Alternative titles; symbols
HGNC Approved Gene Symbol: LRPAP1
Cytogenetic location: 4p16.3 Genomic coordinates (GRCh38): 4:3,503,612-3,532,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p16.3 | Myopia 23, autosomal recessive | 615431 | Autosomal recessive | 3 |
The alpha-2-macroglobulin (103950) receptor complex (see 107770), as purified by affinity chromatography, contains 3 polypeptides: a 515-kD heavy chain, an 85-kD light chain, and a 39-kD associated protein. The 515- and 85-kD components are derived from a 600-kD precursor whose complete sequence was determined by cDNA cloning (Herz et al., 1988). Strickland et al. (1991) determined the primary structure of the 39-kD polypeptide, termed alpha-2-macroglobulin receptor-associated protein (MRAP) by them, by cDNA cloning. The deduced amino acid sequence contains a putative signal sequence that precedes the 323-residue mature protein. The sequence showed 73% identity with a rat protein reported to be a pathogenic domain of the Heymann nephritis antigen gp330 and 77% identity to a 44-kD mouse heparin-binding protein termed HBP-44. There are also similarities between MRAP and apolipoprotein E (107741). Studies indicated that the molecule is present on the cell surface, forming a complex with the heavy and light chains of the alpha-2-macroglobulin receptor.
By NMR spectroscopy, Nielsen et al. (1997) determined the 3-dimensional structure of the N-terminal domain (residues 18-112) of alpha-2-macroglobulin receptor-associated protein, specifically the 3-dimensional structure of the pathogenic epitope for the rat disease Heymann nephritis, an experimental model of human membranous glomerulonephritis. From the structure, it was possible to rationalize published results obtained from studies of fragments of the N-terminal domain.
Van Leuven et al. (1995) cloned the mouse gene coding for HBP-44 from a cosmid library and determined that its structure is very similar to that of the LRPAP1 gene: in both species, the known coding part of the cDNA is encoded by 8 exons and the position of the boundaries of the exons is conserved.
Using a human 1.5-kb cDNA clone encoding MRAP, Korenberg et al. (1994) performed fluorescence in situ hybridization (FISH) to map the gene to human chromosome 4p16.3.
Jou et al. (1994) used the direct cDNA selection approach to isolate the LRPAP1 gene from cloned genomic DNA from the region of the Huntington disease gene (HTT; 613004) located at 4p16.3.
Van Leuven et al. (1995) assigned the LRPAP1 gene to chromosome 4 by PCR of human-hamster hybrid cell lines and to 4p16.3 by FISH.
The 39-kD MRAP copurifies and binds in vitro with high affinity to both LRP1 (107770) and LRP2 (600073) (see Kounnas et al., 1992) and can specifically inhibit ligand binding to both receptors. Although previous studies localized MRAP to the cell surface, Korenberg et al. (1994) stated that its intracellular localization has led to suggestions that it might function in the biosynthesis of gp330 (LRP2) and LRP, perhaps acting as a chaperone, preventing ligand binding during receptor trafficking. The gene was symbolized also as LRPAP1 (low density lipoprotein receptor-related protein-associated protein-1).
Willnow et al. (1995) obtained knockout mice deficient in RAP expression. They found that the amount of mature, processed LRP1 was reduced in the liver and brain of RAP-deficient mice, consistent with the hypothesis that RAP stabilizes LRP1 in the secretory pathway. Willnow et al. (1996) further examined the tissues of RAP-deficient mice and found that, in the absence of RAP, LRP1 receptors aggregate in the endoplasmic reticulum (ER). They also found that the export of LRP2 and VLDL receptors (192977) from the ER is impaired. Willnow et al. (1996) concluded that RAP defines a novel class of molecular chaperones that selectively protect endocytic receptors by binding to newly synthesized receptor polypeptides, thereby preventing ligand-induced aggregation and subsequent degradation in the ER.
Wolf-Hirschhorn Syndrome
Korenberg et al. (1994) noted that the location of the LRPAP1 gene is in the vicinity of the 2.5-Mb deletion associated with the Wolf-Hirschhorn syndrome (194190) and suggested that the kidney hypoplasia associated with Wolf-Hirschhorn syndrome may be relevant in view of the high MRAP expression that is observed in this organ.
Using an LRPAP1 genomic probe for FISH, Van Leuven et al. (1995) studied 2 patients with deletions of 4p, resulting in the Wolf-Hirschhorn syndrome. One patient retained both copies of the gene, whereas the other patient displayed no signal for LRPAP1 on the deleted chromosome.
Myopia 23
In affected members of 3 consanguineous Saudi Arabian families with autosomal recessive extreme myopia (MYP23; 615431), Aldahmesh et al. (2013) identified homozygosity for truncating mutations in the LRPAP1 gene (104225.0001 and 104225.0002). The mutations, which segregated fully with myopia in each family, were not found in 210 Saudi exome files or in the SNP databases of the 1000 Genomes Project or Exome Variant Server. Analysis of the LRPAP1 gene in 100 individuals with myopia of -6 diopters or greater did not reveal any evidence of an increased load of rare variants compared to 100 similarly screened controls.
In a 5-year-old Chinese boy (HM759), born to consanguineous parents, with bilateral high myopia, Jiang et al. (2015) identified homozygosity for a frameshift mutation in the LRPAP1 gene (104225.0003). Segregation analysis and functional studies were not performed.
