The ALG1 gene provides instructions for making an enzyme involved in a biological process known as glycosylation. This enzyme plays a role in attaching sugar chains, called oligosaccharides, to proteins and fats (lipids). The ALG1 gene is important for ensuring that many proteins and lipids within the body can perform their intended functions.
ALG1’s Role in N-Linked Glycosylation
The ALG1 gene produces an enzyme called mannosyltransferase 1, also known as beta-1,4-mannosyltransferase. This enzyme is located on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. It catalyzes a step in the biosynthesis of lipid-linked oligosaccharides (LLOs), which are precursors for N-linked glycosylation.
The enzyme adds the first mannose sugar unit to a growing oligosaccharide chain on a dolichol pyrophosphate lipid. This initial step is important for the N-linked glycosylation pathway, which ultimately produces a 14-sugar oligosaccharide. Without this step, LLO assembly is impaired, leading to insufficient N-glycosylation of proteins.
The Broad Importance of Glycosylation
N-linked glycosylation is a widespread and highly conserved modification in eukaryotic cells. It involves attaching complex carbohydrate structures to proteins at asparagine residues. This modification is important for proper protein folding and stability within the endoplasmic reticulum, acting as a quality control checkpoint.
Glycosylation also plays diverse roles in physiological processes throughout the body. These include facilitating cell-to-cell communication, supporting the immune system’s ability to recognize foreign particles, and contributing to the development and function of numerous organs. The presence of glycans on proteins can influence their solubility, enzymatic activity, trafficking, and localization within the cell. Disruptions in this process can have widespread effects, impacting multiple bodily systems.
ALG1 Congenital Disorder of Glycosylation
Mutations in the ALG1 gene are directly linked to ALG1-Congenital Disorder of Glycosylation (ALG1-CDG). This condition is an inherited disorder, typically appearing in infancy, where individuals inherit a defective copy of the ALG1 gene from each parent. At least 15 different mutations in the ALG1 gene have been identified as causes of this disorder.
These mutations result in an abnormal ALG1 enzyme with reduced activity. The poorly functioning enzyme cannot efficiently add mannose to the sugar chains, leading to incomplete oligosaccharides. Although these shortened oligosaccharides can still be transferred to proteins, the process is not as efficient as with full-length chains, resulting in under-glycosylated proteins. This impairment in the N-linked glycosylation pathway underlies the symptoms observed in individuals with ALG1-CDG.
Recognizing and Addressing ALG1-CDG
Individuals with ALG1-CDG exhibit a range of symptoms, often appearing during infancy, that can affect multiple body systems. Neurological manifestations are common, including developmental delay, intellectual disability, weak muscle tone (hypotonia), seizures, and movement problems such as tremors or difficulties with balance and coordination.
Beyond neurological issues, other symptoms can include liver dysfunction, gastrointestinal problems like diarrhea, and blood clotting abnormalities that may lead to bleeding or thrombotic episodes. Physical abnormalities such as small head size (microcephaly), unusual facial features, or joint contractures can also be present.
Diagnosis begins with a clinical evaluation and laboratory tests for abnormal glycosylation patterns. A definitive diagnosis is confirmed through genetic testing to identify specific mutations in the ALG1 gene. Currently, there is no specific cure for ALG1-CDG; management focuses on supportive care and addressing individual symptoms through a multidisciplinary approach.