Alternative titles; symbols
HGNC Approved Gene Symbol: LRP2
SNOMEDCT: 702418009;
Cytogenetic location: 2q31.1 Genomic coordinates (GRCh38): 2:169,127,109-169,362,534 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q31.1 | Donnai-Barrow syndrome | 222448 | Autosomal recessive | 3 |
Lipoprotein receptor-related protein-2 (LRP2), also called glycoprotein-330 or megalin (Farquhar, 1995), is part of the Heymann nephritis antigenic complex with RAP (LRPAP1; 104225) (Farquhar et al., 1995) and is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR; 606945).
LRP2 was originally identified as the target antigen of Heymann nephritis, a rat model of membranous glomerulonephritis. Its location in clathrin-coated pits suggested that gp330 is an endocytic receptor. Gp330 is expressed in specialized epithelia, including those of the inner ear (Farquhar et al., 1995), neural tube, lung airway, epididymis, yolk sac, glomeruli, and proximal renal tubules (Kerjaschki and Farquhar, 1983; Chatelet et al., 1986; Buc-Caron et al., 1987). Raychowdhury et al. (1989) sequenced a partial cDNA clone which clearly established that gp330 is a member of the LDL receptor gene family.
Saito et al. (1994) reported the complete amino acid sequence of the 517,715-Da megalin protein. Hjalm et al. (1996) determined the nucleotide sequence of human gp330. They reported that the deduced 4,655-amino acid mature protein has a molecular mass of approximately 519,636 Da and consists of a probable 25-amino acid N-terminal signal peptide, an extracellular region of 4,398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acids. Three types of cysteine-rich repeats characteristic of the LDLR superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising 4 distinct domains, 16 growth factor repeats separated by 8 YWTD spacer regions, and 1 epidermal growth factor-like repeat. Hjalm et al. (1996) detected no consensus cleavage sequence for the processing endoprotease furin. The intracellular tail contains 2 copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, as well as potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II, and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330, with minor differences between the extra- and intracellular regions.
In kidney tubule epithelial cells, gp330 has been shown to bind in vitro to lipoprotein lipase and apolipoprotein E-enriched beta-VLDL, suggesting a role for this receptor in lipoprotein metabolism. Kounnas et al. (1995) showed that gp330 can bind apolipoprotein J/clusterin (CLU; 185430) with high affinity. Cells that express gp330 can mediate APOJ endocytosis, leading to its lysosomal degradation.
Moestrup et al. (1995) demonstrated that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides and polymyxin B, compete for binding of radioiodinated urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. (Aprotinin, also known as bovine pancreatic trypsin inhibitor, is a 6-kD protein used clinically in acute pancreatitis and antifibrinolytic therapy. Intravenously administered aprotinin accumulates in the lysosomes of kidney proximal tubules and is only very slowly degraded.) Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae demonstrated that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human alpha-2-macroglobulin receptor (107770). However, the rapid glomerular filtration of the drugs suggested kidney gp330 to be the quantitatively most important target. Thus, a novel role of gp330 as a drug receptor was demonstrated. Moestrup et al. (1995) stated that the insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for design of drugs with reduced toxicity. Farquhar (1995) reviewed briefly the literature on LRP2/gp330/megalin in light of these new findings.
Megalin, a member of the low density lipoprotein receptor family abundant in kidney proximal tubules, mediates endocytic uptake of complexes between the steroid 25(OH) vitamin D3 and vitamin D-binding protein (DBP; 139200) filtered in the glomeruli. The receptor-mediated uptake is required to prevent loss of 25(OH)D3 in the urine and to deliver the precursor for generation of 1,25(OH)2 vitamin D3, a potent regulator of calcium homeostasis and bone turnover. Nykjaer et al. (1999) showed that accordingly, megalin knockout mice lose DBP and 25(OH)D3 in the urine and develop severe vitamin D deficiency and bone disease. Megalin binds a large number of structurally unrelated ligands, and coreceptors may confer ligand specificity by sequestering and presenting their cargo to megalin. For example, the gastric intrinsic factor (IF; 609342)-B12 complex is taken up in the intestine by a tandem receptor-mediated mechanism: the complex is first bound to a receptor, cubilin (602997), anchored to the outer leaflet of the plasma membrane possibly by an amphipathic helix, followed by endocytosis of cubilin and its cargo mediated by megalin (summary by Nykjaer et al., 2001).
