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ALG1
ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase
The ALG1 gene provides instructions for an enzyme crucial in glycosylation, a process that modifies proteins and lipids, and is associated with ALG1-congenital disorder of glycosylation (ALG1-CDG). The ALG1 gene encodes an enzyme called chitobiosyldiphosphodolichol beta-mannosyltransferase, which plays a vital role in the initial stages of N-linked glycosylation.
ALG1 is located on the short (p) arm of chromosome 16, at band 16p13.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALG1 gene, also known as asparagine-linked glycosylation 1 homolog, is fundamental for proper cellular function through its involvement in glycosylation. This enzymatic process is critical for modifying proteins and lipids by attaching complex sugar molecules to them. These modifications are necessary for the proteins to achieve their full functional capacity and for lipids to facilitate cell-to-cell interactions.
Disruptions in ALG1's function due to genetic variants can have significant health implications, particularly manifesting as congenital disorders of glycosylation. Understanding the role of ALG1 helps to explain the molecular basis of these conditions.
What the gene does
The ALG1 gene produces the enzyme chitobiosyldiphosphodolichol beta-mannosyltransferase, which is integral to the glycosylation pathway. Specifically, this enzyme catalyses a crucial step where it transfers a mannose sugar molecule to growing oligosaccharide chains. These oligosaccharides are complex sugar structures that are built up in a stepwise manner.
Once completed, these complex sugar chains are then attached to proteins or lipids, a process that is vital for their correct folding, stability, and function within the cell. The enzyme's activity is therefore essential for the proper formation of these modified molecules, which are involved in a wide array of biological processes, including cell signalling and immune response.
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Chromosome location
The ALG1 gene is located on chromosome 16, specifically at position 16p13.3. This region of the chromosome contains various genes that are important for normal biological processes. The precise genomic location helps in understanding the gene's organisation and its potential proximity to other functionally related genes.
Protein structure
The ALG1 protein is composed of 464 amino acids. Its structure includes a notable disordered region spanning amino acids 243-262. Disordered regions often play roles in protein-protein interactions and signalling, allowing for flexibility in binding partners and cellular responses.
Key variants
Genetic variations within the ALG1 gene can alter the function of the encoded enzyme. These variants can range from single nucleotide changes to larger deletions or insertions. When these changes impair the enzyme's ability to perform its role in glycosylation, they can lead to various health conditions. Research continues to identify and characterise new variants and their clinical impact.
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.1059C>A | p.Tyr353Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1095_1098del | p.Leu366fs | Pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1095T>A | p.Cys365Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1145T>C | p.Met382Thr | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1187+2T>C | - | Pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1261C>T | p.Gln421Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.1263G>A | p.Gln421= | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.235C>T | p.Gln79Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.295C>T | p.Arg99Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.339C>G | p.Tyr113Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-related disorder |
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
Variants in the ALG1 gene are primarily associated with ALG1-congenital disorder of glycosylation (ALG1-CDG). This is an inherited condition that typically presents with a range of symptoms including intellectual disability, developmental delay, and hypotonia (weak muscle tone). The broad impact of ALG1-CDG reflects the widespread importance of proper glycosylation across multiple body systems.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ALG1 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
In the UK, the ALG1 gene is recognised on several NHS Genomic Medicine Service (GMS) approved panels. These include panels for Congenital disorders of glycosylation, DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), and Undiagnosed metabolic disorders. This indicates its established 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 main function of the ALG1 gene?
The ALG1 gene provides instructions for an enzyme called chitobiosyldiphosphodolichol beta-mannosyltransferase, which is crucial for adding mannose sugars during the initial stages of N-linked glycosylation. This process modifies proteins and lipids, enabling them to function correctly.
What is ALG1-congenital disorder of glycosylation (ALG1-CDG)?
ALG1-CDG is an inherited condition caused by pathogenic variants in the ALG1 gene. It is characterised by symptoms such as intellectual disability, delayed development, and weak muscle tone, affecting multiple body systems due to impaired glycosylation.
How is the ALG1 gene inherited?
The ALG1 gene is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the gene, one from each parent, to develop an associated condition like ALG1-CDG.
References
- Jaeken J, Lefeber D, Matthijs G. Clinical utility gene card for: ALG1 defective congenital disorder of glycosylation. European journal of human genetics : EJHG. 2015. PMID: 25649379
- Morava E, Vodopiutz J, Lefeber DJ. Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics. 2012. PMID: 22966035
- Dupré T, Vuillaumier-Barrot S, Chantret I. Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations. Journal of medical genetics. 2010. PMID: 20679665