In 3 sibs from a consanguineous Saudi Arabian family with extreme myopia (MYP23; 615431), Aldahmesh et al. (2013) identified homozygosity for a 1-bp deletion (c.605delA) in exon 5 of the LRPAP1 gene, causing a frameshift predicted to result in a premature termination codon (Asn202ThrfsTer8) in the D3 domain. The mutation segregated fully with myopia in the family and was not found in 210 Saudi exome files or in the SNP databases of the 1000 Genomes Project or Exome Variant Server. Immunoblot analysis in the proband revealed nearly total absence of LRPAP1 as well as a marked reduction in LRP1 (107770) and a greater than 2-fold increase in TGFB (190180) compared to controls.
In 5 sibs from 2 unrelated consanguineous Saudi Arabian families with extreme myopia (MYP23; 615431), Aldahmesh et al. (2013) identified homozygosity for a 2-bp deletion (c.863_864del) in exon 7 of the LRPAP1 gene, causing a frameshift predicted to result in a premature termination codon (Ile288ArgfsTer118) in the D4 domain. The mutation segregated fully with myopia in each family and was not found in 210 Saudi exome files or in the SNP databases of the 1000 Genomes Project or Exome Variant Server. Immunoblot analysis in the 2 probands revealed nearly total absence of LRPAP1 as well as marked reduction in LRP1 (107770) and a greater than 2-fold increase in TGFB (190180) compared to controls.
In a 5-year-old Chinese boy (HM759), born to consanguineous parents, with bilateral high myopia (MYP23; 615431), Jiang et al. (2015) identified homozygosity for a 1-bp deletion in the LRPAP1 gene (c.199delC), resulting in a frameshift and premature termination (Gln67SerfsTer8). The parents were unaffected, but their DNA was not available for study. The mutation was not found in the Exome Variant Server or the 1000 Genomes Project databases or in 2,010 alleles of Chinese controls. Functional studies were not performed.
Aldahmesh, M. A., Khan, A. O., Alkuraya, H., Adly, N., Anazi, S., Al-Saleh, A. A., Mohamed, J. Y., Hijazi, H., Prabakaran, S., Tacke, M., Al-Khrashi, A., Hashem, M., Reinheckel, T., Assiri, A., Alkuraya, F. S. Mutations in LRPAP1 are associated with severe myopia in humans. Am. J. Hum. Genet. 93: 313-320, 2013. [PubMed: 23830514] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.002]
Herz, J., Hamann, U., Rogne, S., Myklebost, O., Gausepohl, H., Stanley, K. K. Surface location and high affinity for calcium of a 500 kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor. EMBO J. 7: 4119-4127, 1988. [PubMed: 3266596] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03306.x]
Jiang, D., Li, J., Xiao, X., Li, S., Jia, X., Sun, W., Guo, X., Zhang, Q. Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. Invest. Ophthal. Vis. Sci. 56: 339-345, 2015. [PubMed: 25525168] [Full Text: https://doi.org/10.1167/iovs.14-14850]
Jou, Y.-S., Goold, R. D., Myers, R. M. Localization of the alpha-2-macroglobulin receptor-associated protein 1 gene (LRPAP1) and other gene fragments to human chromosome 4p16.3 by direct cDNA selection. Genomics 24: 410-413, 1994. [PubMed: 7535288] [Full Text: https://doi.org/10.1006/geno.1994.1643]
Korenberg, J. R., Argraves, K. M., Chen, X.-N., Tran, H., Strickland, D. K., Argraves, W. S. Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1). Genomics 22: 88-93, 1994. [PubMed: 7959795] [Full Text: https://doi.org/10.1006/geno.1994.1348]
Kounnas, M. Z., Argraves, W. S., Strickland, D. K. The 39-kDa receptor-associated protein interacts with two members of the low density lipoprotein receptor family, alpha-2-macroglobulin receptor and glycoprotein 330. J. Biol. Chem. 267: 21162-21166, 1992. [PubMed: 1400426]
Nielsen, P. R., Ellgaard, L., Etzerodt, M., Thogersen, H. C., Poulsen, F. M. The solution structure of the N-terminal domain of alpha-2-macroglobulin receptor-associated protein. Proc. Nat. Acad. Sci. 94: 7521-7525, 1997. [PubMed: 9207124] [Full Text: https://doi.org/10.1073/pnas.94.14.7521]
Strickland, D. K., Ashcom, J. D., Williams, S., Battey, F., Behre, E., McTigue, K., Battey, J. F., Argraves, W. S. Primary structure of alpha-2-macroglobulin receptor-associated protein: human homologue of a Heymann nephritis antigen. J. Biol. Chem. 266: 13364-13369, 1991. [PubMed: 1712782]
Van Leuven, F., Hilliker, C., Serneels, L., Umans, L., Overbergh, L., De Strooper, B., Fryns, J. P., Van den Berghe, H. Cloning, characterization, and chromosomal localization to 4p16 of the human gene (LRPAP1) coding for the alpha-2-macroglobulin receptor-associated protein and structural comparison with the murine gene coding for the 44-kDa heparin-binding protein. Genomics 25: 492-500, 1995. [PubMed: 7789983] [Full Text: https://doi.org/10.1016/0888-7543(95)80050-v]
Willnow, T. E., Armstrong, S. A., Hammer, R. E., Herz, J. Functional expression of low density lipoprotein receptor-related protein is controlled by receptor-associated protein in vivo. Proc. Nat. Acad. Sci. 92: 4537-4541, 1995. [PubMed: 7538675] [Full Text: https://doi.org/10.1073/pnas.92.10.4537]
Willnow, T. E., Rohlmann, A., Horton, J., Otani, H., Braun, J. R., Hammer, R. E., Herz, J. RAP, a specialized chaperone, prevents ligand-induced ER retention and degradation of LDL receptor-related endocytic receptors. EMBO J. 15: 2632-2639, 1996. [PubMed: 8654360]