Marino et al. (1999) searched for antimegalin antibodies in 78 patients with autoimmune and nonautoimmune thyroid diseases. Significantly elevated values were found in 18 patients, including 13 of 26 (50%) patients with autoimmune thyroiditis and 2 of 19 (11%) patients with Graves disease (275000). Furthermore, 2 of 19 (11%) patients with nontoxic goiter and 1 of 14 (7%) patients with differentiated thyroid cancer had mean fluorescence intensity (MFI) values greater than 50.62, associated with the presence of circulating antithyroid autoantibodies. Binding of serum IgGs to L2 cells was significantly reduced by coincubation with purified megalin in 15 of 18 (83%) positive patients, and by a rabbit antimegalin antibody in 11 (61%) patients. Immunoprecipitation experiments provided further and more conclusive evidence that positive tests (MFI less than 50.62) for binding to L2 cells were attributable to serum antimegalin antibodies. The authors suggested that further studies are needed to determine whether antimegalin antibodies have pathogenic significance or diagnostic value in autoimmune thyroid diseases.
Using yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, Nagai et al. (2003) found that rat Arh (LDLRAP1; 605747) bound the first FxNPxY motif of megalin. Arh colocalized with megalin in clathrin-coated pits and in recycling endosomes in the Golgi region of rat L2 cells. Upon internalization of megalin, megalin and Arh colocalized in clathrin-coated pits, followed by their colocalization in early endosomes and tubular recycling endosomes in the pericentriolar region, and then by their reappearance at the cell surface. Expression of Arh in canine kidney cells expressing megalin minireceptors enhanced megalin-mediated uptake of lactoferrin (LTF; 150210), a megalin ligand. Nagai et al. (2003) concluded that ARH facilitates endocytosis of megalin and escorts megalin along its endocytic route.
Albumin (ALB; 103600) does not readily cross the renal glomerular filter, and the fraction that does is reabsorbed by proximal tubule cells via clathrin- and receptor-mediated endocytosis. Overstressing this endocytic system with prolonged excess of albumin, which is often associated with kidney disease, is injurious to proximal tubule cells and leads to albumin-induced apoptosis. Caruso-Neves et al. (2006) identified megalin as the sensor that determines whether cells will be protected or injured by albumin. Using a porcine kidney cell line, they showed that megalin bound protein kinase B (PKB; see 164730) in a phosphoinositide 3-kinase (see 601232)-independent manner, anchoring PKB in the luminal plasma membrane. Low doses of albumin led to activation of PKB and phosphorylation of Bad (603167), an antiapoptotic protein. In contrast, pathophysiologic levels of albumin reduced the interaction between PKB and megalin, resulting in reduced Bad phosphorylation and albumin-induced apoptosis.
Hammes et al. (2005) found that megalin internalized complexes of sex steroids bound to sex hormone-binding globulin (SHBG; 182205) in cultured rat carcinoma cells. Following internalization, the carrier was degraded in lysosomes while the steroids were released to induce steroid-responsive genes. Lack of megalin expression in knockout mice impaired descent of the testes and blocked vaginal opening, processes critically dependent on sex steroid signaling.
Korenberg et al. (1994) designed degenerate oligonucleotide primers based on conserved regions of gp330, LDLR, and LRP1 (107770) and used homology-PCR cloning to isolate cDNAs encoding human gp330. They then used the human gp330 cDNA as a probe in fluorescence in situ hybridization to map the gene to the border of bands 2q24-q31 (Korenberg et al., 1994). By isotopic in situ hybridization, Chowdhary et al. (1995) found that LRP2 maps to 2q31-q32.1 in human and to 15q22-q24 in pig.
