Disorders of O-linked Protein Glycosylation (incl. glycosaminoglycan synthesis)

name: Disorders of O-linked Protein Glycosylation
display_name: Disorders of O-linked Protein Glycosylation (incl. glycosaminoglycan synthesis)
creation_date: "2026-09-17T00:00:00Z"
description: >-
  Inherited disorders in which the lesion is in an O-linked glycan — a sugar
  attached to the hydroxyl oxygen of a serine or threonine, rather than to an
  asparagine amide as in the N-linked disorders. The branch is defined by its
  first sugar, and the members divide accordingly: O-mannose on
  alpha-dystroglycan, O-fucose and O-glucose on thrombospondin type-1 repeats,
  and the O-xylose linker that starts every glycosaminoglycan chain on a
  proteoglycan core protein. Because each first sugar is added to a different
  client protein family, the clinical pictures diverge sharply — muscular
  dystrophy with brain and eye malformation, anterior-segment dysgenesis, and
  skeletal/connective-tissue disease — while the biosynthetic lesion is the same
  kind of lesion.
grouping_basis:
- SHARED_PATHWAY
- CLINICAL_CONVENTION
grouping_rationale: >-
  Grouped on the shared O-linked branch of protein glycosylation, and on ICIMD's
  own subdivision of category 18, whose O-linked node is titled "Disorders of
  O-linked protein glycosylation (including glycosaminoglycan synthesis)"
  (Ferreira et al. 2021, PMID:33340416). That parenthesis is the reason the
  glycosaminoglycan disorders sit here rather than in a grouping of their own: a
  GAG chain is built on an O-xylose attached to a serine of the core protein, so
  a linker-region or chain-initiation defect is an O-linked glycosylation defect
  by construction.

  Members are kept as separate Disease entries because the first sugar, the
  client protein family, and the resulting disease differ at every point:
  O-mannosylation of alpha-dystroglycan (the dystroglycanopathy gene series,
  POMT1/POMT2 through LARGE1), O-glucosylation of folded thrombospondin type-1
  repeats (B3GLCT, Peters plus syndrome), and the glycosaminoglycan route, itself
  split between the shared linker tetrasaccharide (B3GAT3, a linkeropathy) and
  heparan-sulfate chain initiation and polymerization (EXTL3, EXT2).

  Boundary. This grouping is the O-linked sibling of
  Congenital_Disorders_of_Glycosylation (N-linked),
  Disorders_of_GPI_Anchor_Biosynthesis (lipid), and
  Other_Multiple_Glycosylation_Pathway_Disorders (branch-non-specific), and sits
  with them under Disorders of Protein and Lipid Glycosylation. A disorder whose
  lesion hits several branches at once belongs in the multiple-pathway sibling
  even when O-linked glycosylation is among them — Golgi pH, Golgi calcium, and
  nucleotide-sugar supply defects are not O-linked disorders merely because
  O-glycans are among their casualties. The lysosomal *catabolism* of
  glycosaminoglycans is a different subject again and stays with the
  Mucopolysaccharidoses under Lysosomal_Storage_Disorders; only GAG *synthesis*
  is in scope here.

