Myelin oligodendrocyte glycoprotein

Myelin oligodendrocyte glycoprotein

Crystal structure of rat myelin oligodendrocyte glycoprotein.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols MOG ; BTN6; BTNL11; MOGIG2; NRCLP7
External IDs OMIM: 159465 MGI: 97435 HomoloGene: 111009 GeneCards: MOG Gene
Orthologs
Species Human Mouse
Entrez 4340 17441
Ensembl ENSG00000137345 ENSMUSG00000076439
UniProt Q16653 Q61885
RefSeq (mRNA) NM_001008228 NM_010814
RefSeq (protein) NP_001008229 NP_034944
Location (UCSC) Chr 6:
29.66 – 29.67 Mb		 Chr 17:
37.01 – 37.02 Mb
PubMed search

Myelin Oligodendrocyte Glycoprotein (MOG) is a glycoprotein believed to be important in the myelination of nerves in the central nervous system (CNS). In humans this protein is encoded by the MOG gene.[2][3][4] It is speculated to serve as a necessary “adhesion molecule” to provide structural integrity to the myelin sheath and is known to develop late on the oligodendrocyte.[5]

Molecular function

While the primary molecular function of MOG is not yet known, its likely role with the myelin sheath is either in sheath “completion and/or maintenance”.[4] More specifically, MOG is speculated to be “necessary” as an "adhesion molecule" on the myelin sheath of the CNS to provide the structural integrity of the myelin sheath.[5]”

MOG’s cDNA coding region in humans have been shown to be “highly homologous”[6] to rats, mice, and bovine, and hence highly conserved. This suggests “an important biological role for this protein”.[4]

Physiology

The gene for MOG, found on chromosome 6p21.3-p22,[7] was first sequenced in 1995. It is a transmembrane protein expressed on the surface of oligodendrocyte cell and on the outermost surface of myelin sheaths. “MOG is a quantitatively minor type I transmembrane protein,[8] and is found exclusively in the CNS. “A single Ig-domain is exposed to the extracellular space"[8] and consequently allows autoantibodies easy access. and therefore easily accessible for autoantibodies.[4][8] The MOG “primary nuclear transcript … is 15,561 nucleotides in length"[4] and, for humans, it has eight exons which are “separated by seven introns".[4] The introns "contain numerous reptitive [sic] DNA[4]" sequences, among which is "14 Alu sequences within 3 introns",[4] and have a range varying from 242 to 6484 bp.

Structure

Because of alternatively spliced from human mRNA of MOG gene forming at least nine isoforms.[9]

The crystal structure of myelin oligodendrocyte glycoprotein was determined by x-ray diffraction at a resolution of 1.45 Angstrom, using protein from the Norway rat. This protein is 139 residues long, and is a member of the immunoglobulin superfamily.[10] The dssp secondary structure of the protein is 6% helical and 43% beta sheet: there are three short helical segments and ten beta strands.[11] The beta strands are within two antiparallel beta sheets that form an immunoglobulin-like beta-sandwich fold.[12] Several features of the protein structure suggest MOG has a role as an "adhesin in the completion and/or compaction of the myelin sheath." There is a "significant strip" of electronegative charge beginning near the N-terminus and running about half the length of the molecule. Also, MOG was shown to dimerize in solution, and the shape complementarity index is high at the dimer interface, suggesting a "biologically relevant MOG dimer."[13]

Synthesis

Developmentally, MOG is formed "very late on oligodendrocytes and the myelin sheath".[5]

Role in disease

Non-inflammatory demyelinating diseases

Interest in MOG has centered on its role in demyelinating diseases. Some of them are not-inflammatory, such as adrenoleukodystrophy, vanishing white matter disease, and Rubella induced mental retardation.[14]

Anti-MOG associated inflammatory demyelinating diseases

MOG has received much of its laboratory attention in studies dealing with MS. Several studies have shown a role for antibodies against MOG in the pathogenesis of MS.,[5][15] though most of them were written before the discovery of NMO-IgG and the NMO spectrum of diseases.

Anti-MOG status is different depending whether it is measured by ELISA or by microarray (CBA). The proper way to identify it is by microarray, reacting patient serum with living cells, and detecting the binding IgG via a fluorescent-labeled secondary antibody.[16]

In animal models

Animal models of MS, EAE, have shown that “MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis",[5] but basically explains the part involved in the optic neuritis[17] These models with anti-MOG antibodies have been investigated extensively and are considered the only antibodies with demyelinating capacity[5] but again, EAE pathology is closer to NMO and ADEM than to the confluent demyelination observed in MS.

