LRP2 low density lipoprotein receptor-related protein 2 [Homo sapiens] - Gene

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Summary

Official Symbol: LRP2provided by HGNC
Official Full Name: low density lipoprotein receptor-related protein 2provided by HGNC
Primary source: HGNC:6694
See related: Ensembl:ENSG00000081479; HPRD:02509; MIM:600073; Vega:OTTHUMG00000132179
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: DBS; GP330
Summary: The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain. Mutations in this gene cause Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).[provided by RefSeq, Aug 2009]

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Genomic context

Location :: 2q24-q31

Sequence :: Chromosome: 2; NC_000002.11 (169983619..170219122, complement)

See LRP2 in Epigenomics, MapViewer

Chromosome 2 - NC_000002.11 Genomic Context describing neighboring genes

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Genomic regions, transcripts, and products

Genomic Sequence

Go to nucleotideGraphics FASTA GenBank

Go to reference sequence details

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Bibliography

GeneRIFs: Gene References Into Functions What's a GeneRIF?

megalin and cubilin are involved in the metabolism of vitamin D by reabsorbing vitamin D binding protein; dysfunction of these receptors is likely to be associated with the development of vitamin D deficiency in patients with chronic kidney disease
Title: Role of megalin and cubilin in the metabolism of vitamin D(3).
allele (A) of the rs3755166 polymorphism within LRP2 gene may contribute to Alzheimer's disease risk in the Chinese Han Population
Title: A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population.
in anagen VI hair follicles megalin was found in all keratinocytes of the distal region
Title: Analysis of the expression pattern of the carrier protein transthyretin and its receptor megalin in the human scalp skin and hair follicles: hair cycle-associated changes.
Observational study of gene-disease association and gene-gene interaction. (HuGE Navigator)
Title: A single nucleotide polymorphism in LRP2 is associated with susceptibility to Alzheimer's disease in the Chinese population.
Clinical trial of gene-disease association and gene-environment interaction. (HuGE Navigator)
Title: Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.
Data show that MT-I + II and megalin are significantly altered in CNS lymphoma relative to controls.
Title: Metallothionein-I + II and receptor megalin are altered in relation to oxidative stress in cerebral lymphomas.
No defect in the trafficking or function of megalin upon OCRL1 knockdown.
Title: OCRL1 function in renal epithelial membrane traffic.
Interaction of the A2 domain of F8 with LRP2 follows the general mode, requires dissociation of factor VIII from von Willebrand factor, and is activation sensitive.
Title: Interaction of coagulation factor VIII with members of the low-density lipoprotein receptor family follows common mechanism and involves consensus residues within the A2 binding site 484-509.
results show different expression patterns of megalin and cubulin in calculous gallbladders and acalculous gallbladders suggesting an association with gallstone formation and implying a putative role of the two proteins in cholesterol endocytosis
Title: Megalin and cubilin in the human gallbladder epithelium.
Polymorphisms within the megalin gene for associations with prostate cancer risk and outcomes.
Title: Association of megalin genetic polymorphisms with prostate cancer risk and prognosis.

Submit: New GeneRIF Correction See all (27)

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Phenotypes

Review eQTL and phenotype association data in this region using PheGenI

A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa.

Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (ocular hypertelorism, enlarged fontanelle), ocular findings (high myopia, retinal detachment, progressive vision loss, and iris coloboma), sensorineural hearing loss, agenesis of the corpus callosum, intellectual disability, and congenital diaphragmatic hernia (CDH) and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.

Diagnosis Testing

The diagnosis of DBS is based on the combination of characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria. LRP2, encoding the protein low-density lipoprotein receptor-related protein 2 precursor (megalin), is the only gene known to be associated with DBS. Molecular genetic testing is available clinically and on a research basis.

Genetic Counseling

DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one mutant allele; one instance of uniparental disomy has been reported. When both parents are known to be mutation carriers, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier detection for at-risk relatives and prenatal testing of pregnancies at increased risk may be possible through laboratories offering custom mutation testing if both mutations in a family are known.

References

PMID: 20301732

Genome-wide association study of hematological and biochemical traits in a Japanese population.

