Alternative titles; symbols
HGNC Approved Gene Symbol: MAG
SNOMEDCT: 1187470001;
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,292,161-35,313,807 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Spastic paraplegia 75, autosomal recessive | 616680 | Autosomal recessive | 3 |
Myelin-associated glycoprotein (MAG) is a cell adhesion molecule involved in myelin maintenance and glia-axon interaction (summary by Lossos et al., 2015). MAG is a sialic acid-binding SIGLEC (see 604200) protein and is a functional ligand for the NOGO receptor (NGR, or RTN4R; 605566) (Liu et al., 2002).
Spagnol et al. (1989) found that a MAG cDNA clone isolated from a human brain cDNA library encodes a 626-amino acid peptide with a calculated molecular mass of 69.1 kD.
Using a fragment of mouse Mag cDNA to screen a human brain lambda gt11 library, Sato et al. (1989) cloned MAG. The deduced 626-amino acid protein has an N-terminal signal sequence and a C-terminal transmembrane domain. The putative extracellular domain contains 9 potential N-glycosylation sites and a fibronectin (135600) recognition sequence (arg-gly-asp), and the putative intracellular domain has a tyrosine phosphorylation site. Sato et al. (1989) also identified a splice variant that includes exon 12. They noted that in mouse brain, the Mag mRNA lacking exon 12 is expressed mainly during active myelination, while the form containing exon 12 is expressed mainly in adult. The Mag variant containing exon 12 encodes a smaller protein that lacks the cytoplasmic phosphorylation site. Northern blot analysis of mouse, bovine, and human RNA detected a 2,5-kb MAG transcript.
Using quantitative RT-PCR, Lauriat et al. (2008) found that expression of the S-MAG and L-MAG variants, which contain and lack exon 12, respectively, was very low in fetal human prefrontal cortex. However, expression of both variants showed a gradual and linear increase with age into adulthood (up to 46 years of age). Expression of S-MAG and L-MAG also showed a gradual increase with age in hippocampus, although expression appeared to level off in adulthood.
MAG, which is expressed solely by oligodendrocytes and Schwann cells, is an adhesion molecule in the periaxonal layer of the mature noncompact myelin membrane facing the axon (summary by Lossos et al., 2015).
Axonal regeneration in the adult central nervous system is limited by 2 proteins in myelin, NOGO (604475) and MAG. The receptor for NOGO (NgR) had been identified as an axonal glycosylphosphatidylinositol (GPI)-anchored protein, whereas the MAG receptor had remained elusive. Liu et al. (2002) demonstrated that MAG binds directly, with high affinity, to NgR. Cleavage of GPI-linked proteins from axons protects growth cones from MAG-induced collapse, and dominant-negative NgR eliminates MAG inhibition of neurite outgrowth. MAG-resistant embryonic neurons were rendered MAG-sensitive by expression of NgR. MAG and the extracellular domain of NOGO (NOGO-66) activate NgR independently and serve as redundant NgR ligands that may limit axonal regeneration after CNS injury.
Domeniconi et al. (2002) showed that MAG inhibits axonal regeneration through interaction with NgR. They demonstrated that MAG binds specifically to an NgR-expressing cell line in a GPI-dependent and sialic acid-independent manner. Consistent with a direct interaction of MAG and NgR, Domeniconi et al. (2002) observed that MAG precipitates NgR from NgR-expressing cells, dorsal root ganglia, and cerebellar neurons. Experiments blocking NgR from interacting with MAG prevented inhibition of neurite outgrowth by MAG. Using NgR-expressing cell cultures, the authors found that MAG and NOGO-66 compete directly for binding to NgR.
Wong et al. (2002) reported that p75(NTR) (NGFR; 162010) is a coreceptor for the NOGO receptor for MAG signaling. In cultured human embryonic kidney (HEK) cells expressing the NOGO receptor, p75(NTR) was required for MAG-induced intracellular calcium elevation. Coimmunoprecipitation showed an association of the NOGO receptor with p75(NTR) that could be disrupted by an antibody against p75(NTR), and extensive coexpression was observed in the developing rat nervous system. Furthermore, a p75(NTR) antibody abolished MAG-induced repulsive turning of Xenopus axonal growth cones and calcium elevation, both in neurons and in the NOGO receptor/p75(NTR)-expressing HEK cells.
