Alternative titles; symbols
HGNC Approved Gene Symbol: MAN2B1
SNOMEDCT: 124466001, 65524005;
Cytogenetic location: 19p13.13 Genomic coordinates (GRCh38) : 19:12,646,512-12,666,742 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.13 | Mannosidosis, alpha-, types I and II | 248500 | Autosomal recessive | 3 |
Alpha-mannosidase (EC 3.2.1.24) is a lysosomal hydrolase that cleaves alpha-linked mannose residues from the nonreducing end of N-linked glycoproteins (Gotoda et al., 1998).
See also beta-mannosidase (MANBA; 609489).
Nebes and Schmidt (1994) isolated and sequenced a cDNA for alpha-mannosidase. Liao et al. (1996) used RT-PCR to clone 2 cDNAs encoding human lysosomal alpha-mannosidase. The shorter of the 2 cDNAs encodes a 3-kb open reading frame which, when expressed, produces a functional alpha-mannosidase enzyme; the longer cDNA, encoding a 3.6-kb open reading frame, produced no alpha-mannosidase activity when expressed. Northern blot analysis identified a major 3-kb mRNA transcript in all human tissues tested and a minor 3.6-kb mRNA transcript in several adult tissues.
Nilssen et al. (1997) reported purification and characterization of lysosomal alpha-mannosidase, which they symbolized LAMAN, from human placenta. They found that the enzyme was synthesized as a single-chain precursor which is processed into 3 glycopeptides of 70, 42, and 15 kD. The 70-kD peptide is further partially proteolyzed into 3 more peptides that are joined by disulfide bridges. The deduced amino acid sequence contains a putative signal peptide of 48 amino acids followed by a polypeptide sequence of 962 amino acids. Northern blot analysis revealed a single transcript of approximately 3.5 kb present in all tissues examined, but at varying levels.
Berg et al. (1997) reported the purification of feline liver lysosomal alpha-mannosidase and determination of its cDNA sequence. The active enzyme consists of 3 polypeptides, with molecular masses of 72, 41, and 12 kD, joined by noncovalent forces. They demonstrated that the enzyme is synthesized as a single-chain precursor with a putative signal peptide of 50 amino acids followed by a polypeptide chain of 957 amino acids, which is cleaved into the 3 polypeptides of the mature enzyme. The deduced amino acid sequence was 81.1% and 83.2% identical with the human and bovine sequences, respectively. Tollersrud et al. (1997) purified the bovine kidney enzyme to homogeneity and cloned the gene.
Riise et al. (1997) determined that the MANB gene spans 21.5 kb and contains 24 exons. By primer extension analysis, the major transcription initiation sites were mapped to positions -309, -196, and -191 relative to the first in-frame ATG. No CAAT or TATA sequences were identified within the 134 bp upstream of the transcription initiation site, but the 5-prime flanking region contains several GC-rich regions with putative binding sites for the transcription factors Sp1 (189906), AP-2 (107580), and ETF.
By analysis of human-mouse hybrid cells, Kaneda et al. (1987) assigned the MANB gene to chromosome 19p13.2-q12. By PCR analysis of DNA from 2 human/rodent somatic cell hybrid mapping panels, Nebes and Schmidt (1994) mapped the MANB gene to the proximal portion of chromosome 19. In combination with earlier findings, the gene could be mapped to 19cen-q12.
Beccari et al. (1996) mapped the mouse Man2b1 gene to chromosome 8 using the Jackson Laboratory interspecific panel DNA.
In 2 Palestinian sibs with alpha-mannosidosis (MANSA; 248500) originally reported by Bach et al. (1978), Nilssen et al. (1997) identified a homozygous mutation in the MAN2B1 gene (609458.0001).
In unrelated patients with alpha-mannosidosis, Gotoda et al. (1998) identified 5 mutations in the MAN2B1 gene (609458.0001-609458.0005). All mutations were either in the homozygous or compound heterozygous states.
In a screening of 43 patients with mannosidosis from 39 families, mainly of European origin, Berg et al. (1999) identified 21 novel disease-causing mutations in the MAN2B1 gene, and 4 polymorphic amino acid variations. Disease-causing mutations were identified in 72% of the patients' alleles and included 8 splicing, 6 missense, and 3 nonsense mutations, as well as 2 small insertions and 2 small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in 2 or 3 families, except for the R750W substitution (609458.0004), which was found in 13 patients from different European countries and accounted for 21% of the disease alleles. No correlation between the types of mutations and the clinical manifestations was evident.
