Affinage

ALG12

Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase · UniProt Q9BV10

Length
488 aa
Mass
54.7 kDa
Annotated
2026-06-09
11 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALG12 is an ER-resident alpha-1,6-mannosyltransferase that catalyzes addition of the eighth mannose residue to the dolichyl-pyrophosphate-linked GlcNAc2Man7 intermediate during assembly of the N-linked glycan precursor (PMID:12217961). Catalytic necessity of this step was established by yeast complementation, where wild-type human ALG12 cDNA rescued the yeast alg12 growth defect while patient-derived missense mutants did not, and by detection of GlcNAc2Man7 accumulation on dolichyl-PP and nascent glycoproteins in patient cells (PMID:12217961). Loss of ALG12 activity defines a congenital disorder of glycosylation: patient cells accumulate truncated Man5-7-capped lipid-linked oligosaccharides with corresponding depletion of Man8-9 species, and the resulting defect manifests both as N-glycosylation site underoccupancy and as accumulation of aberrantly processed high-mannose and hybrid glycans on serum glycoproteins (PMID:31529350, PMID:34467644, PMID:39984963). ALG12 expression is responsive to ER stress, being upregulated through an ER stress response element in a bidirectional promoter it shares with CRELD2, consistent with ATF6-mediated control (PMID:21106106).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2002 High

    Established the molecular identity and catalytic role of ALG12, answering what enzymatic step it performs in N-glycan precursor assembly and which residues are essential.

    Evidence Yeast complementation with site-directed ALG12 mutants plus metabolic labeling of patient fibroblasts detecting GlcNAc2Man7 accumulation

    PMID:12217961

    Open questions at the time
    • No in vitro reconstitution of the purified enzyme with defined substrate
    • No structural model of the mannosyltransferase active site
    • Topology and ER membrane orientation not directly resolved
  2. 2010 Medium

    Addressed how ALG12 expression is regulated, showing it is transcriptionally responsive to ER stress via a shared bidirectional promoter.

    Evidence Bidirectional reporter assays with ERSE variants in Neuro2a cells plus microarray/qPCR after thapsigargin, tunicamycin, and brefeldin A treatment

    PMID:21106106

    Open questions at the time
    • Direct ATF6 binding to the ERSE not demonstrated by ChIP
    • Functional consequence of co-regulation with CRELD2 unclear
    • Mouse promoter data not confirmed in human cells
  3. 2019 Medium

    Demonstrated that the consequences of ALG12 deficiency extend beyond site underoccupancy to downstream mis-processing of protein-linked glycans.

    Evidence MALDI-MS and LC-ESI-MS profiling of serum transferrin, IgG, and total serum N-glycans from an ALG12-CDG patient

    PMID:31529350

    Open questions at the time
    • Single patient, no independent replication
    • Mechanism linking lipid-linked precursor truncation to hybrid glycan formation not dissected
    • Tissue specificity of the dual defect unknown
  4. 2021 Medium

    Confirmed that a novel homozygous missense variant impairs the alpha-1,6-mannosyltransferase step through the expected glycomic signature.

    Evidence Mass spectrometry of serum N-glycans, transferrin isoelectric focusing, and genetic analysis of a patient

    PMID:34467644

    Open questions at the time
    • No in vitro reconstitution of mutant enzyme activity
    • Single patient
    • Quantitative residual activity of the variant not measured
  5. 2025 Medium

    Showed that a non-coding splice-disrupting variant causes disease by drastically lowering ALG12 transcript abundance rather than altering protein sequence, expanding the mutational mechanisms underlying ALG12-CDG.

    Evidence Metabolic radiolabelling of patient fibroblasts detecting Man7GlcNAc2-PP-dolichol, cDNA sequencing, and quantitative mRNA measurement

    PMID:39984963

    Open questions at the time
    • Single lab and patient
    • Residual enzyme function from the ~3% mRNA not quantified
    • Genotype-phenotype relationship for hypomorphic loss not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALG12 is recruited into the ER glycosylation machinery and the structural basis of its substrate specificity remain unresolved.
  • No structural model or active-site characterization
  • No identified physical interaction partners within the ALG mannosyltransferase pathway
  • No purified-enzyme kinetic characterization

