Alternative titles; symbols
HGNC Approved Gene Symbol: MSN
SNOMEDCT: 1179285006;
Cytogenetic location: Xq12 Genomic coordinates (GRCh38) : X:65,588,377-65,741,931 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq12 | Immunodeficiency 50 | 300988 | X-linked recessive | 3 |
Moesin belongs to the family of highly homologous ERM (ezrin-radixin-moesin) proteins that function by stabilizing cell surface projections including microvilli, filopodia, and lamellipodia via the regulated formation of linkages between the plasma membrane and underlying cytoskeleton. Moesin and the other ERM proteins are subject to complex regulatory mechanisms that activate soluble monomers and facilitate formation of oligomeric surface linking structures. Moesin is the quantitatively dominant ERM protein in human lymphocytes and the sole ERM protein in human platelets (summary by Shcherbina et al., 1999).
Lankes et al. (1988) isolated from bovine uterus a protein, which they called moesin (for membrane-organizing extension spike protein), that is a candidate receptor for heparin or heparan sulfate in the interaction of basement membrane heparan sulfate and cells. Further studies indicated a significant homology in sequence to ezrin (123900), protein 4.1 (130500), talin (186745), radixin (179410), and merlin (607379). These proteins constitute a family with structural and probably functional relationships; all of them are localized to the submembranous cytoskeleton. Moesin is widely expressed in different tissues in cells, where it is localized to filopodia and other membranous protrusions that are important for cell-cell recognition and signaling and for cell movement.
Lankes and Furthmayr (1991) cloned and sequenced the complete cDNA of moesin, which represents a single 4.2-kb mRNA encoding a protein of 577 amino acids. It contains no apparent signal peptide or transmembrane domain.
The immunologic synapse is the T cell-APC (antigen-presenting cell) contact site where T-cell receptors (TCRs), coreceptors, signaling molecules, and adhesion receptors polarize upon antigen recognition. The formation of the immunologic synapse is thought to be important for receptor signal transduction and full T-lymphocyte activation. CD43 (SPN; 182160) is a large sialoprotein diffusely expressed in unactivated T cells. Using antigen-activated T cells and confocal microscopy, Delon et al. (2001) demonstrated that moesin is excluded from the region of T cell-APC contact and colocalizes with CD43. Western blot and immunocytochemical analyses showed that moesin is rapidly dephosphorylated upon antigen recognition and then rephosphorylated on threonine residues. Only phosphorylated moesin was able to bind CD43. Delon et al. (2001) concluded that T-cell activation requires the removal of CD43 from the immunologic synapse to allow efficient engagement of the TCR with molecules on the APC.
Using mouse helper T cell lines and confocal microscopy, Allenspach et al. (2001) determined that the cytoplasmic tail of CD43 is necessary and sufficient for CD43 removal from the immunologic synapse. In at least some cells, CD43 is located at the distal pole of the T cell together with ezrin and moesin. No differences in the behavior of ezrin and moesin were noted throughout the study. Using cells from Cd43 -/- mice, Allenspach et al. (2001) observed that ezrin-radixin-moesin (ERM) family proteins move independently of the large CD43 mucin. Overexpression of a dominant-negative ERM mutant containing the N-terminal 320 amino acids of ezrin inhibited the activation-induced movement of CD43 without affecting conjugate formation. The dominant-negative mutant reduced cytokine production but not the expression of T-cell activation markers.
Speck et al. (2003) showed that the sole Drosophila ERM protein moesin promotes cortical actin assembly and apical-basal polarity. As a result, cells lacking moesin lose epithelial characteristics and adopt invasive migratory behavior. Speck et al. (2003) concluded that moesin facilitates epithelial morphology not by providing an essential structural function, but rather by antagonizing activity of the small GTPase Rho (RHOA; 165390). Thus, moesin functions in maintaining epithelial integrity by regulating cell-signaling events that affect actin organization and polarity. Furthermore, Speck et al. (2003) demonstrated negative feedback between ERM activation and activity of the Rho pathway.
Using antigen-activated T cells, Faure et al. (2004) showed that the ERM proteins are rapidly inactivated through a VAV1 (164875)-RAC1 (602048) pathway. The resulting disanchoring of the cortical actin cytoskeleton from the plasma membrane decreased cellular rigidity, leading to more efficient T cell-APC conjugate formation. The authors concluded that this pathway favors immunologic synapse formation and the development of an effective immune response.
By yeast 2-hybrid screening and coimmunoprecipitation analysis, Henning et al. (2011) found that amino acids 990 to 1155 of human PDZD8 (614235) interacted with amino acids 158 to 279 of moesin. Expression of PDZD8 or moesin reduced the levels of stable microtubules in the human CHME3 microglial cell line. In addition, expression of PDZD8 or moesin reduced the cytopathic effects of herpes simplex virus (HSV)-1, as well as HSV-1 replication and spread, in CHME3 cells.
