Alg1 is a gene involved in the early steps of the N-glycosylation pathway , in the synthesis of the N-glycan precursor. As almost all the genes involved in this process, it is associated with a Congenital Disorder of Glycosylation.

Disease relevance of ALG1

• The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907) [1].

Psychiatry related information on ALG1

• A mannosyltransferase gene at 11q23 is disrupted by a translocation breakpoint that co-segregates with bipolar affective disorder in a small family [2]. (no it refers to ALG9)
• Congenital disorder of glycosylation type Id is an inherited glycosylation disorder based on a defect of the first mannosyltransferase involved in N-glycan biosynthesis inside the endoplasmic reticulum [3].

High impact information on ALG1

• In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif [4]. (no this is another gene)
• In the absence of catalytically active Hmt1, yeast cells display increased transcription from silent chromatin regions and increased mitotic recombination within tandem repeats of rDNA [5].
• The developmental timing regulator AIN-1 interacts with miRISCs and may target the argonaute protein ALG-1 to cytoplasmic P bodies in C. elegans [6].
• When coexpressed from transgenes, AIN-1 targets ALG-1 to the foci [6].
• The mannosyltransferase is the structural and functional orthologue of the Saccharomyces cerevisiae ALG3 gene [7].

Biological context of ALG1

• Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I [8].
• Glycosylation and growth of Alg1-deficient PRY56 yeast cells, showing a temperature-sensitive phenotype, could be restored by the human wild-type allele, whereas only slight restoration was observed after transformation with the patients' alleles [8].
• The amino acid sequence deduced from the Hmat-1 gene showed several highly conserved regions shared with the yeast and nematode MT-I sequences [9].
• Here we show that the molecular defect in the index patient is a missense mutation in the gene encoding the mannosyltransferase that transfers mannose from dolichyl-phosphate mannose on to the lipid-linked oligosaccharide (LLO) intermediate Man(5)GlcNAc(2)-PP-dolichol [7].
• Recombinant Sbp1p modified by Hmt1p in vivo were isolated by affinity chromatography followed by electrophoresis on a polyacrylamide gel and subjected to acid hydrolysis [10].

Anatomical context of ALG1

• The disease-causing nature of the hALG1 mutation for the glycosylation defect was verified by a retroviral complementation approach in patient-derived primary fibroblasts and was confirmed by the expression of wild-type and mutant hALG1 in the Saccharomyces cerevisiae alg1-1 strain [1].
• The dolichol-dependent mannosyltransferase activities were highest for the rough endoplasmic reticulum, lower for the smooth endoplasmic reticulum, and lowest for the Golgi complex [11].
• Further identification of the glycosylated residues suggests that both Csg1 and Csh1 exhibit membrane topology with their C termini in the cytosol and their mannosyltransferase domains in the lumen [12].
• Deficiency of the endoplasmic reticulum enzyme dolichyl-phosphate mannose (Dol-P-Man):Man(7)GlcNAc(2)-PP-dolichyl mannosyltransferase leads to a new type of congenital disorder of glycosylation, designated type Ig [13].
• Although GDP-4FMan and Dol-P-4FMan were identified as metabolites of 4FMan in BHK cells labelled with [1-14C]4FMan, GDP-4FMan was a very poor substrate for GDP-Man:Dol-P mannosyltransferase and Dol-P-4FMan could only be synthesized in vitro if the chick-embryo cell membranes were primed with Dol-P [14].

Associations of ALG1 with chemical compounds

• Genetic analysis of the patient's hALG1 gene identified a homozygous mutation leading to the exchange of a serine residue to leucine at position 258 in the hALG1 protein [1].
• The accumulation pattern suggested a deficiency of the ALG1 beta1,4 mannosyltransferase, which adds the first mannose residue to lipid-linked oligosaccharides [15].
• Incubation of patient fibroblast extracts with Man1GlcNAc2-PP-dolichol and GDP-mannose revealed a severely reduced activity of the mannosyltransferase elongating Man1GlcNAc2-PP dolichol [16].
• In the patient's fibroblasts, the biosynthetic intermediate GlcNAc(2)Man(7) oligosaccharide was detected both on the lipid carrier dolichyl pyrophosphate and on newly synthesized glycoproteins, thus pointing to a defect in the dolichyl pyrophosphate-GlcNAc(2)Man(7)-dependent ALG12 alpha1,6 mannosyltransferase [17].
• The 4'-OH group of GlcN is essential for the inositol acyltransferase and first mannosyltransferase [18].

Other interactions of ALG1

• Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2-1 yeast cells. hALG2 was shown to act as an alpha1,3-mannosyltransferase [16].
• Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 alpha 1,2 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc(2)Man(6) and -GlcNAc(2)Man(8) structures, which was paralleled by the transfer of incomplete oligosaccharides precursors to protein [19].
• Approximately one-fifth of the WWS patients show mutations in POMT1, which result in complete loss of protein mannosyltransferase activity [20].
• 8. The majority of N-acetylglucosaminyltransferase (90%) and mannosyltransferase (85%) activities is particulate but approximately 90% of both activities can be released into supernatant fluids by using Triton X-100 in the homogenizing buffer [21].

Analytical, diagnostic and therapeutic context of ALG1

• Using the findings from this meta-analysis, along with suggestions and guidelines of previous researchers, we developed the Human Motor Area Template (HMAT) that can be used for ROI analysis [22].

References