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 3

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ALG12 encodes an ER-localized alpha1,6-mannosyltransferase that adds the eighth mannose residue (in an α1,6 linkage) to the dolichyl pyrophosphate-GlcNAc2Man7 intermediate during N-linked glycan assembly. Loss-of-function mutations (T67M and R146Q in human; homologous T61M and R161Q in yeast) abolished complementation of the yeast alg12 growth defect, while wild-type human ALG12 cDNA rescued it, establishing catalytic necessity of these residues. Yeast complementation assay with site-directed mutant ALG12 constructs; metabolic labeling of patient fibroblasts detecting GlcNAc2Man7 accumulation on dolichyl-PP and nascent glycoproteins Human molecular genetics High 12217961
2019 ALG12 deficiency causes dual glycosylation defects: in addition to the expected CDG-I underoccupancy of N-glycosylation sites (detected on transferrin), it also produces accumulation of high-mannose and hybrid N-glycan structures on total serum proteins and IgG, demonstrating that impaired Man8 addition on the lipid-linked precursor propagates to aberrant processing of protein-linked glycans. MALDI-MS and LC-ESI-MS profiling of serum transferrin, IgG, and total serum N-glycans from an ALG12-CDG patient Glycoconjugate journal Medium 31529350
2010 The mouse ALG12 gene shares a bidirectional promoter with CRELD2 containing an ER stress response element (ERSE). Treatment with ER stress inducers (thapsigargin, tunicamycin, brefeldin A) increases ALG12 mRNA, and the ERSE motif in the intergenic region contributes to this transcriptional upregulation, suggesting ALG12 expression is regulated by ATF6-mediated ER stress signaling. Bidirectional reporter construct assays in Neuro2a cells with ERSE variant constructs; microarray and qPCR of ALG12 mRNA after ER stress induction BMC genomics Medium 21106106
2021 A homozygous ALG12 mutation (c.1439T>C, p.Leu480Pro) results in impaired ALG12 enzymatic activity evidenced by accumulation of GlcNAc2Man5-7 and decreased GlcNAc2Man8-9 in patient serum N-glycans, consistent with loss of the α1,6-mannosyltransferase step. Mass spectrometry of neutral serum N-glycans from patient fibroblasts/serum; isoelectric focusing of transferrin; genetic analysis American journal of medical genetics. Part A Medium 34467644
2025 An intronic ALG12 variant (c.-79+2 T>C) upstream of the first coding exon disrupts the canonical splice donor site of intron 1, causing a 4-base insertion in the mRNA between exon 1 and exon 2 and reducing ALG12 mRNA to ~3% of control levels in patient fibroblasts, with consequent Man7GlcNAc2-PP-dolichol accumulation confirming loss of ALG12 mannosyltransferase function. Metabolic radiolabelling of patient fibroblasts detecting lipid-linked oligosaccharide intermediates; ALG12 cDNA sequencing; quantitative mRNA measurement Orphanet journal of rare diseases Medium 39984963

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 ALG12 mannosyltransferase defect in congenital disorder of glycosylation type lg. Human molecular genetics 62 12217961
2014 Diagnosis of ALG12-CDG by exome sequencing in a case of severe skeletal dysplasia. Molecular genetics and metabolism reports 20 25019053
2019 ALG12-CDG: novel glycophenotype insights endorse the molecular defect. Glycoconjugate journal 19 31529350
2020 ALG12-CDG: An unusual patient without intellectual disability and facial dysmorphism, and with a novel variant. Molecular genetics & genomic medicine 13 32530140
2021 A novel homozygous mutation in the human ALG12 gene results in an aberrant profile of oligomannose N-glycans in patient's serum. American journal of medical genetics. Part A 10 34467644
2010 Role of an ER stress response element in regulating the bidirectional promoter of the mouse CRELD2 - ALG12 gene pair. BMC genomics 7 21106106
2020 A mutation in Asparagine-Linked Glycosylation 12 (ALG12) leads to receptor misglycosylation and attenuated responses to multiple microbial elicitors. FEBS letters 4 32484235
2022 The Role of SBI2/ALG12/EBS4 in the Regulation of Endoplasmic Reticulum-Associated Degradation (ERAD) Studied by a Null Allele. International journal of molecular sciences 2 35628619
2021 A Novel Homozygous ALG12 Mutation in a Patient with CDG Type Ig: New Report of a Case with a Mild Phenotype. Molecular syndromology 2 34602961
2024 Expanded prenatal phenotype of ALG12-associated congenital disorder of glycosylation including bilateral multicystic kidneys. American journal of medical genetics. Part A 1 38717015
2025 An ALG12-CDG patient with a novel homozygous intronic mutation associated with low ALG12 mRNA. Orphanet journal of rare diseases 0 39984963

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