Using expression cloning, Atwal et al. (2008) found that paired immunoglobulin-like receptor B (PIRB; 604820), which has been implicated in nervous system plasticity, is a high-affinity receptor for NOGO, MAG, and OMGP (164345). Interfering with PIRB activity, either with antibodies or genetically, partially rescued neurite inhibition by NOGO66, MAG, OMGP, and myelin in cultured neurons. Blocking both PIRB and NGR activities led to near-complete release from myelin inhibition. Atwal et al. (2008) concluded that their results implicated PIRB in mediating regeneration block, identified PIRB as a potential target for axon regeneration therapies, and provided an explanation for the similar enhancements of visual system plasticity in PIRB and NGR knockout mice.
Quaking (QKI; 609590) proteins bind RNA and regulate splicing, intracellular localization, stability, and translation. Using quantitative RT-PCR, Lauriat et al. (2008) found no L-Mag and substantially reduced S-Mag in brains of qk(e5) mice, which show decreased expression of all 3 Qki isoforms. Lauriat et al. (2008) suggested that QKI may be required for MAG expression.
Using a Schwann cell-specific element (SSE) in the promoter region of rat Mag as bait, Hoshikawa et al. (2008) identified an interaction between Mag and Rnf10 (615998) in rat Schwann cells. EMSA and chromatin immunoprecipitation assays confirmed the interaction of Rnf10 with the SSE of Mag. Overexpression of Rnf10 in Schwann cells increased Mag promoter activity, and activation of the Mag promoter required the RING finger domain of Rnf10. Knockdown of Rnf10 in cultured Schwann cells decreased Mag expression, increased Schwann cell proliferation, and reduced myelination of neurons in Schwann cell-neuron cocultures. Rnf10 showed lower activation of the Mag reporter when expressed in rat osteosarcoma cells, suggesting that Rnf10 requires a Schwann cell-specific partner for maximal Mag activation.
Using a cDNA encoding the amino-terminal half of rat MAG, Barton et al. (1987) assigned the MAG locus to human chromosome 19 in studies of somatic cell hybrids. The homologous locus was found to be located on mouse chromosome 7.
By study of sorted chromosomes, Spagnol et al. (1989) assigned the MAG gene to chromosome 19 and regionalized the assignment to 19q12-q13.2 by restriction enzyme analysis of somatic cell hybrid DNA containing only that region.
By fluorescence in situ hybridization, Trask et al. (1993) assigned the MAG gene to 19q13.1.
In 2 affected sisters from a consanguineous family (family 1226) with autosomal recessive spastic paraplegia-75 (SPG75; 616680), Novarino et al. (2014) identified a homozygous missense mutation in the MAG gene (C430G; 159460.0001). Functional studies of the variant were not reported.
In 3 sibs, born of consanguineous Palestinian parents, with SPG75, Lossos et al. (2015) identified a homozygous missense mutation in the MAG gene (S133R; 159460.0002). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. In vitro functional expression studies showed that the mutation affected posttranslational modification and glycosylation of MAG, and that the mutant protein was retained in the endoplasmic reticulum and was subject to proteasomal degradation. The clinical features were consistent with abnormalities of both the central and peripheral nervous system.
In 2 affected sisters from a consanguineous family (family 1226) with autosomal recessive spastic paraplegia-75 (SPG75; 616680), Novarino et al. (2014) identified homozygosity for a c.1288T-G transversion in the MAG gene, resulting in a cys430-to-gly (C430G) substitution. Both sisters presented with spastic gait at about 3 years of age; in late childhood, they had difficulty walking with support. Both had cerebellar signs, nystagmus, and clonus. Brain MRI was normal, and intellectual disability was reported as 'poor school achievement.'
In 3 sibs, born of consanguineous Palestinian parents, with autosomal recessive spastic paraplegia-75 (SPG75; 616680), Lossos et al. (2015) identified a homozygous c.399C-G transversion (chr19.35,786,868, GRCh37) in the MAG gene, resulting in a ser133-to-arg (S133R) substitution at a conserved residue in an Ig-like domain. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. It was not found in the Exome Variant Server, 1000 Genomes Project, or ExAC databases, or in 192 ethnically-matched chromosomes. Expression of the mutation in COS-7 cells resulted in only a single band detected by Western blot analysis, whereas wildtype resulted in multiple bands; these findings suggested that the mutation affected posttranslational modification and glycosylation. Immunolabeling of transfected COS-7, HEK293, and neuronal cells showed that the mutant protein was not expressed at the cell surface, but was retained in the endoplasmic reticulum, consistent with abnormal folding and processing. The mutant protein was subject to proteasomal degradation. Sural nerve biopsy of 1 patient showed complete absence of MAG immunostaining at the myelin sheath.
