	1.0000
1:53257312:CTGAG:C	donor_gain	1.0000
1:53257316:G:C	donor_gain	1.0000
1:53260458:GCTCA:G	donor_loss	1.0000
1:53260459:CTCAC:C	donor_loss	1.0000
1:53260460:TCA:T	donor_loss	1.0000
1:53260461:CACC:C	donor_loss	1.0000
1:53260462:ACC:A	donor_loss	1.0000
1:53260463:CCT:C	donor_gain	1.0000
1:53262063:CTCA:C	donor_loss	1.0000
1:53262064:TCACC:T	donor_loss	1.0000
1:53262065:CA:C	donor_loss	1.0000
1:53262067:C:G	donor_loss	1.0000
1:53262208:C:CC	acceptor_gain	1.0000
1:53262209:T:C	acceptor_gain	1.0000
1:53262209:T:TC	acceptor_gain	1.0000
1:53262440:GCTCA:G	donor_loss	1.0000
1:53262441:CTCAC:C	donor_loss	1.0000
1:53262442:TCACC:T	donor_loss	1.0000
1:53262443:CA:C	donor_loss	1.0000
1:53262444:A:AC	donor_gain	1.0000
1:53262444:A:C	donor_loss	1.0000
1:53262444:AC:A	donor_gain	1.0000
1:53262445:C:CC	donor_gain	1.0000

AlphaMissense

6366 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:53271301:C:G	C351S	1.000
1:53271302:A:T	C351S	1.000
1:53258327:C:G	C734S	0.999
1:53258328:A:T	C734S	0.999
1:53258372:C:G	C719S	0.999
1:53258373:A:T	C719S	0.999
1:53258417:C:G	C704S	0.999
1:53258418:A:T	C704S	0.999
1:53258429:C:G	C700S	0.999
1:53258430:A:T	C700S	0.999
1:53260593:A:G	W643R	0.999
1:53260593:A:T	W643R	0.999
1:53262184:A:G	W600R	0.999
1:53262184:A:T	W600R	0.999
1:53262463:G:T	P586H	0.999
1:53264254:C:G	A524P	0.999
1:53264287:A:G	W513R	0.999
1:53264287:A:T	W513R	0.999
1:53264290:A:C	Y512D	0.999
1:53264306:C:A	W506C	0.999
1:53264306:C:G	W506C	0.999
1:53264317:C:G	A503P	0.999
1:53266602:C:G	R433P	0.999
1:53266629:A:G	L424P	0.999
1:53271039:C:G	C414S	0.999
1:53271040:A:T	C414S	0.999
1:53271077:G:C	C401W	0.999
1:53271078:C:G	C401S	0.999
1:53271079:A:G	C401R	0.999
1:53271079:A:T	C401S	0.999

dbSNP variants (sampled 300 via entrez): RS1000018656 (1:53326619 C>T), RS1000027267 (1:53282197 C>T), RS1000058365 (1:53281903 C>A), RS1000063384 (1:53323661 C>T), RS1000086949 (1:53281115 G>T), RS1000161433 (1:53289015 T>C), RS1000188554 (1:53281295 G>A), RS1000300383 (1:53275139 T>C), RS1000348077 (1:53322665 C>T), RS1000355097 (1:53295706 G>A,T), RS1000376918 (1:53315589 C>A,G), RS1000407144 (1:53288192 A>G,T), RS1000425760 (1:53267848 AC>A), RS1000513514 (1:53289292 C>A,T), RS1000557079 (1:53294570 G>T)

Disease associations

OMIM: gene MIM:602600 | disease phenotypes: MIM:608446

GenCC curated gene-disease

Disease	Classification	Inheritance
Tourette syndrome	No Known Disease Relationship	Unknown

Mondo (2): myocardial infarction, susceptibility to (MONDO:0012039), Tourette syndrome (MONDO:0007661)