Riise Stensland et al. (2012) identified 96 different pathogenic mutations in the MAN2B1 gene, including 83 novel mutations, in 130 unrelated patients with alpha-mannosidosis from 30 countries. Most of the mutations were private, but R750W was found in 50 patients from 16 countries and accounted for 27.3% of disease alleles. Haplotype analysis indicated at least 4 independent events causing R750W, with 1 haplotype accounting for 95% of the alleles. Population-based analysis suggested that the mutant allele arose in eastern Europe. Other recurrent mutations included a splice site mutation in intron 14 (609458.0006), found in 13 disease alleles, and L809P (609458.0007), found in 8 disease alleles. Twenty-nine novel missense mutations were identified. Most did not show any residual enzyme activity when expressed in COS-7 cells, but 10 showed some activity, including 5 with 30% or more residual activity. There were no apparent genotype/phenotype correlations.
Roces et al. (2004) reported correction of storage of neutral oligosaccharides in a mouse model of alpha-mannosidosis after intravenous administration of Man2b1 from bovine kidney and human and mouse recombinant MAN2B1. The bovine and human enzymes were barely phosphorylated, whereas the bulk of the mouse Man2b1 contained mannose 6-phosphate recognition markers. Clearance and apparent half-life of the internalized enzyme was dependent on the enzyme source as well as tissue type. The corrective effect was time-, tissue- and dose-dependent, and the effects were observed to be transient. After a single dose injection of MAN2B1, the maximum corrective effect was observed between 2 and 6 days. Injection of 250 microU of human MAN2B1 per gram of body weight followed by a subsequent injection 3.5 days later was sufficient to clear liver, kidney, and heart of neutral oligosaccharides. A decrease in mannose-containing oligosaccharides was also observed in the brain, with storage levels in treated mice less than 30% of levels found in control mice.
Blanz et al. (2008) demonstrated that the neuropathology of a mouse model for alpha-mannosidosis could be efficiently treated using recombinant human alpha-mannosidase (rhLAMAN). After intravenous administration of various doses (25-500 U/kg), rhLAMAN was widely distributed among tissues, and immunohistochemistry revealed lysosomal delivery of the injected enzyme. Whereas low doses (25 U/kg) led to a greater than 70% clearance of stored substrates in visceral tissues and doses of 250 U/kg were sufficient for clearance in peripheral neurons of the trigeminal ganglion, repeated high-dose injections (500 U/kg) were required to achieve a greater than 50% reduction of brain storage. Successful transfer across the blood-brain barrier was evident as the injected enzyme was found in hippocampal neurons, leading to nearly complete disappearance of storage vacuoles. In addition, the decrease in neuronal storage in the brain correlated with an improvement of the neuromotor disabilities found in untreated alpha-mannosidosis mice. Uptake of rhLAMAN seemed to be independent of mannose-6-phosphate receptors, consistent with the low phosphorylation profile of the enzyme.
In 2 sibs with alpha-mannosidosis (MANSA; 248500), born of consanguineous parents, Nilssen et al. (1997) identified a homozygous 212A-T transversion in exon 2 of the MANB gene, resulting in a his71-to-leu (H71L) substitution. Residue his71 is conserved among lysosomal alpha-mannosidases from several species. The sibs were thought to be mildly affected and residual acidic alpha-mannosidase activity of 20% of normal was detected in the patient's fibroblasts, according to the report of this family by Bach et al. (1978). Nevertheless, the patients showed vacuolated leukocytes and fibroblasts consistent with the disease phenotype. The authors suggested that mutant mannosidase enzymes, even though containing residual activity upon testing at the appropriate pH, may be mislocalized to nonlysosomal compartments and therefore functionally inactive.
Gotoda et al. (1998) identified the same mutation, which they designated HIS72LEU in keeping with the codon numbering system of Wakamatsu et al. (1997). The patient, represented by cell line GM2051, was one of the patients reported by Nilssen et al. (1997).
In a 47-year-old Japanese woman with mannosidosis (MANSA; 248500), born to first-cousin parents, Gotoda et al. (1998) identified a homozygous C-to-T transition in exon 19 of the MAN2B1 gene, resulting in an arg760-to-ter (R760X) substitution. The lysosomal alpha-mannosidase activity of the peripheral leukocytes was decreased to less than 1% of control values.
In fibroblast cell lines from a 7-year-old Finnish boy with alpha-mannosidosis (MANSA; 248500), who was originally described by Autio et al. (1973), Gotoda et al. (1998) identified compound heterozygosity for 2 mutations in the MAN2B1 gene: a C-to-T transition in exon 15, resulting in a gln639-to-ter (Q639X) substitution, and a C-to-T transition in exon 18, resulting in an arg750-to-trp substitution (R750W; 609458.0004). Alpha-mannosidase activity was reduced to approximately 2% of normal.
