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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 complex sugar chains. ALG12 codes for alpha-1,6-mannosyltransferase, an enzyme vital for building specific sugar chains during glycosylation.
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 encodes an enzyme known as alpha-1,6-mannosyltransferase, which plays a fundamental role in the cellular process called glycosylation. Glycosylation involves the attachment of intricate sugar chains, known as oligosaccharides, to proteins and fats (lipids). This modification is essential for proteins to function correctly within the body.
Disruptions in the ALG12 gene's function can impair the glycosylation pathway, leading to a group of rare genetic conditions known as congenital disorders of glycosylation (CDG). Specifically, it is associated with ALG12-congenital disorder of glycosylation (ALG12-CDG).
What the gene does
The ALG12 gene directs the production of an enzyme crucial for the precise assembly of oligosaccharide chains. These complex sugar structures are built in a step-by-step manner. The ALG12 enzyme's specific function is to add a mannose sugar molecule at a particular stage during the formation of these growing oligosaccharide chains.
Once fully constructed, these oligosaccharide chains are then attached to proteins or lipids. This attachment process modifies the target molecules, enabling them to perform their designated biological roles. Without a properly functioning ALG12 enzyme, the correct mannose transfer cannot occur, resulting in incomplete or abnormal oligosaccharides and consequently, impaired protein and lipid function.
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Chromosome location
The ALG12 gene is located on chromosome 22, specifically at position 22q13.33. This chromosomal address indicates its precise place on the long arm of chromosome 22.
Protein structure
The ALG12 gene produces a protein that is 488 amino acids long.
Key variants
Variants within the ALG12 gene can alter the enzyme's structure and function, affecting its ability to correctly transfer mannose during glycosylation. These genetic changes can range from single base pair substitutions to larger deletions or insertions within the gene sequence. Such variants are typically inherited in an autosomal recessive manner.
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-related disorder |
c.30del | p.Leu12fs | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.437G>A | p.Arg146Gln | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-related disorder |
c.604C>T | p.Arg202Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.768+1dup | - | Pathogenic/Likely pathogenic | ★★☆☆ | ALG12-congenital disorder of glycosylation |
c.930_931del | p.Arg311fs | 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
At least 13 pathogenic variants in the ALG12 gene have been identified that cause ALG12-congenital disorder of glycosylation (ALG12-CDG). This condition typically presents with symptoms such as delayed growth and development, weak muscle tone (hypotonia), and other signs and symptoms. The clinical presentation can vary among affected individuals.
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 included in several NHS Genomic Medicine Service national test panels. These panels cover conditions such as congenital disorders of glycosylation, intellectual disability, foetal anomalies, and undiagnosed metabolic disorders, indicating its clinical relevance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ALG12 gene?
The ALG12 gene provides instructions for making an enzyme called alpha-1,6-mannosyltransferase. This enzyme is crucial for adding a specific mannose sugar molecule during the construction of complex sugar chains, known as oligosaccharides, in a process called glycosylation.
What is ALG12-congenital disorder of glycosylation (ALG12-CDG)?
ALG12-CDG is a genetic condition caused by pathogenic variants in the ALG12 gene. It is characterised by a range of symptoms including delayed growth and development, as well as weak muscle tone, due to the impaired glycosylation process.
How is ALG12-CDG inherited?
ALG12-congenital disorder of glycosylation is inherited in an autosomal recessive manner. This means that an individual must inherit two copies of the altered ALG12 gene, one from each parent, to develop the condition.
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