Neisch et al. (2013) found that Drosophila conundrum (Conu), an ortholog of human ARHGAP18 (613351), preferentially localized to apical cortex in Drosophila epithelium and immunoprecipitated with moesin from S2 Drosophila epithelial cells. Moesin recruited Conu to the cell cortex, and cortical Conu functioned as a GAP for Rho1, an ortholog of RHOA, inhibiting Rho1 activity. Coexpression of moesin and Conu led to overgrowth and convoluted folding of epithelium in vivo. Conu also induced overproliferation by synergistically functioning with the small GTPase Arf6 (600464) to promote activation of Rac1. Neisch et al. (2013) concluded that moesin regulates epithelial growth by recruiting Conu to the cell cortex, resulting in Rho1 inhibition and Rac1 activation.
Using in vitro angiogenesis screens with short interfering RNA (siRNA) and chemical inhibitors, Vitorino et al. (2015) defined a MAP4K4 (604666)-moesin-talin (TLN; 186745)-beta-1-integrin (ITGB1; 135630) molecular pathway that promotes efficient plasma membrane retraction during endothelial cell migration. Loss of MAP4K4 decreased membrane dynamics, slowed endothelial cell migration, and impaired angiogenesis in vitro and in vivo. In migrating endothelial cells, MAP4K4 phosphorylates moesin in retracting membranes at sites of focal adhesion disassembly. Epistasis analyses indicated that moesin functions downstream of MAP4K4 to inactivate integrin by competing with talin for binding to the beta-1-integrin intracellular domain. Consequently, loss of moesin or MAP4K4 reduced adhesion disassembly rate in endothelial cells. Additionally, alpha-5 (ITGA5; 135620)/beta-1-integrin blockade reversed the membrane retraction defects associated with loss of MAP4K4 in vitro and in vivo. Vitorino et al. (2015) concluded that their study uncovered a novel aspect of endothelial cell migration and that loss of MAP4K4 function suppresses pathologic angiogenesis.
Wilgenbus et al. (1994) found that the human moesin gene has 12 exons distributed over more than 30 kb.
By Southern and Western blot analyses of Chinese hamster/human somatic cell hybrids and by fluorescence chromosomal in situ hybridization, Wilgenbus et al. (1994) localized the MSN gene to Xq11.2-q12. Moesin-like sequences were identified also on chromosomes 5 and 6. The murine Msn locus was similarly mapped to the X chromosome by study of a rodent/mouse hybrid panel.
In 6 male patients from 4 unrelated families with immunodeficiency-50 (IMD50; 300988), Lagresle-Peyrou et al. (2016) identified a hemizygous missense mutation in the MSN gene (R171W; 309845.0001). The mutations in 2 families were identified by whole-exome sequencing and confirmed by Sanger sequencing. A seventh man from a fifth family carried a hemizygous truncating mutation in the MSN gene (R553X; 309845.0002). Patient T cells showed impaired proliferative responses after activation by certain mitogens, and this defect could be rescued by expression of wildtype MSN. Patient T cells showed variable defects in cell migration and adhesion, as well as some alterations in expression of adhesion and chemokine receptors. Formation of immunologic synapses was normal.
In 6 males from 4 unrelated families with immunodeficiency-50 (IMD50; 300988), Lagresle-Peyrou et al. (2016) identified a hemizygous c.511C-T transition in exon 5 of the MSN gene, resulting in an arg171-to-trp (R171W) substitution at a highly conserved residue. The mutation in the first 2 families was found by whole-exome sequencing and confirmed by Sanger sequencing. It was not found in the 1000 Genomes Project or ExAC databases, or in an in-house database of 6,000 controls. Four unaffected mothers carried the mutation in the heterozygous state; their peripheral blood cells showed completely skewed X-inactivation patterns, whereas buccal cells showed normal X inactivation. Western blot analysis showed low levels of the mutant protein in patient T-cell blasts. Intracellular flow cytometric analysis showed that patient granulocytes, monocytes, and platelets expressed normal MSN, whereas a subset of patient T and B cells were MSN-negative. Patient cells showed a decrease in MSN expression over time, particularly in senescent CD8+ T cells, activated CD4+ T cells, and switched CD27+ memory B cells. Patient T cells showed impaired proliferative responses after activation by certain mitogens, and this defect could be rescued by expression of wildtype MSN. Patient T cells also showed variable defects in cell migration and adhesion. Formation of immunologic synapses was normal.
In a 69-year-old man (patient 7) with immunodeficiency-50 (IMD50; 300988), Lagresle-Peyrou et al. (2016) identified a hemizygous c.1657C-T transition in the MSN gene, resulting in an arg553-to-ter (R553X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project or ExAC databases, or in an in-house database of 6,000 controls. Parental DNA was not available for segregation studies. Western blot analysis showed that the truncated protein was expressed in patient T-cell blasts. (In the article by Lagresle-Peyrou et al. (2016), the amino acid change in this variant is listed as arg533-to-ter in the abstract but as arg553-to-ter elsewhere. Andre-Schmutz (2016) confirmed that the c.1657C-T transition (c.1657C-T, ENST00000360270.6) results in an arg553-to-ter substitution.)
