Alternative titles; symbols
HGNC Approved Gene Symbol: MAN2C1
Cytogenetic location: 15q24.2 Genomic coordinates (GRCh38) : 15:75,355,792-75,368,607 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.2 | Congenital disorder of deglycosylation 2 | 619775 | Autosomal recessive | 3 |
MAN2C1 hydrolyzes mannose residues from the cytosolic free oligosaccharides (fOS) derived from N-glycans during the degradation of misfolded N-glycoproteins (Wang and Suzuki, 2013; Paciotti et al., 2014).
Maia et al. (2022) stated that the MAN2C1 gene encodes a 1,040-amino acid protein.
Maia et al. (2022) stated that the MAN2C1 gene contains 26 exons.
Cytoplasmic alpha-mannosidase (MANA) was assigned to chromosome 15q11-qter by study of an X;15 translocation in man-mouse hybrids (Champion et al., 1978). Neri et al. (1983) described a boy with a ring chromosome 15 derived from a t(15q;15q) chromosome of the mother. The ring chromosome was duplicated for a portion of the long arms near the centromere, probably cen-q13. Dosage effects suggested that the alpha-mannosidase gene is located in this segment. Since a shortest region of overlap (SRO) of 15q11-qter had been estimated by Ferguson-Smith and Westerveld (1979), the new information places the MAN2C1 gene in the 15q11-q13 segment.
Maia et al. (2022) studied fOS processing in MAN2C1 knockout HAP1 cells. Larger fOS species predominated in the knockout cells compared to wildtype cells; after mannose pulse-chase metabolic labeling, the knockout cells showed a complete lack of fOS processing.
Using knockdown analysis in HeLa cells, Wang and Suzuki (2013) showed that downregulation of MAN2C1 impaired processing of cytosolic fOS, leading to increased accumulation of fOS in the cytosol and apoptosis of the cells. The apoptosis was mitochondria-dependent, as the downregulation stimulated release of mitochondrial cytochrome c to the cytosol and thereby induced the caspase-9-dependent apoptotic signaling pathway. CHOP (126337) was involved in the apoptosis, as the MAN2C1 downregulation also caused enhanced CHOP expression. The downregulation did not trigger ER stress, indicating that ER stress was not involved in the apoptosis. The apoptosis was not related to the enzymatic function of MAN2C1. Further analysis demonstrated that the apoptosis was not specific to HeLa cells, as the same results were seen in 2 other types of human cells.
Maia et al. (2022) identified biallelic mutations in the MAN2C1 gene in 6 patients from 4 families, including 2 sib pairs, with CDDG2. Five different mutations were identified, including 3 missense, 1 splicing, and 1 deletion. The mutations were identified by whole-exome sequencing. Whereas decreased mannosidase activity was demonstrated for MAN2C1 with 2 of the missense mutations (R768Q, 154580.0002; G203R, 154580.0005), the activity was normal with the C871S mutation (154580.0003). Maia et al. (2022) hypothesized that the C871S mutation might lead to abnormal intersubunit interactions or tetramer formation.
Paciotti et al. (2014) found that Man2c1 -/- mice were fertile and showed no difference from wildtype mice in growth, weight, or life span up to 12 months. Oligosaccharide analysis showed accumulation of higher oligomannosides species, particularly Man8-9GlcNAc1, in Man2c1 -/- tissues. Accumulation of Man8-9GlcNAc1 species was tissue-specific, being more abundant in liver and spleen than in brain and heart. Smaller mannose-containing oligosaccharide species Man1GlcNAc1 to Man7GlcNAc1 were also present, indicating that another cellular alpha-mannosidase was able to trim Man2c1 substrates. Histologic analysis revealed major histopathologic changes in several organs, with most impressive alteration in liver, small intestine, kidney, and CNS.
In 3 patients, including 2 Portuguese sibs (individuals 1 and 2, family 1) and an American man (individual 6, family 5), with congenital disorder of deglycosylation-2 (CDDG2; 619775), Maia et al. (2022) identified compound heterozygous mutations in the MAN2C1 gene. All 3 patients had a c.601-2A-G transition (c.601-2A-G, NM_006715.3) in intron 5, resulting in a frameshift and premature termination (Gly201ProfsTer10), on one allele. On the other allele, the sibs had a c.2303G-A transition in exon 20, resulting in an arg768-to-gln (R768Q; 154580.0002) substitution, and the American patient had a c.2612G-C transversion, resulting in a cys871-to-ser (C871S; 154580.0003). The mutations, which were identified by whole-exome sequencing, were found in the carrier state in the parents in both families. The c.601-2A-G variant was present in the gnomAD database at an allele frequency of 0.11% in only heterozygous state; the R768Q was present at an allele frequency of 0.33% and was found in 5 homozygotes; and the C871S variant was present at an allele frequency of 0.049% in only heterozygous state. Complementation of MAN2C1 knockout HAP1 cells with MAN2C1 with the R768Q mutation demonstrated a free oligosaccharide processing defect.