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001753_2	Body mass index (alcohol intake interaction)	6.000000e-06
GCST004069_8	Cerebrospinal fluid AB1-42 levels	2.000000e-08
GCST006585_2241	Blood protein levels	1.000000e-09
GCST007021_4	Type 2 diabetes nephropathy	1.000000e-06
GCST007325_180	General risk tolerance (MTAG)	1.000000e-08
GCST007326_90	Number of sexual partners	5.000000e-13
GCST009733_44	Urinary metabolite levels in chronic kidney disease	4.000000e-18
GCST010696_8	Cortical thickness (min-P)	3.000000e-08
GCST010697_47	Cortical surface area (min-P)	7.000000e-14
GCST010698_52	Subcortical volume (min-P)	2.000000e-10
GCST010699_95	Brain morphology (min-P)	3.000000e-12
GCST010700_60	Cortical thickness (MOSTest)	1.000000e-09
GCST010701_101	Cortical surface area (MOSTest)	2.000000e-12
GCST010702_171	Subcortical volume (MOSTest)	3.000000e-16
GCST010703_172	Brain morphology (MOSTest)	4.000000e-11

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0008579	risk-taking behaviour
EFO:0005116	urinary metabolite measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D005879	Tourette Syndrome	C10.228.140.079.898; C10.228.662.825.800; C10.574.500.850; C16.320.400.820; F03.625.992.850