In 4 affected sibs with Donnai-Barrow syndrome (DBS; 222448) from the United Arab Emirates, Kantarci et al. (2007) identified a homozygous mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also identified pathogenic mutations in the LRP2 gene in affected individuals reported by Donnai and Barrow (1993) (600073.0004-600073.0006) and Chassaing et al. (2003) (see, e.g., 600073.0002-600073.0003). In addition, Kantarci et al. (2007) identified mutations in the LRP2 gene (600073.0007; 600073.0008) in a Belgian child reported by Devriendt et al. (1998) as having faciooculoacousticorenal syndrome (FOAR). Urine samples from affected individuals showed proteinuria with spillage of retinol-binding proteins (see RBP1, 180260) and vitamin D-binding proteins (see DBP, 139200). The findings confirmed that FOAR and Donnai-Barrow syndrome are the same entity.
For discussion of a possible association between variation in the LRP2 gene and susceptibility to autism, see 209850.
Willnow et al. (1996) constructed gp330/megalin knockout mice by targeted disruption of the murine gene. Homozygous knockout mice manifested abnormalities in epithelial tissues including lung and kidney that normally express the protein. The mice died perinatally from respiratory insufficiency. In brain, impaired proliferation of neuroepithelium produced a holoprosencephalic syndrome, characterized by lack of olfactory bulbs, forebrain fusion, and a common ventricular system. Because megalin can bind lipoproteins, these investigators proposed that the receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage.
Although most megalin-deficient mice die perinatally from holoprosencephaly, approximately 1 in 50 of these mice survive to adulthood. Nykjaer et al. (1999) used surviving knockout animals to study the role of megalin in the renal proximal tubules. They found that complexes of 25-(OH) vitamin D3 and the 58-kD vitamin D-binding protein (DBP) are filtered through the glomerulus and reabsorbed by megalin into the proximal tubular cells. Abnormal urinary excretion of 25-(OH) vitamin D3 and DBP in megalin knockout mice resulted in severe vitamin D deficiency and bone disease. Thus, Nykjaer et al. (1999) identified a renal uptake pathway that is essential to preserve vitamin D metabolites and to deliver the precursor for generation of 1,25-(OH)2 vitamin D3.
Using the megalin-deficient mouse model, Schmitz et al. (2002) found that megalin is a major contributor to renal aminoglycoside accumulation and nephrotoxicity. In normal mice, they found that the aminoglycoside gentamicin accumulated only in the kidney and in urine; within the kidney, it accumulated exclusively within proximal tubular cells. Megalin-deficient mice excreted similar amounts of labeled gentamicin but exhibited no renal accumulation.
Similarly, Leheste et al. (1999) demonstrated that megalin-deficient mice exhibit tubular resorption deficiency and excrete low molecular mass plasma proteins in the urine. Proteins excreted included small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha-1-microglobulin, and odorant-binding protein. Megalin normally binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins resulted in concomitant loss of lipophilic vitamins bound to the carriers. Leheste et al. (1999) showed that patients with Fanconi syndrome, who have low molecular mass proteinuria, also excrete vitamin/carrier complexes. Thus, these results identified a crucial role of the proximal tubule in retrieval of filtered vitamin/carrier complexes and the central role played by megalin in this process.
Tramontano and Makker (2004) showed that rats immunized with a soluble, secreted 563-amino acid N-terminal sequence of megalin encoded by a baculovirus construct elicited a response consistent with active Heymann nephritis (AHN). In contrast, bacterial or nonsecreted insect cell proteins induced a milder antimegalin response and no disease. All 3 recombinant proteins were detectable in Western blot analysis using rabbit antimegalin antiserum, although the insect proteins reacted preferentially with autoantibodies from rats with AHN induced by native megalin. Lectin blot analysis detected only the secreted protein, suggesting that it is glycosylated. Tramontano and Makker (2004) proposed that the megalin N-terminal domain contains epitopes sufficient for a pathogenic autoimmune response and that conformational B-cell epitopes, as well as glycosidic posttranslational modifications, are involved in nephritogenicity.
