Alternative titles; symbols
HGNC Approved Gene Symbol: LRP8
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38): 1:53,242,364-53,328,070 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.3 | {Myocardial infarction, susceptibility to} | 608446 | 3 |
Apolipoprotein E (APOE; 107741) is a 34-kD lipophilic protein that mediates high-affinity binding of APOE-containing lipoproteins to the low density lipoprotein receptor (see LDLR; 606945) and the very low density lipoprotein receptor (VLDLR; 192977). By screening a human placenta cDNA library with degenerate oligonucleotides based on a highly conserved region between LDLR and VLDLR, Kim et al. (1996) identified a cDNA encoding APOE receptor-2 (APOER2). The predicted 963-amino acid protein contains a putative 41-amino acid signal sequence and 5 functional domains that resemble those of LDLR and VLDLR. APOER2 appears specific for APOE-containing ligands: LDLR-deficient mammalian cells expressing APOER bound APOE-rich beta-VLDL with high affinity, but bound LDL and VLDL with much lower affinities. Northern blot analysis revealed that APOER2 is expressed as 4.5- and 8.5-kb mRNAs in brain and placenta.
Layering of neurons in the cerebral cortex and cerebellum requires reelin (RELN; 600514), an extracellular matrix protein, and mammalian disabled (DAB1; 603448), a cytosolic protein that activates tyrosine kinases. By targeted disruption experiments in mice, Trommsdorff et al. (1999) showed that 2 cell surface receptors, VLDLR and APOER2, are also required. Both receptors bound Dab1 on their cytoplasmic tails and were expressed in cortical and cerebellar layers adjacent to layers expressing Reln. Dab1 expression was upregulated in knockout mice lacking both the Vldlr and Apoer2 genes. Inversion of cortical layers, absence of cerebellar foliation, and the migration of Purkinje cells in these animals precisely mimicked the phenotype of mice lacking Reln or Dab1. These findings established novel signaling functions for the LDL receptor gene family and suggested that VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1.
Using in vitro binding experiments, Hiesberger et al. (1999) showed that Reln binds directly and specifically to the extracellular domains of Vldlr and ApoER2. Blockade of Vldlr and ApoER2 ligand binding correlated with loss of Reelin-induced Dab1 tyrosine phosphorylation. With Western blot analysis, they demonstrated that mice lacking either Reln or Vldlr and ApoER2 (Trommsdorff et al., 1999) exhibit a dramatic increase in the phosphorylation level of the microtubule-stabilizing protein tau (MAPT; 157140). Hiesberger et al. (1999) concluded that Reln acts via Vldlr and ApoER2 to regulate Dab1 tyrosine phosphorylation and microtubule function in neurons.
Senturk et al. (2011) showed that the neuronal guidance cues ephrin B proteins are essential for Reelin signaling during the development of laminated structures in the brain. They showed that ephrin Bs genetically interact with Reelin. Notably, compound mouse mutants (Reln heterozygotes null for either Efnb2 (600527) or Efnb3 (602297)) and triple Efnb1 (300035)/Efnb2/Efnb3 knockouts showed neuronal migration defects that recapitulated the ones observed in the neocortex, hippocampus, and cerebellum of the reeler mouse. Mechanistically, Senturk et al. (2011) showed that Reelin binds to the extracellular domain of ephrin Bs, which associate at the membrane with VLDLR and ApoER2 in neurons. Clustering of ephrin Bs leads to the recruitment and phosphorylation of Dab1, which is necessary for Reelin signaling. Conversely, loss of function of ephrin Bs severely impairs Reelin-induced Dab1 phosphorylation. Importantly, activation of ephrin Bs can rescue the reeler neuronal migration defects in the absence of Reelin protein. Senturk et al. (2011) concluded that their results identified ephrin Bs as essential components of the Reelin receptor/signaling pathway to control neuronal migration during the development of the nervous system.
Kim et al. (1997) reported that the APOER2 gene contains 19 exons and spans approximately 60 kb. Alternative splicing generates multiple transcripts encoding receptors with different numbers of cysteine-rich repeats in the ligand-binding domain.