Allenspach, E. J., Cullinan, P., Tong, J., Tang, Q., Tesciuba, A. G., Cannon, J. L., Takahashi, S. M., Morgan, R., Burkhardt, J. K., Sperling, A. I. ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse. Immunity 15: 739-750, 2001. [PubMed: 11728336] [Full Text: https://doi.org/10.1016/s1074-7613(01)00224-2]
Andre-Schmutz, I. Personal Communication. Paris, France December 20, 2016.
Delon, J., Kaibuchi, K., Germain, R. N. Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin. Immunity 15: 691-701, 2001. [PubMed: 11728332] [Full Text: https://doi.org/10.1016/s1074-7613(01)00231-x]
Faure, S., Salazar-Fontana, L. I., Semichon, M., Tybulewicz, V. L. J., Bismuth, G., Trautmann, A., Germain, R. N., Delon, J. ERM proteins regulate cytoskeleton relaxation promoting T cell-APC conjugation. Nature Immun. 5: 272-279, 2004. [PubMed: 14758359] [Full Text: https://doi.org/10.1038/ni1039]
Henning, M. S., Stiedl, P., Barry, D. S., McMahon, R., Morham, S. G., Walsh, D., Naghavi, M. H. PDZD8 is a novel moesin-interacting cytoskeletal regulatory protein that suppresses infection by herpes simplex virus type 1. Virology 415: 114-121, 2011. [PubMed: 21549406] [Full Text: https://doi.org/10.1016/j.virol.2011.04.006]
Lagresle-Peyrou, C., Luce, S., Ouchani, F., Soheili, T. S., Sadek, H., Chouteau, M., Durand, A., Pic, I., Majewski, J., Brouzes, C., Lambert, N., Bohineust, A., and 20 others. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. J. Allergy Clin. Immun. 138: 1681-1689, 2016. [PubMed: 27405666] [Full Text: https://doi.org/10.1016/j.jaci.2016.04.032]
Lankes, W., Griesmacher, A., Grunwald, J., Schwartz-Albiez, R., Keller, R. A heparin-binding protein involved in inhibition of smooth-muscle cell proliferation. Biochem. J. 251: 831-842, 1988. [PubMed: 3046603] [Full Text: https://doi.org/10.1042/bj2510831]
Lankes, W. T., Furthmayr, H. Moesin: a member of the protein 4.1-talin-ezrin family of proteins. Proc. Nat. Acad. Sci. 88: 8297-8301, 1991. [PubMed: 1924289] [Full Text: https://doi.org/10.1073/pnas.88.19.8297]
Neisch, A. L., Formstecher, E., Fehon, R. G. Conundrum, an ARHGAP18 orthologue, regulates RhoA and proliferation through interactions with moesin. Molec. Biol. Cell 24: 1420-1433, 2013. [PubMed: 23468526] [Full Text: https://doi.org/10.1091/mbc.E12-11-0800]
Shcherbina, A., Bretscher, A., Rosen, F. S., Kenney, D. M., Remold-O'Donnell, E. The cytoskeletal linker protein moesin: decreased levels in Wiskott-Aldrich syndrome platelets and identification of a cleavage pathway in normal platelets. Brit. J. Haemat. 106: 216-223, 1999. Note: Erratum: Brit. J. Haemat. 107: 218 only, 1999. [PubMed: 10444190] [Full Text: https://doi.org/10.1046/j.1365-2141.1999.01508.x]
Speck, O., Hughes, S. C., Noren, N. K., Kulikauskas, R. M., Fehon, R. G. Moesin functions antagonistically to the Rho pathway to maintain epithelial integrity. Nature 421: 83-87, 2003. [PubMed: 12511959] [Full Text: https://doi.org/10.1038/nature01295]
Vitorino, P., Yeung, S., Crow, A., Bakke, J., Smyczek, T., West, K., McNamara, E., Eastham-Anderson, J., Gould, S., Harris, S. F., Ndubaku, C., Ye, W. MAP4K4 regulates integrin-FERM binding to control endothelial cell motility. Nature 519: 425-430, 2015. [PubMed: 25799996] [Full Text: https://doi.org/10.1038/nature14323]
Wilgenbus, K. K., Hsieh, C.-L., Lankes, W. T., Milatovich, A., Francke, U., Furthmayr, H. Structure and localization on the X chromosome of the gene coding for the human filopodial protein moesin (MSN). Genomics 19: 326-333, 1994. [PubMed: 8188263] [Full Text: https://doi.org/10.1006/geno.1994.1065]