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MAN2B1
mannosidase alpha class 2B member 1
The MAN2B1 gene provides instructions for the alpha-mannosidase enzyme, which is essential for breaking down complex sugar molecules within cellular lysosomes. The MAN2B1 gene encodes the alpha-mannosidase enzyme, a key component in the cellular process of breaking down specific sugar molecules called oligosaccharides.
MAN2B1 is located on the short (p) arm of chromosome 19, at band 19p13.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The MAN2B1 gene is responsible for producing alpha-mannosidase, an enzyme that plays a critical role in cellular metabolism. This enzyme functions within lysosomes, which are specialised compartments inside cells that digest and recycle various cellular components. The proper functioning of alpha-mannosidase is essential for maintaining cellular health and preventing the accumulation of waste products.
Defects in the MAN2B1 gene can lead to the impaired activity of the alpha-mannosidase enzyme. This impairment can result in the build-up of specific sugar molecules within cells, contributing to the development of inherited metabolic disorders, such as alpha-mannosidosis.
What the gene does
The MAN2B1 gene provides the genetic blueprint for the alpha-mannosidase enzyme. This enzyme is primarily active within the lysosomes, which are often referred to as the 'recycling centres' of the cell. Within these organelles, alpha-mannosidase is responsible for breaking down complex sugar molecules, specifically oligosaccharides, that are attached to certain proteins known as glycoproteins. This process is a crucial step in the cell's waste disposal and recycling pathways.
More precisely, the alpha-mannosidase enzyme encoded by MAN2B1 focuses on breaking down oligosaccharides that contain mannose sugar units. If this enzyme is deficient or non-functional due to genetic changes in MAN2B1, these complex sugar molecules cannot be properly degraded. Consequently, they accumulate within the lysosomes, disrupting normal cellular processes and leading to the characteristic features of associated conditions.
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Chromosome location
The MAN2B1 gene is situated on the short arm of chromosome 19 at position 13.13, denoted as 19p13.13. This specific genomic location places it within a region that is significant for various cellular functions. The gene provides instructions for a protein that is 1011 amino acids in length.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the MAN2B1 gene can alter the production or function of the alpha-mannosidase enzyme. More than 120 different genetic changes have been identified in individuals with alpha-mannosidosis. These variants can include changes to single protein building blocks (amino acids) or larger alterations that impact the gene's ability to produce a functional enzyme. Such genetic variations can lead to a range of clinical presentations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1132_1133del | p.Phe378fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.131del | p.Ala44fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.1527+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.1545T>G | p.Tyr515Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.1858dup | p.Thr620fs | Pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.1963del | p.Gln655fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.2279_2280del | p.Arg760fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.2368C>T | p.Gln790Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.664_667del | p.Asp222fs | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
c.681G>A | p.Trp227Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Deficiency of alpha-mannosidase |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the MAN2B1 gene are primarily associated with Alpha-mannosidosis, a rare inherited disorder. This condition is characterised by the accumulation of undigested sugar molecules in cells, leading to a variety of symptoms affecting multiple organs and tissues. Individuals with alpha-mannosidosis may experience intellectual disability, distinctive facial features, and skeletal abnormalities.
UK clinical status
MAN2B1 is included in several expert-curated panels within the UK's NHS Genomic Medicine Service via PanelApp. These include panels for conditions such as Bilateral congenital or childhood onset cataracts, Hydrocephalus, Intellectual disability, and Lysosomal storage disorder. It is also listed under the broader categories of DDG2P (developmental disorders), Likely inborn error of metabolism, and Undiagnosed metabolic disorders, highlighting its broad clinical relevance.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the MAN2B1 gene?
The MAN2B1 gene provides instructions for the alpha-mannosidase enzyme, which is crucial for breaking down complex sugar molecules (oligosaccharides) containing mannose within the lysosomes of cells.
What condition is most commonly associated with MAN2B1 gene variants?
Variants in the MAN2B1 gene are primarily associated with Alpha-mannosidosis, a rare inherited disorder affecting multiple body systems due to the accumulation of undigested sugar molecules.
Where in the body does the enzyme produced by MAN2B1 work?
The alpha-mannosidase enzyme produced by the MAN2B1 gene functions within the lysosomes of cells, which are cellular compartments responsible for digesting and recycling waste materials.
References
- Kuokkanen E, Riise Stensland HM, Smith W. Molecular and cellular characterization of novel {alpha}-mannosidosis mutations. Human molecular genetics. 2011. PMID: 21505070
- Malm D, Nilssen Ø. Alpha-mannosidosis. Orphanet journal of rare diseases. 2008. PMID: 18651971
- Pittis MG, Montalvo AL, Heikinheimo P. Funtional characterization of four novel MAN2B1 mutations causing juvenile onset alpha-mannosidosis. Clinica chimica acta; international journal of clinical chemistry. 2007. PMID: 16919251
- Sbaragli M, Bibi L, Pittis MG. Identification and characterization of five novel MAN2B1 mutations in Italian patients with alpha-mannosidosis. Human mutation. 2005. PMID: 15712269
- Hansen G, Berg T, Riise Stensland HM. Intracellular transport of human lysosomal alpha-mannosidase and alpha-mannosidosis-related mutants. The Biochemical journal. 2004. PMID: 15035660
- Sun H, Wolfe JH. Recent progress in lysosomal alpha-mannosidase and its deficiency. Experimental & molecular medicine. 2001. PMID: 11322479