Anti-MOG mediated demyelination was shown to behave similar to NMO in animal models,[17] and currently it is considered even a biomarker against the MS diagnosis[18][19]

In seronegative neuromyelitis optica

Anti-MOG autoimmunity has been found to be involved in the seronegative NMO[20][21] and also in optic neuritis and some fulminant forms of ADEM[22] MOG antibodies in NMOSD are variable depending on the seropositivity status[23]

In other conditions

The presence of anti-MOG autoantibodies has been associated with the following conditions[24]

In pediatric demyelination

The anti-mog spectrum in children is equally variated: Out of a sample of 41 children with MOG-antibodies 29 had clinical NMOSD (17 relapsing), 8 had ADEM (4 relapsing with ADEM-ON), 3 had a single clinical event CIS, and 1 had a relapsing tumefactive disorder. Longitudinal myelitis was evident on MRI in 76[percent]. It has also been noted that percentage of children with anti-mog antibodies respect a demyelinating sample is higher than for adults[28]

References

  1. ↑ PDB: 1PKO​; Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, Jacob U (August 2003). "Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein". Proc. Natl. Acad. Sci. U.S.A. 100 (16): 9446–51. doi:10.1073/pnas.1133443100. PMC 170938. PMID 12874380.
  2. ↑ Pham-Dinh D, Della Gaspera B, Kerlero de Rosbo N, Dautigny A (September 1995). "Structure of the human myelin/oligodendrocyte glycoprotein gene and multiple alternative spliced isoforms". Genomics 29 (2): 345–52. doi:10.1006/geno.1995.9995. PMID 8666381.
  3. ↑ Pham-Dinh D, Jones EP, Pitiot G, Della Gaspera B, Daubas P, Mallet J, Le Paslier D, Fischer Lindahl K, Dautigny A (1995). "Physical mapping of the human and mouse MOG gene at the distal end of the MHC class Ib region". Immunogenetics 42 (5): 386–91. doi:10.1007/bf00179400. PMID 7590972.
  4. 1 2 3 4 5 6 7 8 Roth MP, Malfroy L, Offer C, Sevin J, Enault G, Borot N, Pontarotti P, Coppin H (July 1995). "The human myelin oligodendrocyte glycoprotein (MOG) gene: complete nucleotide sequence and structural characterization". Genomics 28 (2): 241–50. doi:10.1006/geno.1995.1137. PMID 8530032.
  5. 1 2 3 4 5 6 Berger, T., Innsbruck Medical University Dept. of Neurology interviewed by S. Gillooly, Nov. 24, 2008.
  6. ↑ Pham-Dinh D, Allinquant B, Ruberg M, Della Gaspera B, Nussbaum JL, Dautigny A (December 1994). "Characterization and expression of the cDNA coding for the human myelin/oligodendrocyte glycoprotein". J. Neurochem. 63 (6): 2353–6. doi:10.1046/j.1471-4159.1994.63062353.x. PMID 7964757.
  7. ↑ Pham-Dinh D, Mattei MG, Nussbaum JL, Roussel G, Pontarotti P, Roeckel N, Mather IH, Artzt K, Lindahl KF, Dautigny A (September 1993). "Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex". Proc. Natl. Acad. Sci. U.S.A. 90 (17): 7990–4. doi:10.1073/pnas.90.17.7990. PMC 47273. PMID 8367453.
  8. 1 2 3 Berger T, Reindl M (August 2007). "Multiple sclerosis: disease biomarkers as indicated by pathophysiology". J. Neurol. Sci. 259 (1-2): 21–6. doi:10.1016/j.jns.2006.05.070. PMID 17367811.
  9. ↑ Boyle LH, Traherne JA, Plotnek G, Ward R, Trowsdale J (September 2007). "Splice variation in the cytoplasmic domains of myelin oligodendrocyte glycoprotein affects its cellular localisation and transport". J. Neurochem. 102 (6): 1853–62. doi:10.1111/j.1471-4159.2007.04687.x. PMC 2156149. PMID 17573820.
  10. ↑ Breithaupt C, Schubart A, Zander H, et al. (August 2003). "Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein". Proc. Natl. Acad. Sci. U.S.A. 100 (16): 9446–51. doi:10.1073/pnas.1133443100. PMC 170938. PMID 2874380.
  11. ↑ Kabsch W, Sander C (December 1983). "Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features". Biopolymers 22 (12): 2577–637. doi:10.1002/bip.360221211. PMID 6667333.