  The `tsr_o_glycosylation_quality_control` module covers the O-fucose/O-glucose
  quality-control mechanism that Peters plus syndrome conforms to. A module is
  never a grouping member, so it is named here rather than listed.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0015286
      label: congenital disorder of glycosylation
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO has no class corresponding to the O-linked subdivision alone, so this
      grouping is anchored as a narrowMatch to the broad
      congenital-disorder-of-glycosylation class that its parent grouping matches
      exactly. narrowMatch, not exactMatch, because the mapped class additionally
      covers the N-linked, GPI-anchor, and multiple-pathway branches that the
      sibling groupings hold.
    consistency:
    - reference: MONDO
      consistent: INCONSISTENT
      notes: >-
        Re-derived 2026-09-27 with just grouping-mondo-consistency, which walks
        each member's own MONDO term up to its ancestors rather than expanding
        the class downward: 3 of the 5 members are hierarchical descendants of
        MONDO:0015286. The two outside it are Dystroglycanopathy
        (MONDO:0018276, which MONDO classifies under muscular dystrophy) and
        Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities
        (MONDO:0044312, under skeletal system disorder). Both are MONDO
        classifying a disease by clinical presentation rather than by the
        glycosylation lesion, which is a candidate MONDO term request and not a
        membership error here; Peters plus syndrome, the Larsen-like B3GAT3
        entry and the EXT2 entry all do descend, so the anticipated
        presentation-classification problem is real but narrower than expected.
        Recorded INCONSISTENT because that is the measurement, not because the
        membership is doubted.
membership_criteria:
- description: >-
    A member's primary lesion is in the synthesis or extension of a glycan
    attached through an O-linkage to a serine or threonine of a protein —
    including the O-xylose-linked glycosaminoglycan chains of proteoglycans,
    which ICIMD places in this subdivision. Lesions that hit several
    glycosylation branches at once, and the lysosomal catabolism of
    glycosaminoglycans, are excluded.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    description: >-
      Perturbs protein O-linked glycosylation, or the biosynthesis of a
      glycosaminoglycan or proteoglycan — the two arms ICIMD's O-linked
      subdivision names. Ontology closure carries the first-sugar-specific
      classes (O-mannose, O-glucose, O-fucose) into the first operand.
    operands:
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        Impairs protein O-linked glycosylation, at any first sugar.
      biological_processes:
      - preferred_term: protein O-linked glycosylation
        term:
          id: GO:0006493
          label: protein O-linked glycosylation
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        Impairs glycosaminoglycan biosynthesis — the linker tetrasaccharide or
        chain extension.
      biological_processes:
      - preferred_term: glycosaminoglycan biosynthetic process
        term:
          id: GO:0006024
          label: glycosaminoglycan biosynthetic process
    - criterion_predicate: HAS_BIOLOGICAL_PROCESS
      description: >-
        Impairs proteoglycan biosynthesis. Carried alongside the
        glycosaminoglycan operand because the KB annotates several of these
        disorders at the proteoglycan-product classes (heparan sulfate,
        chondroitin sulfate) rather than at the glycosaminoglycan class.
      biological_processes:
      - preferred_term: proteoglycan biosynthetic process
        term:
          id: GO:0030166
          label: proteoglycan biosynthetic process
  evidence:
  - reference: PMID:33340416
    reference_title: "An international classification of inherited metabolic disorders (ICIMD)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Congenital Disorders of Glycosylation (CDG) are divided into disorders
      affecting N-linked and O-linked protein glycosylation (including
      glycosaminoglycan synthesis), disorders of lipid glycosylation (including
      the disorders of glycosylphosphatidylinositol biosynthesis), and disorders
      with the potential to affect multiple glycosylation pathways (dolichol
      metabolism, Golgi transport and homeostasis, sialic acid metabolism, and
      others).
    explanation: >-
      Establishes the O-linked subdivision this grouping occupies, and the
      parenthesis placing glycosaminoglycan synthesis inside it rather than in a
      separate category — which is what admits the B3GAT3, EXTL3 and EXT2
      members.
members:
- member: Dystroglycanopathy
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      O-mannosylation of alpha-dystroglycan. The matriglycan that binds laminin
      is built on an O-mannose, so the whole gene series (POMT1, POMT2,
      POMGNT1/2, POMK, B3GALNT2, B4GAT1, RXYLT1, FKTN, FKRP, LARGE1, CRPPA)
      converges on loss of laminin binding at the muscle and pial basement
      membrane.
    module: pial_basement_membrane_radial_glial_endfoot_failure
- member: Peters plus syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      O-glucosylation of thrombospondin type-1 repeats. B3GLCT extends the
      O-fucose on a correctly folded TSR with glucose, so the client set is the
      TSR-containing ADAMTS and ADAMTSL secreted proteins rather than a membrane
      glycoprotein, and the disease is an anterior-segment dysgenesis with
      skeletal features.
    gene:
      preferred_term: B3GLCT
      term:
        id: hgnc:20207
        label: B3GLCT
    module: tsr_o_glycosylation_quality_control
- member: Larsen-like Syndrome B3GAT3 Type
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      The glycosaminoglycan linker tetrasaccharide. B3GAT3 adds the terminal
      glucuronic acid of the common GlcA-Gal-Gal-Xyl linker, so both heparan and
      chondroitin sulfate chains fail at once — the linkeropathy pattern of joint
      dislocation, short stature and congenital heart defect.
    gene:
      preferred_term: B3GAT3
      term:
        id: hgnc:923
        label: B3GAT3
- member: Immunoskeletal Dysplasia with Neurodevelopmental Abnormalities
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heparan sulfate chain initiation. EXTL3 transfers the first GlcNAc onto the
      completed linker, committing the chain to heparan sulfate, which is why the
      phenotype adds T-cell immunodeficiency and neurodevelopmental involvement to
      the skeletal dysplasia rather than reproducing the linkeropathy.
    gene:
      preferred_term: EXTL3
      term:
        id: hgnc:3518
        label: EXTL3
- member: Seizures-scoliosis-macrocephaly syndrome
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Heparan sulfate chain polymerization. Biallelic hypomorphic EXT2 shortens
      the chain rather than initiating it, and is a distinct disease from the
      heterozygous EXT2 loss that causes hereditary multiple exostoses — the same
      gene, a different dose and a different phenotype.
    gene:
      preferred_term: EXT2
      term:
        id: hgnc:3513
        label: EXT2
notes: >-
  Created to fill the O-linked hole in Disorders of Protein and Lipid
  Glycosylation, which nested the N-linked, lipid and multiple-pathway children
  of ICIMD category 18 but had no member for its O-linked subdivision. The five
  members were already carrying classifications.icimd_category
  o_linked_protein_glycosylation and were surfaced as candidates by that
  grouping's SUFFICIENT criterion.

  Three of the five are glycosaminoglycan-synthesis disorders and only two are
  protein O-glycosylation disorders in the narrow sense. That ratio is a
  consequence of ICIMD's subdivision, not of a curation choice here, and it is
  worth knowing when reading the group: if the GAG disorders later outgrow this
  home, the split to make is B3GAT3/EXTL3/EXT2 into a grouping of the linker and
  heparan-sulfate disorders nested *below* this one, not a move out to a sibling,
  because the O-xylose linkage is what puts them in this branch.

  Dystroglycanopathy is itself a grouping-shaped Disease entry — one file
  covering an 18-gene series — and is listed as a DISEASE member because that is
  how the KB curates it. If it is ever split into per-gene entries, this
  membership row becomes a nested GROUPING row rather than five new direct rows.

  Not included, deliberately: Short Stature, Amelogenesis Imperfecta, and
  Skeletal Dysplasia with Scoliosis and Autosomal Recessive Cutis Laxa Type 2A
  both annotate protein O-linked glycosylation, but their lesions are Golgi
  calcium homeostasis and Golgi acidification respectively, which cripple N- and
  O-linked glycosylation together; both carry
  icimd_category multiple_glycosylation_pathways and belong to the
  multiple-pathway sibling. O-glycosylation being among a disorder's casualties
  does not make it an O-linked disorder.