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Interactions

Products	Interactant	Other Gene	Source	Pubs	Description
P98164	P02768	ALB	HPRD	PubMed
P98164	Q9H9E1	ANKRA2	HPRD	PubMed
P98164	E2a-Pbx1 associated protein	ANKS1B	HPRD	PubMed
P98164	Q99767	APBA2	HPRD	PubMed
P98164	O00213	APBB1	HPRD	PubMed
P98164	P04114	APOB	HPRD	PubMed
P98164	P02649	APOE	HPRD	PubMed
P98164	P02749	APOH	HPRD	PubMed
P98164	P54259	ATN1	HPRD	PubMed
P98164	P10909	CLU	HPRD	PubMed
P98164	O60494	CUBN	HPRD	PubMed
P98164	O75553	DAB1	HPRD	PubMed
P98164	P98082	DAB2	HPRD	PubMed
P98164	Q12959	DLG1	HPRD	PubMed
P98164	Q15700	DLG2	HPRD	PubMed
P98164	Q92796	DLG3	HPRD	PubMed
P98164	P78352	DLG4	HPRD	PubMed
P98164	P02774	GC	HPRD	PubMed
P98164	O14908	GIPC1	HPRD	PubMed
P98164	Q5JY77	GPRASP1	HPRD	PubMed
P98164	P01308	INS	HPRD	PubMed
P98164	O14713	ITGB1BP1	HPRD	PubMed
P98164	P80188	LCN2	HPRD	PubMed
P98164	Q5SW96	LDLRAP1	HPRD	PubMed
P98164	P08519	LPA	HPRD	PubMed
P98164	P06858	LPL	HPRD	PubMed
P98164	P98164	LRP2	HPRD	PubMed
P98164	Megalin binding protein	LRP2BP	HPRD	PubMed
P98164	P30533	LRPAP1	HPRD	PubMed
P98164	Q96QZ7	MAGI1	HPRD	PubMed
P98164	Q9UQF2	MAPK8IP1	HPRD	PubMed
P98164	Q13387	MAPK8IP2	HPRD	PubMed
P98164	P21741	MDK	HPRD	PubMed
P98164	O75052	NOS1AP	HPRD	PubMed
P98164	O60331	PIP5K1C	HPRD	PubMed
P98164	P00749	PLAU	HPRD	PubMed
P98164	P09455	RBP1	HPRD	PubMed
P98164	P11684	SCGB1A1	HPRD	PubMed
P98164	P05121	SERPINE1	HPRD	PubMed
P98164	P48764	SLC9A3	HPRD	PubMed
P98164	P57105	SYNJ2BP	HPRD	PubMed
P98164	P01266	TG	HPRD	PubMed
P98164	Q9Y490	TLN1	HPRD	PubMed
P98164	P02766	TTR	HPRD	PubMed
BioGRID:110216	BioGRID:158123	ALB	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:115665	ANAPC10	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:121758	ANKRA2	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:121229	ANKS1B	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:106818	APBA2	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:106845	APOE	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:106847	APOH	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:107603	CLU	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:107970	DAB1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:107971	DAB2	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:108084	DLG2	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:108085	DLG3	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:108086	DLG4	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:108908	GC	BioGRID	PubMed	Affinity Capture-Western
BioGRID:110216	BioGRID:115978	GIPC1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:114689	ITGB1BP1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:117561	LDLRAP1	BioGRID	PubMed	Affinity Capture-Western; Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:110202	LPA	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:110205	LPL	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:120916	LRP2BP	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:110221	LRPAP1	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:114655	MAGI1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:114864	MAPK8IP1	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:117086	MAPK8IP2	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:115071	NOS1AP	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:111344	PLAU	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:111881	RBP1	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:113203	SCGB1A1	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:112233	SCN3A	BioGRID	PubMed	Two-hybrid
BioGRID:110216	BioGRID:115128	SNX17	BioGRID	PubMed	Reconstituted Complex
BioGRID:110216	BioGRID:120614	SYNJ2BP	BioGRID	PubMed	Reconstituted Complex; Two-hybrid
BioGRID:110216	BioGRID:112915	THBS1	BioGRID	PubMed	Reconstituted Complex