  12. ↑ Murzin AG, Brenner SE, Hubbard T, Chothia C (April 1995). "SCOP: a structural classification of proteins database for the investigation of sequences and structures". J. Mol. Biol. 247 (4): 536–40. doi:10.1016/S0022-2836(05)80134-2. PMID 7723011.
  13. ↑ Clements CS, Reid HH, Beddoe T, et al. (September 2003). "The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis". Proc. Natl. Acad. Sci. U.S.A. 100 (19): 11059–64. doi:10.1073/pnas.1833158100. PMC 196926. PMID 12960396.
  14. ↑ Cong H, Jiang Y, Tien P (November 2011). "Identification of the myelin oligodendrocyte glycoprotein as a cellular receptor for rubella virus". J. Virol. 85 (21): 11038–47. doi:10.1128/JVI.05398-11. PMC 3194935. PMID 21880773.
  15. ↑ Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M (July 2003). "Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event". N. Engl. J. Med. 349 (2): 139–45. doi:10.1056/NEJMoa022328. PMID 12853586.
  16. ↑ Ichiro Nakashima, Anti-myelin oligodendrocyte glycoprotein antibody in demyelinating diseases
  17. 1 2 Kezuka et al. Relationship Between NMO-Antibody and Anti–MOG Antibody in Optic Neuritis. Journal of Neuro-Ophthalmology: June 2012 - Volume 32 - Issue 2 - p 107–110 doi: 10.1097/WNO.0b013e31823c9b6c
  18. ↑ Immy A Ketelslegers, Daniëlle E Van Pelt, Susanne Bryde, Rinze F Neuteboom, Coriene E Catsman-Berrevoets, Dörte Hamann, and Rogier Q Hintzen Anti-MOG antibodies plead against MS diagnosis in an Acquired Demyelinating Syndromes cohort Mult Scler 1352458514566666, first published on February 6, 2015 doi:10.1177/1352458514566666
  19. ↑ Joanna Kitley, et al. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology September 18, 2012 vol. 79 no. 12 1273-1277. doi: 10.1212/WNL.0b013e31826aac4e
  20. ↑ Anne-Katrin Pröbstel et al. Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. Journal of Neuroinflammation Volume 12, 2015, 12:46 doi:10.1186/s12974-015-0256-1
  21. ↑ CYNTHIA MCKELVEY, Press Report, What’s the Role of Myelin Oligodendrocyte Glycoprotein in NMO?
  22. 1 2 Franziska Di Pauli et al. Fulminant demyelinating encephalomyelitis, Neurol Neuroimmunol Neuroinflamm December 2015 vol. 2 no. 6 e175, doi: http://dx.doi.org/10.1212/NXI.0000000000000175
  23. ↑ T. Berger, M. Reindl, Antibody biomarkers in CNS demyelinating diseases – a long and winding road, DOI: 10.1111/ene.12759, European Journal of Neurology, Volume 22, Issue 8, pages 1162–1168, August 2015
  24. 1 2 3 Reindl M, Di Pauli F, Rostásy K, Berger T. The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol. 2013 Aug;9(8):455-61. doi: 10.1038/nrneurol.2013.118. Epub 2013 Jun 25. PMID 23797245
  25. ↑ Melania Spadaro et al. Histopathology and clinical course of MOG-antibody-associated encephalomyelitis. Annals of Clinical and Translational Neurology Volume 2, Issue 3, pages 295–301, March 2015. DOI: 10.1002/acn3.164
  26. ↑ M. Baumann, E.M. Hennes, K. Schanda, M. Karenfort, B. Bajer-Kornek, K. Diepold, B. Fiedler, I. Marquardt, J. Strautmanis, S. Vieker, M. Reindl, K. Rostásy. Clinical characteristics and neuroradiological findings in children with multiphasic demyelinating encephalomyelitis and MOG antibodies. European Journal of Paediatric Neurology, Volume 19, Supplement 1, May 2015, Pages S21, Abstracts of the 11th EPNS Congress. 22 May 2015. doi:10.1016/S1090-3798(15)30066-0
  27. ↑ Konstantina Chalmoukou et al. Recurrent Optic Neuritis (rON) is characterised by Anti-MOG Antibodies: A follow-up study. Neurology April 6, 2015 vol. 84 no. 14 Supplement P5.274
  28. ↑ Silvia Tenembaum et al. Spectrum of MOG Autoantibody-Associated Inflammatory Diseases in Pediatric Patients, Neurology April 6, 2015 vol. 84 no. 14 Supplement I4-3A

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