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ALG1
ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase
The ALG1 gene encodes an enzyme vital for glycosylation, a process that modifies proteins and lipids by attaching complex sugar chains, influencing their proper function in the body. ALG1 provides instructions for an enzyme known as chitobiosyldiphosphodolichol beta-mannosyltransferase.
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 chitobiosyldiphosphodolichol beta-mannosyltransferase, is central to a vital cellular process called glycosylation. This process involves the attachment of complex sugar chains, known as oligosaccharides, to proteins and lipids. These modifications are critical for ensuring that proteins and lipids can perform their designated roles within the cell and throughout the body.
Disruptions in the ALG1 gene can lead to conditions where glycosylation is impaired, affecting multiple body systems. Understanding the function of ALG1 is therefore important for comprehending certain inherited metabolic disorders.
What the gene does
The ALG1 gene provides instructions for creating an enzyme that functions as a beta-mannosyltransferase. This enzyme is specifically involved in the early stages of N-linked glycosylation, a complex pathway where oligosaccharide chains are built and then attached to specific proteins or lipids. N-linked glycosylation is essential for the proper folding, stability, and function of many proteins, particularly those destined for secretion or insertion into cell membranes.
During glycosylation, sugar molecules are added step-by-step to form an oligosaccharide. The ALG1 enzyme catalyses a specific step in this process: it transfers a mannose sugar molecule to a growing oligosaccharide chain. This precise addition is crucial for the correct assembly of the sugar chain, which in turn ensures that the modified proteins and lipids can carry out their functions, such as cell-to-cell communication and enzymatic activity.
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Chromosome location
The ALG1 gene is located on chromosome 16, specifically at position 16p13.3. This designation refers to the short (p) arm of chromosome 16, within region 13 and band 3. The precise location of ALG1 helps in understanding its genetic neighbourhood and potential interactions with other genes.
Protein structure
The ALG1 gene codes for a protein that is 464 amino acids long. Structural analysis of the ALG1 protein indicates the presence of a Disordered region spanning amino acids 243-262. This disordered region may contribute to the protein's flexibility and its ability to interact with various molecules during the glycosylation process.
Key variants
Variants within the ALG1 gene can alter the function of the enzyme it produces, potentially leading to impaired glycosylation. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions. The impact of a specific variant depends on its location and how it affects the enzyme's ability to catalyse the transfer of mannose during oligosaccharide synthesis.
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.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.295C>T | p.Arg99Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.339C>G | p.Tyr113Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-related disorder |
c.539+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-congenital disorder of glycosylation |
c.598C>T | p.Arg200Ter | Pathogenic/Likely pathogenic | ★★☆☆ | ALG1-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 ALG1 gene are associated with ALG1-congenital disorder of glycosylation (ALG1-CDG). This is an inherited metabolic disorder characterised by a range of symptoms affecting multiple body systems. Individuals with ALG1-CDG typically experience intellectual disability, developmental delays, and reduced muscle tone (hypotonia). The severity and presentation of ALG1-CDG can vary among affected individuals.
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
The ALG1 gene is recognised within the UK's NHS Genomic Medicine Service pathways. It is included on several NHS national genomic test directories via PanelApp, demonstrating its clinical relevance. Specifically, ALG1 is listed as 'green' on 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, indicating strong evidence for its association with these conditions.
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 that plays a key role in glycosylation, a process where complex sugar chains are attached to proteins and lipids. This modification is crucial for these molecules to function correctly within the body.
What is ALG1-congenital disorder of glycosylation (ALG1-CDG)?
ALG1-CDG is an inherited condition caused by pathogenic variants in the ALG1 gene. It results from impaired glycosylation and can lead to symptoms such as intellectual disability, developmental delay, and weak muscle tone, affecting multiple body systems.
How is ALG1 relevant to UK clinical genetics?
The ALG1 gene is included in several NHS national genomic test directories, such as those for congenital disorders of glycosylation, intellectual disability, and early-onset epilepsy. This indicates its importance in diagnosing and understanding a range of inherited conditions within the UK healthcare system.
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