Kim et al. (1997) mapped the APOER2 gene to 1p34 by somatic cell hybrid analysis and fluorescence in situ hybridization.
Fetal growth restriction (FGR) affects more than 200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. To study the role of genetic factors in the development of this complex trait, Wang et al. (2006) conducted a candidate gene association study of birth weight and FGR in 2 independent study samples. They first investigated the association between maternal genotypes of 68 SNPs from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia (189800), 92 of whom had preeclampsia. They found significant association between a SNP, rs2297660, in the LRP8 gene and birth weight. Subsequently, they replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The 'A' allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the 'A' allele reduced the risk of FGR by 33%.
In a genomewide linkage scan of 428 nuclear families, Wang et al. (2004) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on 1p36-p34 (MCI1; 608446). Shen et al. (2007) analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from 381 cases from these nuclear families and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q (602600.0001), in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. The results were replicated in 2 of 3 other populations.
Shen et al. (2007) identified association of an arg952-to-gln (R952Q) missense change in LRP8 with susceptibility to premature coronary artery disease and/or myocardial infarction (MCI1; 608446). Transfection assays showed that the R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase (600289) by oxidized low density lipoprotein.
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., Herz, J. Direct binding of reelin to VLDL receptor and apoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron 24: 481-489, 1999. [PubMed: 10571241] [Full Text: https://doi.org/10.1016/s0896-6273(00)80861-2]
Kim, D.-H., Iijima, H., Goto, K., Sakai, J., Ishii, H., Kim, H.-J., Suzuki, H., Kondo, H., Saeki, S., Yamamoto, T. Human apolipoprotein E receptor 2: a novel lipoprotein receptor of the low density lipoprotein receptor family predominantly expressed in brain. J. Biol. Chem. 271: 8373-8380, 1996. [PubMed: 8626535] [Full Text: https://doi.org/10.1074/jbc.271.14.8373]
Kim, D.-H., Magoori, K., Inoue, T. R., Mao, C. C., Kim, H.-J., Suzuki, H., Fujita, T., Endo, Y., Saeki, S., Yamamoto, T. T. Exon/intron organization, chromosome localization, alternative splicing, and transcription units of the human apolipoprotein E receptor 2 gene. J. Biol. Chem. 272: 8498-8504, 1997. [PubMed: 9079678] [Full Text: https://doi.org/10.1074/jbc.272.13.8498]
Senturk, A., Pfennig, S., Weiss, A., Burk, K., Acker-Palmer, A. Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature 472: 356-360, 2011. Note: Erratum: Nature 478: 274 only, 2011. [PubMed: 21460838] [Full Text: https://doi.org/10.1038/nature09874]
Shen, G.-Q., Li, L., Girelli, D., Seidelmann, S. B., Rao, S., Fan, C., Park, J. E., Xi, Q., Li, J., Hu, Y., Olivieri, O., Marchant, K., and 9 others. An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction. Am. J. Hum. Genet. 81: 780-791, 2007. [PubMed: 17847002] [Full Text: https://doi.org/10.1086/521581]
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., Herz, J. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97: 689-701, 1999. [PubMed: 10380922] [Full Text: https://doi.org/10.1016/s0092-8674(00)80782-5]
Wang, L., Wang, X., Laird, N., Zuckerman, B., Stubblefield, P., Xu, X. Polymorphism in maternal LRP8 gene is associated with fetal growth. Am. J. Hum. Genet. 78: 770-777, 2006. [PubMed: 16642433] [Full Text: https://doi.org/10.1086/503712]
Wang, Q., Rao, S., Shen, G.-Q., Li, L., Moliterno, D. J., Newby, L. K., Rogers, W. J., Cannata, R., Zirzow, E., Elston, R. C., Topol, E. J. Premature myocardial infarction novel susceptibility locus on chromosome 1p34-36 identified by genomewide linkage analysis. Am. J. Hum. Genet. 74: 262-271, 2004. Note: Erratum: Am. J. Hum. Genet. 74: 1080 only, 2004. [PubMed: 14732905] [Full Text: https://doi.org/10.1086/381560]