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ALG12
ALG12 alpha-1,6-mannosyltransferase
The ALG12 gene provides instructions for an enzyme crucial in glycosylation, a process that modifies proteins and lipids by attaching sugar chains, essential for their proper function. The ALG12 gene encodes an alpha-1,6-mannosyltransferase enzyme involved in building complex sugar chains, known as oligosaccharides.
ALG12 is located on the long (q) arm of chromosome 22, at band 22q13.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALG12 gene, also known as ALG12 alpha-1,6-mannosyltransferase, is fundamental for cellular function due to its role in glycosylation. This critical biological process involves the attachment of sugar molecules to proteins and lipids, modifying them to ensure they can perform their intended roles within the body.
Dysfunction of the ALG12 gene can lead to a specific type of inherited metabolic disorder, ALG12-congenital disorder of glycosylation (ALG12-CDG), which can affect various bodily systems.
What the gene does
The ALG12 gene provides instructions for creating an enzyme known as an alpha-1,6-mannosyltransferase. This enzyme plays a specific role in the complex process of glycosylation, where chains of sugar molecules (oligosaccharides) are assembled and then attached to proteins and lipids. These modifications are essential for the proper structure and function of many molecules within the body.
Specifically, the ALG12 enzyme is responsible for adding a simple sugar called mannose to a growing oligosaccharide chain at a particular stage of its formation. This stepwise assembly of sugar molecules is crucial for creating the correctly structured oligosaccharide. Once fully assembled, these sugar chains are transferred to target proteins or lipids, enabling them to function correctly in various biological processes.
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Chromosome location
The ALG12 gene is located on chromosome 22, specifically at position 22q13.33. This indicates its position on the long (q) arm of chromosome 22, within region 13 and band 33.
Protein structure
The ALG12 gene encodes a protein that is 488 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations, or variants, within the ALG12 gene can alter the function of the enzyme it produces. These variants can range from single base pair changes to larger deletions or insertions within the gene sequence. Pathogenic variants can lead to a non-functional or less active enzyme, disrupting the normal glycosylation process.
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.1001del | p.Asn334fs | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1156dup | p.Gln386fs | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.117del | p.Gln40fs | Pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.200C>T | p.Thr67Met | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.295+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.30del | p.Leu12fs | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.437G>A | p.Arg146Gln | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-related disorder |
c.768+1dup | - | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.930_931del | p.Arg311fs | Pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.904_908del | p.Tyr302fs | Pathogenic | ★☆☆☆ | ALG12-congenital disorder of glycosylation |
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 ALG12 gene are primarily associated with ALG12-congenital disorder of glycosylation (ALG12-CDG). This condition is characterised by a range of symptoms, often including developmental delays, growth impairment, and reduced muscle tone. These symptoms arise from the impaired ability to properly glycosylate proteins and lipids, affecting their function in various tissues and organs.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ALG12 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ALG12 gene is recognised within the UK's NHS Genomic Medicine Service. It is currently listed as 'green' on several NHS England National Genomic Test Directory panels, including Congenital disorders of glycosylation, DDG2P, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This indicates that there is strong evidence for the gene's involvement in these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is ALG12-congenital disorder of glycosylation (ALG12-CDG)?
ALG12-congenital disorder of glycosylation is a rare inherited condition caused by pathogenic variants in the ALG12 gene. It affects the body's ability to properly attach sugar chains to proteins and lipids, which can lead to a variety of symptoms including developmental delays, growth issues, and muscle weakness.
How does the ALG12 gene contribute to health?
The ALG12 gene produces an enzyme that adds a specific sugar molecule, mannose, to growing sugar chains during a process called glycosylation. This process is essential for modifying many proteins and lipids in the body, ensuring they function correctly in various biological roles, from cell signalling to immune response.
Is ALG12-CDG an inherited condition?
Yes, ALG12-CDG is an inherited condition. It typically follows an autosomal recessive pattern of inheritance, meaning an individual must inherit two pathogenic variants, one from each parent, to develop the condition. Parents who each carry one pathogenic variant are generally unaffected but are carriers.
References
- Chantret I, Dupré T, Delenda C. Congenital disorders of glycosylation type Ig is defined by a deficiency in dolichyl-P-mannose:Man7GlcNAc2-PP-dolichyl mannosyltransferase. The Journal of biological chemistry. 2002. PMID: 11983712
- Thiel C, Schwarz M, Hasilik M. Deficiency of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl mannosyltransferase causes congenital disorder of glycosylation type Ig. The Biochemical journal. 2002. PMID: 12093361
- Grubenmann CE, Frank CG, Kjaergaard S. ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics. 2002. PMID: 12217961