For discussion of the arg750-to-trp (R750W) mutation in the MAN2B1 gene that was found in compound heterozygous state in a patient with alpha-mannosidosis (MANSA; 248500) by Gotoda et al. (1998), see 609458.0003.
Berg et al. (1999) identified the arg750-to-trp (R750W) mutation in 13 patients with alpha-mannosidosis from different European countries. R750W accounted for 21% of disease alleles.
Riise Stensland et al. (2012) identified the R750W mutation in 50 of 130 unrelated patients with alpha-mannosidosis from 30 countries. It was the most common mutation, accounting for 27.3% of disease alleles. Haplotype analysis indicated at least 4 independent events causing R750W, with 1 haplotype accounting for 95% of the alleles. Population-based analysis suggested that the mutant allele arose in eastern Europe. The mutation was found in patients with mild, moderate, and severe disease.
In a fibroblast cell line from a 2-year-old girl with severe alpha-mannosidosis (MANSA; 248500), Gotoda et al. (1998) identified a homozygous C-to-T transversion in exon 8 of the MAN2B1 gene, resulting in a pro356-to-arg (P356R) substitution. The patient showed severe growth failure with hypotonia, psychomotor retardation, and hepatosplenomegaly.
In a study of 130 unrelated patients with alpha-mannosidosis (MANSA; 248500) from 30 countries, Riise Stensland et al. (2012) found that a G-to-C transversion in intron 14 (IVS14+1G-C) of the MAN2B1 gene (Berg et al., 1999) was present on 13 disease alleles, making it the second most common mutation after R750W (609458.0004).
In a study of 130 unrelated patients with alpha-mannosidosis (MANSA; 248500) from 30 countries, Riise Stensland et al. (2012) found that a 2426T-C transition in exon 20 of the MAN2B1 gene (Berg et al., 1999) was present on 8 disease alleles, making it the third most common mutation after R750W (609458.0004) and a splice site mutation in intron 14 (609458.0006).
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Berg, T., Tollersrud, O. K., Walkley, S. U., Siegel, D., Nilssen, O. Purification of feline lysosomal alpha-mannosidase, determination of its cDNA sequence and identification of a mutation causing alpha-mannosidosis in Persian cats. Biochem. J. 328: 863-870, 1997. [PubMed: 9396732] [Full Text: https://doi.org/10.1042/bj3280863]
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Nebes, V. L., Schmidt, M. C. Human lysosomal alpha-mannosidase: isolation and nucleotide sequence of the full-length cDNA. Biochem. Biophys. Res. Commun. 200: 239-245, 1994. Note: Erratum: Biochem. Biophys. Res. Commun. 232: 583 only, 1997. [PubMed: 8166692] [Full Text: https://doi.org/10.1006/bbrc.1994.1440]
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Riise, H. M. F., Berg, T., Nilssen, O., Romeo, G., Tollersrud, O. K., Ceccherini, I. Genomic structure of the human lysosomal alpha-mannosidase gene (MANB). Genomics 42: 200-207, 1997. [PubMed: 9192839] [Full Text: https://doi.org/10.1006/geno.1997.4668]
Riise Stensland, H. M. F., Klenow, H. B., Van Nguyen, L., Hansen, G. M., Malm, D., Nilssen, O. Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum. Mutat. 33: 511-520, 2012. Note: Erratum: Hum. Mutat. 37: 827 only, 2016. [PubMed: 22161967] [Full Text: https://doi.org/10.1002/humu.22005]
Roces, D. P., Lullmann-Rauch, R., Peng, J., Balducci, C., Andersson, C., Tollersrud, O., Fogh, J., Orlacchio, A., Beccari, T., Saftig, P., von Figura, K. Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study. Hum. Molec. Genet. 13: 1979-1988, 2004. [PubMed: 15269179] [Full Text: https://doi.org/10.1093/hmg/ddh220]
Tollersrud, O. K., Berg, T., Healy, P., Evjen, G., Ramachandran, U., Nilssen, O. Purification of bovine lysosomal alpha-mannosidase, characterization of its gene and determination of two mutations that cause alpha-mannosidosis. Europ. J. Biochem. 246: 410-419, 1997. [PubMed: 9208932] [Full Text: https://doi.org/10.1111/j.1432-1033.1997.00410.x]
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