Atwal, J. K., Pinkston-Gosse, J., Syken, J., Stawicki, S., Wu, J., Shatz, C., Tessier-Lavigne, M. PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322: 967-970, 2008. [PubMed: 18988857] [Full Text: https://doi.org/10.1126/science.1161151]
Barton, D. E., Arquint, M., Roder, J., Dunn, R., Francke, U. The myelin-associated glycoprotein gene: mapping to human chromosome 19 and mouse chromosome 7 and expression in quivering mice. Genomics 1: 107-112, 1987. [PubMed: 2447011] [Full Text: https://doi.org/10.1016/0888-7543(87)90002-4]
Domeniconi, M., Cao, Z., Spencer, T., Sivasankaran, R., Wang, K. C., Nikulina, E., Kimura, N., Cai, H., Deng, K., Gao, Y., He, Z., Filbin, M. T. Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35: 283-290, 2002. [PubMed: 12160746] [Full Text: https://doi.org/10.1016/s0896-6273(02)00770-5]
Hoshikawa, S., Ogata, T., Fujiwara, S., Nakamura, K., Tanaka, S. A novel function of RING finger protein 10 in transcriptional regulation of the myelin-associated glycoprotein gene and myelin formation in Schwann cells. PLoS One 3: e3464, 2008. Note: Electronic Article. [PubMed: 18941509] [Full Text: https://doi.org/10.1371/journal.pone.0003464]
Lauriat, T. L., Shiue, L., Haroutunian, V., Verbitsky, M., Ares, M., Jr., Ospina, L., McInnes, L. A. Developmental expression profile of quaking, a candidate gene for schizophrenia, and its target genes in human prefrontal cortex and hippocampus shows regional specificity. J. Neurosci. Res. 86: 785-796, 2008. [PubMed: 17918747] [Full Text: https://doi.org/10.1002/jnr.21534]
Liu, B. P., Fournier, A., GrandPre, T., Strittmatter, S. M. Myelin-associated glycoprotein as a functional ligand for the Nogo-66 receptor. Science 297: 1190-1193, 2002. [PubMed: 12089450] [Full Text: https://doi.org/10.1126/science.1073031]
Lossos, A., Elazar, N., Lerer, I., Schueler-Furman, O., Fellig, Y., Glick, B., Zimmerman, B.-E., Azulay, H., Dotan, S., Goldberg, S., Gomori, J. M., Ponger, P., and 10 others. Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. Brain 138: 2521-2536, 2015. [PubMed: 26179919] [Full Text: https://doi.org/10.1093/brain/awv204]
Novarino, G., Fenstermaker, A. G., Zaki, M. S., Hofree, M., Silhavy, J. L., Heiberg, A. D., Abdellateef, M., Rosti, B., Scott, E., Mansour, L., Masri, A., Kayserili, H., and 41 others. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343: 506-511, 2014. [PubMed: 24482476] [Full Text: https://doi.org/10.1126/science.1247363]
Sato, S., Fujita, N., Kurihara, T., Kuwano, R., Sakimura, K., Takahashi, Y., Miyatake, T. cDNA cloning and amino acid sequence for human myelin-associated glycoprotein. Biochem. Biophys. Res. Commun. 163: 1473-1480, 1989. [PubMed: 2476987] [Full Text: https://doi.org/10.1016/0006-291x(89)91145-5]
Spagnol, G., Williams, M., Srinivasan, J., Golier, J., Bauer, D., Lebo, R. V., Latov, N. Molecular cloning of human myelin-associated glycoprotein. J. Neurosci. Res. 24: 137-142, 1989. [PubMed: 2479762] [Full Text: https://doi.org/10.1002/jnr.490240203]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Wong, S. T., Henley, J. R., Kanning, K. C., Huang, K., Bothwell, M., Poo, M. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nature Neurosci. 5: 1302-1308, 2002. [PubMed: 12426574] [Full Text: https://doi.org/10.1038/nn975]