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

84 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, affects expression	6
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
methylmercuric chloride	increases expression, affects cotreatment	4
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	4
Aflatoxin B1	affects expression, decreases expression, increases expression	4
bisphenol A	affects cotreatment, decreases expression, decreases methylation, increases expression	3
Arsenic	affects methylation, increases abundance, increases expression, affects cotreatment	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tobacco Smoke Pollution	affects expression, increases expression	3
Cyclosporine	increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression, affects cotreatment	3
trichostatin A	decreases expression, affects expression	2
cobaltous chloride	decreases expression, increases expression	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Copper	affects binding, increases expression, decreases expression	2
Nickel	increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Tretinoin	decreases expression	2
Tunicamycin	decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	increases expression	1
sodium arsenate	increases abundance, increases expression	1
2-butenal	decreases expression	1
methylparaben	decreases expression	1
sulforaphane	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F0VN	HEK293H-hLRP8	Transformed cell line	Female
CVCL_SV93	HAP1 LRP8 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00152750	PHASE4	UNKNOWN	Study of Clonidine on Sleep Architecture in Children With Tourette’s Syndrome (TS) and Comorbid ADHD
NCT00226824	PHASE4	TERMINATED	Safety Study of Galantamine in Tic Disorders
NCT00241176	PHASE4	COMPLETED	Open Label Trial of Aripiprazole in Children and Adolescents With Tourette’s Disorder
NCT00370838	PHASE4	COMPLETED	Comparison of Keppra and Clonidine in the Treatment of Tics
NCT01018056	PHASE4	COMPLETED	Developing New Treatments for Tourette Syndrome: Therapeutic Trials With Modulators of Glutamatergic Neurotransmission
NCT01547000	PHASE4	COMPLETED	Guanfacine in Children With Tic Disorders
NCT03239210	PHASE4	COMPLETED	Effects of Ondansetron in Obsessive-compulsive and Tic Disorders
NCT00004376	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine for Tourette Syndrome and Attention Deficit Hyperactivity Disorder
NCT00206323	PHASE3	COMPLETED	A Randomized, Placebo-controlled, Tourette Syndrome Study.
NCT00206336	PHASE3	COMPLETED	An Open-label Study to Determine the Efficacy and Safety of Topiramate in the Treatment of Tourette Syndrome.
NCT00478842	PHASE3	COMPLETED	Pallidal Stimulation and Gilles de la Tourette Syndrome
NCT00681863	PHASE3	TERMINATED	Open-label Extension Study of Pramipexole in the Treatment of Children and Adolescents With Tourette Syndrome
NCT01501695	PHASE3	COMPLETED	Phase III Study of 5LGr to Treat Tic Disorder
NCT03087201	PHASE3	COMPLETED	CANNAbinoids in the Treatment of TICS (CANNA-TICS)
NCT03487783	PHASE3	COMPLETED	Aripiprazole Oral Solution in the Treatment of Children and Adolescents With Tourette’s Syndrome
NCT03567291	PHASE3	TERMINATED	Evaluation of Safety and Tolerability of Long-term TEV-50717 (Deutetrabenazine) for Treatment of Tourette Syndrome in Children and Adolescents
NCT03571256	PHASE3	COMPLETED	A Study to Test if TEV-50717 is Effective in Relieving Tics Associated With Tourette Syndrome (TS)
NCT06021522	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Evaluate Long-term Safety of Ecopipam Tablets in Children, Adolescents and Adults With Tourette’s Disorder
NCT00004393	PHASE2	COMPLETED	Phase II Double Blind Placebo Controlled Trial of Risperidone in Tourette Syndrome
NCT00004652	PHASE2	COMPLETED	Phase II Pilot Controlled Study of Short Vs Longer Term Pimozide (Orap) Therapy in Tourette Syndrome
NCT00231985	PHASE2	COMPLETED	Effectiveness of Behavior Therapy and Psychosocial Therapy for the Treatment of Tourette Syndrome and Chronic Tic Disorder
NCT00311909	PHASE2	COMPLETED	Thalamic Deep Brain Stimulation for Tourette Syndrome
NCT00529308	PHASE2	COMPLETED	Transcranial Magnetic Stimulation (TMS) for Individuals With Tourette’s Syndrome
NCT00558467	PHASE2	COMPLETED	Pramipexole Pilot Phase II Study in Children and Adolescents With Tourette Disorder According to DSM-IV Criteria
NCT01043549	PHASE2	TERMINATED	Repetitive Transcranial Magnetic Stimulation of the Posterior Parietal Cortex in Patients Suffering From Gilles de la Tourette Syndrome
NCT01133353	PHASE2	WITHDRAWN	A Study of the Effectiveness and Safety of Tetrabenazine MR in Pediatric Subjects With Tourette’s Syndrome
NCT01475383	PHASE2	WITHDRAWN	Study Evaluating The Safety And Efficacy Of PF-03654746 In Adult Subjects With Tourette’s Syndrome
NCT01647269	PHASE2	COMPLETED	A Trial of Bilateral Deep Brain Stimulation to the Globus Pallidus Internum in Tourette Syndrome
NCT01904773	PHASE2	COMPLETED	Safety, Tolerability, Pharmacokinetic, and Efficacy Study of AZD5213 in Adolescents With Tourette’s Disorder
NCT02102698	PHASE2	COMPLETED	Ecopipam Treatment of Tourette’s Syndrome in Subjects 7-17 Years
NCT02217007	PHASE2	WITHDRAWN	A Trial Evaluating the Efficacy, Safety, and Pharmacokinetics of SNC-102 in Subjects With Tourette Syndrome
NCT02247206	PHASE2	COMPLETED	VoIP Delivered Behavior Therapy for Tourette Syndrome
NCT02581865	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Adults With Tourette Syndrome
NCT02619084	PHASE2	COMPLETED	Subthalamic Stimulation in Tourette’s Syndrome
NCT02679079	PHASE2	COMPLETED	Safety and Efficacy Study of NBI-98854 in Children and Adolescents With Tourette Syndrome
NCT02879578	PHASE2	COMPLETED	Safety and Tolerability Study of NBI-98854 for the Treatment of Subjects With Tourette Syndrome
NCT03066193	PHASE2	COMPLETED	Efficacy of a Therapeutic Combination of Dronabinol and PEA for Tourette Syndrome
NCT03247244	PHASE2	TERMINATED	Safety and Efficacy of Cannabis in Tourette Syndrome
NCT03325010	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome
NCT03444038	PHASE2	COMPLETED	Open-Label Safety and Tolerability Study of NBI-98854 for the Treatment of Pediatric Subjects With Tourette Syndrome