For discussion of the c.2303G-A transition (c.2303G-A, NM_006715.3) in exon 20 of the MAN2C1 gene, resulting in an arg768-to-gln (R768Q) substitution, that was identified in compound heterozygous state in 2 sibs with congenital disorder of deglycosylation-2 (CDDG2; 619775), by Maia et al. (2022), see 154580.0001.
For discussion of the c.2612G-C transversion (c.2612G-C, NM_006715.3) in exon 22 of the MAN2C1 gene, resulting in a cys871-to-ser (C871S) substitution, that was identified in compound heterozygous state in 2 sibs with congenital disorder of deglycosylation-2 (CDDG2; 619775), by Maia et al. (2022), see 154580.0001.
In 2 French sibs (individuals 3 and 4, family 2) with congenital disorder of deglycosylation-2 (CDDG2; 619775), Maia et al. (2022) identified compound heterozygous mutations in the MAN2C1 gene: a 2-bp deletion (c.2733_2734del, NM_006715.3) in exon 23, resulting in a frameshift and premature termination (His911GlnfsTer67), and a C871S mutation (154580.0003). The mutations, which were identified by whole-exome sequencing, were found in the carrier state in the parents. The c.2733_2734del variant was present in the gnomAD database in only heterozygous state at an allele frequency of 0.013%.
In a Moroccan patient with congenital disorder of deglycosylation-2 (CDDG2; 619775), Maia et al. (2022) identified homozygosity for a c.607G-A transition (c.607G-A, NM_006715.3) in exon 6 in the MAN2C1 gene, resulting in a gly203-to-arg (G203R) substitution. The mutation, which was identified by whole-exome sequencing, was found in the carrier state in the parents. The G203R variant was present in the gnomAD database in only heterozygous state at an allele frequency of 0.049%. Complementation of MAN2C1 knockout HAP1 cells with MAN2C1 with the RG203R mutation demonstrated a free oligosaccharide processing defect.
Champion, M. J., Brown, J. A., Shows, T. B. Assignment of cytoplasmic alpha-mannosidase (MAN-A) and confirmation of the mitochondrial isocitrate dehydrogenase (IDH-M) genes to the q11--qter region of chromosome 15 in man. Cytogenet. Cell Genet. 22: 498-502, 1978. [PubMed: 752528] [Full Text: https://doi.org/10.1159/000131007]
Ferguson-Smith, M. A., Westerveld, A. Report of the committee on the genetic constitution of chromosomes 13, 14, 15, 16, 17, 18, 19, 20, 21, and 22 (HGM5). Cytogenet. Cell Genet. 25: 59-73, 1979. [PubMed: 396129] [Full Text: https://doi.org/10.1159/000131400]
Maia, N., Potelle, S., Yildirim, H., Duvet, S., Akula, S. K., Schulz, C., Wiame, E., Gheldof, A., O'Kane, K., Lai, A., Sermon, K., Proisy, M., and 13 others. Impaired catabolism of free oligosaccharides due to MAN2C1 variants causes a neurodevelopmental disorder. Am. J. Hum. Genet. 109: 345-360, 2022. [PubMed: 35045343] [Full Text: https://doi.org/10.1016/j.ajhg.2021.12.010]
Neri, G., Ricci, R., Pelino, A., Bova, R., Tedeschi, B., Serra, A. A boy with ring chromosome 15 derived from a t(15q;15q) Robertsonian translocation in the mother: cytogenetic and biochemical findings. Am. J. Med. Genet. 14: 307-314, 1983. [PubMed: 6220608] [Full Text: https://doi.org/10.1002/ajmg.1320140211]
Paciotti, S., Persichetti, E., Klein, K., Tasegian, A., Duvet, S., Hartmann, D., Gieselmann, V., Beccari, T. Accumulation of free oligosaccharides and tissue damage in cytosolic alpha-mannosidase (Man2c1)-deficient mice. J. Biol. Chem 289: 9611-9622, 2014. [PubMed: 24550399] [Full Text: https://doi.org/10.1074/jbc.M114.550509]
Wang, L., Suzuki, T. Dual functions for cytosolic alpha-mannosidase (Man2C1): its down-regulation causes mitochondria-dependent apoptosis independently of its alpha-mannosidase activity. J. Biol. Chem. 288: 11887-11896, 2013. [PubMed: 23486476] [Full Text: https://doi.org/10.1074/jbc.M112.425702]