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General gene information

Markers

WI-17537 (e-PCR)
- UniSTS:26882

SHGC-80045 (e-PCR)
- UniSTS:101654

LRP2_7816 (e-PCR)
- UniSTS:467751

G32722 (e-PCR)
- UniSTS:117304

D2S2879 (e-PCR)
- UniSTS:1344

A009P03 (e-PCR)
- UniSTS:2385

D2S1416 (e-PCR)
- UniSTS:75117

RH124065 (e-PCR)
- UniSTS:138872

RH45139 (e-PCR)
- UniSTS:26027

RH123671 (e-PCR)
- UniSTS:138681

RH120397 (e-PCR)
- UniSTS:132540

Genotypes

See LRP2 SNP Geneview Report
See LRP2 SNP Genotype Report
See LRP2 SNP Variation Viewer Report

Homology

Homologs of the LRP2 gene: The LRP2 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish, fruit fly, mosquito, and C.elegans.
Map Viewer (Mouse, Rat)

Pathways from BioSystems

Hedgehog signaling pathway, organism-specific biosystem (from KEGG)
Hedgehog signaling pathway, organism-specific biosystemThe Hedgehog (Hh) family of secreted signaling proteins plays a crucial role in development of diverse animal phyla, from Drosophila to humans, regulating morphogenesis of a variety of tissues and or...
Hedgehog signaling pathway, conserved biosystem (from KEGG)
Hedgehog signaling pathway, conserved biosystemThe Hedgehog (Hh) family of secreted signaling proteins plays a crucial role in development of diverse animal phyla, from Drosophila to humans, regulating morphogenesis of a variety of tissues and or...
Metabolism, organism-specific biosystem (from REACTOME)
Metabolism, organism-specific biosystemMetabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as th...
Metabolism of lipids and lipoproteins, organism-specific biosystem (from REACTOME)
Metabolism of lipids and lipoproteins, organism-specific biosystemLipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphi...
Metabolism of steroid hormones and vitamins A and D, organism-specific biosystem (from REACTOME)
Metabolism of steroid hormones and vitamins A and D, organism-specific biosystemSteroid hormones are synthesized primarily in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual devel...
Signaling events mediated by the Hedgehog family, organism-specific biosystem (from Pathway Interaction Database)
Signaling events mediated by the Hedgehog family, organism-specific biosystem
Signaling events mediated by the Hedgehog family
Vitamin D (calciferol) metabolism, organism-specific biosystem (from REACTOME)
Vitamin D (calciferol) metabolism, organism-specific biosystemVitamin D3 (cholecalciferol) is a steroid hormone that plays a role in regulating calcium and bone metabolism. It is obtained from the diet and produced in the skin by photolysis of 7-dehydrocholeste...

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
SH3 domain binding	IEA Inferred from Electronic Annotation more info
calcium ion binding	IEA Inferred from Electronic Annotation more info
protein binding	IPI Inferred from Physical Interaction more info	PubMed
receptor activity	IEA Inferred from Electronic Annotation more info

Process	Evidence Code	Pubs
cell proliferation	IEA Inferred from Electronic Annotation more info
endocytosis	TAS Traceable Author Statement more info	PubMed
forebrain development	IEA Inferred from Electronic Annotation more info
lipid metabolic process	TAS Traceable Author Statement more info	PubMed
protein glycosylation	TAS Traceable Author Statement more info	PubMed
receptor-mediated endocytosis	IEA Inferred from Electronic Annotation more info
small molecule metabolic process	TAS Traceable Author Statement more info
steroid metabolic process	TAS Traceable Author Statement more info
vitamin D metabolic process	TAS Traceable Author Statement more info
vitamin metabolic process	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
Golgi apparatus	IEA Inferred from Electronic Annotation more info
apical plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
brush border membrane	IEA Inferred from Electronic Annotation more info
coated pit	IEA Inferred from Electronic Annotation more info
endocytic vesicle	IEA Inferred from Electronic Annotation more info
endoplasmic reticulum	IEA Inferred from Electronic Annotation more info
endosome	IEA Inferred from Electronic Annotation more info
integral to membrane	IEA Inferred from Electronic Annotation more info
lysosome	TAS Traceable Author Statement more info	PubMed
membrane fraction	IEA Inferred from Electronic Annotation more info
plasma membrane	TAS Traceable Author Statement more info

