Alternative titles; symbols
HGNC Approved Gene Symbol: MPP1
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,778,684-154,805,485 (from NCBI)
EMP55 is the prototype of a family of membrane-associated proteins termed MAGUKs (membrane-associated guanylate kinase homologs). MAGUKs interact with the cytoskeleton and regulate cell proliferation, signaling pathways, and intracellular junctions (Kim et al., 1996).
Ruff et al. (1991) deduced the complete amino acid sequence of a 55-kD erythrocyte membrane protein from cDNA clones isolated from a human reticulocyte library. This protein, p55, was copurified during the isolation of dematin, an actin-bundling protein of the erythrocyte membrane cytoskeleton. Its tight association with the plasma membrane was reminiscent of an integral membrane protein. Protein p55 is the most extensively palmitoylated protein of the erythrocyte membrane. Predicted primary structure of p55 contained a conserved sequence, called the SH3 (src homology 3) motif, found in several other proteins that associate with the cytoskeleton and are suspected to play important roles in signal transduction.
Metzenberg and Gitschier (1992) found a gene located in a CpG island 30 kb 3-prime to the factor VIII gene (F8; 300841). The 2-kb transcript encoded a previously described palmitoylated membrane protein, p55, containing an src homology motif, SH3. Although originally described in reticulocytes (Ruff et al., 1991), Metzenberg and Gitschier (1992) found that the transcript was expressed in a wide variety of human tissues. The gene was also found in the mouse where it was expressed in all tissues examined. The EMP55 gene did not appear to be developmentally regulated in erythrocytes; p55 is constitutively and abundantly expressed in erythroid cells during their development from stem cells to fully differentiated reticulocytes. In contrast, other red cell membrane-associated proteins such as 4.1, ankyrin, and band 3 are expressed late in erythropoiesis. These results suggested that the p55 protein may have a housekeeping function. Other work indicated that it is a peripheral membrane protein. Bryant and Woods (1992) demonstrated that p55 is homologous to the yeast guanylate kinase and to the product of a Drosophila tumor suppressor gene.
Elder et al. (1996) cloned and sequenced the mouse MPP1 gene. The mouse gene shares 89% sequence identity with the coding sequence of human MPP1. The coding region size and intron/exon structures of the mouse and human genes are identical. The human and mouse sequences and structures are highly homologous to the MPP1 gene of fish (Fugu), suggesting that the gene serves an essential function in development.
By yeast 2-hybrid analysis of a mouse embryo cDNA library, Mburu et al. (2006) found that whirlin (WHRN; 607928) interacted with p55. p55 was expressed in mouse outer hair cells in long stereocilia that made up the stereocilia bundle and in surrounding shorter stereocilia structures. Since p55 and protein 4.1R (EPB41; 130500) form complexes critical for actin cytoskeletal assembly in erythrocytes, Mburu et al. (2006) proposed that p55 and whirlin may have a similar role in hair cell stereocilia.
Metzenberg and Gitschier (1992) estimated that the EMP55 gene spans 20 to 30 kb.
Kim et al. (1996) reported the complete intron/exon map of the human erythroid p55 gene. The structure of the p55 gene was determined from cosmid clones isolated from a cosmid library specific for the human X chromosome. There is a single copy of the p55 gene, composed of 12 exons and spanning approximately 28 kb in the Xq28 region. Several of the exon boundaries corresponded to the boundaries of functional domains in the p55 protein. These domains include an SH3 motif and a region that binds to cytoskeletal protein 4.1.
Metzenberg and Gitschier (1992) identified the EMP55 gene in a CpG island 30 kb 3-prime to the factor VIII gene (300841). They confirmed the Xq28 localization of the EMP55 gene by study of hybrid cell lines containing various parts of the human X chromosome in rodent backgrounds. They proved that the gene is located between the F8 and glucose-6 phosphate dehydrogenase (G6PD; 305900) genes by hybridization to a YAC clone that extends approximately 60 kb beyond the F8C gene. The EMP55 gene appeared to be transcribed in the same direction as F8C. No known factor VIII gene deletions extended into the EMP55 gene. Since the function of the p55 protein was not known, the gene was formally a candidate for any of the many disease genes that are closely linked genetically to the F8C gene.
Metzenberg et al. (1994) failed to find evidence of mutation in the EMP55 gene in either of 2 disorders that on the grounds of phenotype and map location are candidate disorders: dyskeratosis congenita (305000) and Emery-Dreifuss muscular dystrophy (310300).
Liu et al. (1997) reported a method of determination of clonality using allele-specific PCR (ASPCR) to detect exonic polymorphisms in p55 and G6PD (305900). They demonstrated a significant sex difference in allele frequencies in African Americans but not in Caucasians, and linkage disequilibrium for the p55 and G6PD alleles in Caucasians but not in African Americans.
Bryant, P. J., Woods, D. F. A major palmitoylated membrane protein of human erythrocytes shows homology to yeast guanylate kinase and to the product of a Drosophila tumor suppressor gene. Cell 68: 621-622, 1992. [PubMed: 1310897] [Full Text: https://doi.org/10.1016/0092-8674(92)90136-z]
Elder, B., Kuo, K., Gitschier, J., Kim, A., Chishti, A., Metzenberg, A. cDNA sequence and genomic structure of the murine p55 (Mpp1) gene. Genomics 38: 231-234, 1996. [PubMed: 8954807] [Full Text: https://doi.org/10.1006/geno.1996.0621]
Kim, A. C., Metzenberg, A. B., Sahr, K. E., Marfatia, S. M., Chisti, A. H. Complete genomic organization of the human erythroid p55 gene (MPP1), a membrane-associated guanylate kinase homologue. Genomics 31: 223-229, 1996. [PubMed: 8824805] [Full Text: https://doi.org/10.1006/geno.1996.0035]
Liu, Y., Phelan, J., Go, R. C. P., Prchal, J. F., Prchal, J. T. Rapid determination of clonality by detection of two closely-linked X chromosome exonic polymorphisms using allele-specific PCR. J. Clin. Invest. 99: 1984-1990, 1997. [PubMed: 9109443] [Full Text: https://doi.org/10.1172/JCI119366]
Mburu, P., Kikkawa, Y., Townsend, S., Romero, R., Yonekawa, H., Brown, S. D. M. Whirlin complexes with p55 at the stereocilia tip during hair cell development. Proc. Nat. Acad. Sci. 103: 10973-10978, 2006. [PubMed: 16829577] [Full Text: https://doi.org/10.1073/pnas.0600923103]
Metzenberg, A. B., Gitschier, J. The gene encoding the palmitoylated erythrocyte membrane protein, p55, originates at the CpG island 3-prime to the factor VIII gene. Hum. Molec. Genet. 1: 97-101, 1992. [PubMed: 1301163] [Full Text: https://doi.org/10.1093/hmg/1.2.97]
Metzenberg, A. B., Pan, Y., Das, S., Pai, G. S., Gitschier, J. Molecular evidence that the p55 gene is not responsible for either of two Xq28-linked disorders: Emery-Dreifuss muscular dystrophy and dyskeratosis congenita. (Letter) Am. J. Hum. Genet. 54: 920-922, 1994. [PubMed: 8178832]
Ruff, P., Speicher, D. W., Husain-Chishti, A. Molecular identification of a major palmitoylated erythrocyte membrane protein containing the src homology 3 motif. Proc. Nat. Acad. Sci. 88: 6595-6599, 1991. [PubMed: 1713685] [Full Text: https://doi.org/10.1073/pnas.88.15.6595]