Alternative titles; symbols
HGNC Approved Gene Symbol: MAN2A1
Cytogenetic location: 5q21.3 Genomic coordinates (GRCh38): 5:109,689,927-109,869,625 (from NCBI)
Alpha-mannosidase II (EC 3.2.1.114) is a Golgi enzyme that catalyzes the final hydrolytic step in the asparagine-linked oligosaccharide (N-glycan) maturation pathway, acting as the committed step in the conversion of high mannose to complex type structures. Misago et al. (1995) noted that lysosomal alpha-mannosidases (609458) are soluble and involved in degradation of N-glycans. Endoplasmic reticulum (ER) and Golgi alpha-mannosidases are involved in processing of newly synthesized N-glycans. Cytoplasmic alpha-mannosidases (154580) may be involved in degradation of dolichol intermediates that are not needed for protein glycosylation or oligosaccharides derived from glycoprotein turnover in the ER. Alpha-mannosidase II is a type II membrane protein residing mainly in the medial Golgi cisternae.
Moremen and Robbins (1991) isolated cDNAs encoding the murine enzyme and also isolated partial human alpha-mannosidase II cDNA clones.
Misago et al. (1995) cloned the human MANA2 gene and reported genomic and cDNA cloning of a MANA2 isozyme designated alpha-mannosidase IIX (MANA2X, or MAN2A2; 600988). Whereas the MANA2 gene predicted a protein of 1,144 amino acid residues, the MANA2X gene was predicted to encode a truncated polypeptide with 796 amino acid residues. Comparison of the sequence of PCR products with the MANA2X genomic sequence revealed that alternative splicing of the transcript can result in an additional transcript encoding a 1,139-amino acid polypeptide.
Moremen and Robbins (1991) localized the MANA2 gene to human chromosome 5 by study of human/rodent somatic cell hybrids. By isotopic in situ hybridization, Misago et al. (1995) mapped the MANA2 gene to 5q21-q22 and the MANA2X gene to 15q25.
Alpha-mannosidase II catalyzes the first committed step in the biosynthesis of complex N-glycans. Genetic deficiency of this enzyme should abolish complex N-glycan production as reportedly does inhibition of the enzyme by swainsonine. Chui et al. (1997) found that mice in whom the alpha-mannosidase II gene had been disrupted developed a dyserythropoietic anemia concurrent with loss of erythrocyte complex N-glycans. Unexpectedly, nonerythroid cell types continued to produce complex N-glycans by an alternate pathway comprising a distinct alpha-mannosidase. These studies revealed cell type-specific variations in N-linked oligosaccharide biosynthesis and an essential role for alpha-mannosidase II in the formation of erythroid complex N-glycans. Alpha-mannosidase II deficiency elicited a phenotype in mice that corresponds to human congenital dyserythropoietic anemia type II (224100).
Protein glycosylation in the Golgi apparatus produces structural variation at the cell surface and contributes to immune self-recognition. Altered protein glycosylation and antibodies that recognize endogenous glycans have been associated with various autoimmune syndromes, with the possibility that such abnormalities may reflect genetic defects in glycan formation. Studying mice with a null allele for alpha-mannosidase II, Chui et al. (2001) showed that mutation in this gene, which regulates the hybrid to complex branching pattern of extracellular asparagine (N)-linked oligosaccharide chains (N-glycans), results in a systemic autoimmune disease similar to human systemic lupus erythematosus (152700). The findings demonstrated a genetic cause of autoimmune disease provoked by a defect in the pathway of protein N-glycosylation.
Akama et al. (2006) produced Man2a1 and Man2a2 double-knockout mice. Some double-null mice died between embryonic days 15.5 and 18.5, but most survived until shortly after birth and died of respiratory failure. Recombinant mouse Man2a1 and Man2a2 showed identical substrate specificities toward N-glycan substrates, suggesting that either can biochemically compensate for deficiency of the other in vivo.
Akama, T. O., Nakagawa, H., Wong, N. K., Sutton-Smith, M., Dell, A., Morris, H. R., Nakayama, J., Nishimura, S.-I., Pai, A., Moremen, K. W., Marth, J. D., Fukuda, M. N. Essential and mutually compensatory roles of alpha-mannosidase II and alpha-mannosidase IIx in N-glycan processing in vivo in mice. Proc. Nat. Acad. Sci. 103: 8983-8988, 2006. [PubMed: 16754854] [Full Text: https://doi.org/10.1073/pnas.0603248103]
Chui, D., Oh-Eda, M., Liao, Y.-F., Panneerselvam, K., Lai, A., Marek, K. W., Freeze, H. H., Moremen, K. W., Fukuda, M. N., Marth, J. D. Alpha-mannosidase-II deficiency results in dyserythropoiesis and unveils an alternate pathway in oligosaccharide biosynthesis. Cell 90: 157-167, 1997. [PubMed: 9230311] [Full Text: https://doi.org/10.1016/s0092-8674(00)80322-0]
Chui, D., Sellakumar, G., Green, R. S., Sutton-Smith, M., McQuistan, T., Marek, K. W., Morris, H. R., Dell, A., Marth, J. D. Genetic remodeling of protein glycosylation in vivo induces autoimmune disease. Proc. Nat. Acad. Sci. 98: 1142-1147, 2001. [PubMed: 11158608] [Full Text: https://doi.org/10.1073/pnas.98.3.1142]
Misago, M., Liao, Y.-F., Kudo, S., Eto, S., Mattei, M.-G., Moremen, K. W., Fukuda, M. N. Molecular cloning and expression of cDNAs encoding human alpha-mannosidase II and a previously unrecognized alpha-mannosidase II(X) isozyme. Proc. Nat. Acad. Sci. 92: 11766-11770, 1995. [PubMed: 8524845] [Full Text: https://doi.org/10.1073/pnas.92.25.11766]
Moremen, K. W., Robbins, P. W. Isolation, characterization, and expression of cDNAs encoding murine alpha-mannosidase II, a Golgi enzyme that controls conversion of high mannose to complex N-glycans. J. Cell Biol. 115: 1521-1534, 1991. [PubMed: 1757461] [Full Text: https://doi.org/10.1083/jcb.115.6.1521]