Naccache et al. (2006) found that synectin (GIPC1; 605072)-null mice, like megalin-null mice, showed proteinuria. Urine from synectin-null mice contained retinol-binding protein (see RBP1; 180260), a known megalin ligand. Megalin expression in proximal tubules of synectin-null mouse kidneys was normal compared to wildtype, suggesting that megalin recycling is defective in synectin-null mice. Naccache et al. (2006) concluded that synectin is required for proper megalin trafficking in vivo.
In 4 affected sibs with Donnai-Barrow syndrome (DBS; 222448), Kantarci et al. (2007) identified a homozygous 7564T-C transition in exon 41 of the LRP2 gene, resulting in a tyr2522-to-his (Y2522H) substitution in a highly conserved residue within the LDL-receptor class B domain. The sibs were born of consanguineous parents from the United Arab Emirates and showed characteristic clinical features, including large anterior fontanel, sensorineural deafness, diaphragmatic eventration, absence of the corpus callosum, and proteinuria. The mutation was not identified in 96 ethnically matched controls.
In 2 affected sibs of a French family with Donnai-Barrow syndrome (DBS; 222448) originally described by Chassaing et al. (2003), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 2-bp deletion (9484delGT) in exon 50, resulting in a frameshift and premature termination, and a transition in intron 18 (600073.0003). Both patients had brain malformations and 1 had congenital diaphragmatic hernia. Neither mutation was identified in 96 ethnically matched controls.
In 2 affected sibs of a French family with Donnai-Barrow syndrome (DBS; 222448) originally described by Chassaing et al. (2003), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 18 (IVS18-1G-A) and a 2-bp deletion (600073.0002).
In a girl with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified a homozygous 4-bp deletion (8516delTTTA) in exon 45 of the LRP2 gene.
In 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 44 and R3399X (600073.0006).
In 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 10195C-T transition in exon 53, resulting in an arg3399-to-ter (R3399X) substitution, and a splice site mutation in intron 44 (600073.0005).
In a child with Donnai-Barrow syndrome (DBS; 222448) originally reported by Devriendt et al. (1998), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a T-to-G transversion in exon 11 and R365X (600073.0008).
In a child with Donnai-Barrow syndrome (DBS; 222448) originally reported by Devriendt et al. (1998), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 1093C-T transition in exon 10 resulting in an arg365-to-ter (R365X) substitution, and a splice site mutation in intron 11 (600073.0007).
In a 36-year-old man studied as part of a cohort of individuals with intellectual disability, de Ligt et al. (2012) identified a heterozygous de novo mutation in the LRP2 gene, a 1-bp deletion at position 12437, resulting in a frameshift (Gly4146GlufsTer2). The patient had had seizures from the first day of life and showed developmental delay. As an adult, he was slender but of normal stature and head circumference. Facial dysmorphism included hypertelorism, mild scaphocephaly, deeply set eyes, prominent cheek bones, over-folded helices with bilateral ear tags, broad nasal bridge, and large mouth with downturned corners and a full lower lip; he also had poor vision. The man was diagnosed with Donnai-Barrow syndrome (DBS; 222448) after an additional mutation was detected in the LRP2 gene: a rare, paternally inherited 6160G-A transition, resulting in an asp2054-to-asn (D2054N) substitution (600073.0010).
For discussion of the asp205-to-asn (D205N) mutation in the LRP2 gene that was found in compound heterozygous state in a patient with Donnai-Barrow syndrome (DBS; 222448) by de Ligt et al. (2012), see 600073.0009.
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