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General protein information

Preferred Names: low-density lipoprotein receptor-related protein 2

Names: low-density lipoprotein receptor-related protein 2; LRP-2; megalin; glycoprotein 330; calcium sensor protein; Heymann nephritis antigen homolog

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NCBI Reference Sequences (RefSeq)

RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_012634.1 RefSeqGene

Range

5001..240504

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_004525.2 → NP_004516.2 low-density lipoprotein receptor-related protein 2 precursor

Status: REVIEWED

Source sequence(s)

AC007556, AY265357, AY265358, CD673312, DA200673, DA339827, DA401915, U33837

Consensus CDS

CCDS2232.1

UniProtKB/Swiss-Prot

P98164

UniProtKB/TrEMBL

Q7Z5C0

UniProtKB/TrEMBL

Q7Z5C1

Related

ENSP00000263816, OTTHUMP00000163042, ENST00000263816, OTTHUMT00000255231

Conserved Domains (5) summary

cd00112
Location:3759 – 3793
Blast Score: 136

LDLa; Low Density Lipoprotein Receptor Class A domain, a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism; the receptor protein binds LDL and transports it into cells by endocytosis; 7 successive cysteine-rich repeats of about ...

COG3391
Location:1747 – 2025
Blast Score: 101

COG3391; Uncharacterized conserved protein [Function unknown]

cl00104
Location:2784 – 2814
Blast Score: 102

LDLa; Low Density Lipoprotein Receptor Class A domain, a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism; the receptor protein binds LDL and transports it into cells by endocytosis; 7 successive cysteine-rich repeats of about ...

cl09941
Location:3132 – 3155
Blast Score: 117

EGF_CA; Calcium-binding EGF-like domain, present in a large number of membrane-bound and extracellular (mostly animal) proteins. Many of these proteins require calcium for their biological function and calcium-binding sites have been found to be located at the ...

cl10508
Location:1501 – 1543
Blast Score: 146

Ldl_recept_b; Low-density lipoprotein receptor repeat class B

RefSeqs of Annotated Genomes: Build 37.3

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh37.p5 Primary Assembly

Genomic

NC_000002.11 Reference GRCh37.p5 Primary Assembly

Range

169983619..170219122, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

Alternate HuRef

Genomic

AC_000134.1 Alternate HuRef

Range

161880497..162110457, complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

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Related Sequences

Nucleotide		Protein
Heading	Accession and Version	Protein
genomic	AC007556.3	AAX88965.1
genomic	AC008178.3	AAY24266.1
genomic	AF065440.2	AAC17129.2
genomic	CH471058.2	EAX11280.1
mRNA	AK295005.1	BAG58066.1
mRNA	AK302843.1	BAG64033.1
mRNA	AY265357.1	AAP88585.1
mRNA	AY265358.1	AAP88586.1
mRNA	CD673312.1	None
mRNA	DA200673.1	None
mRNA	DA339827.1	None
mRNA	DA401915.1	None
mRNA	S73145.1	AAB30825.1
mRNA	U04441.1	AAB02882.1
mRNA	U33837.1	AAB41649.1

Protein Accession	Links
Protein Accession	GenePept Link	UniProtKB Link
P98164.3	GenPept	UniProtKB/Swiss-Prot:P98164
Q4ZG84	GenPept	UniProtKB/TrEMBL:Q4ZG84
Q53TL0	GenPept	UniProtKB/TrEMBL:Q53TL0
Q7Z5C0	GenPept	UniProtKB/TrEMBL:Q7Z5C0
Q7Z5C1	GenPept	UniProtKB/TrEMBL:Q7Z5C1
Q9NP34	GenPept	UniProtKB/TrEMBL:Q9NP34