Osteogenesis Imperfecta

name: Osteogenesis Imperfecta
display_name: Osteogenesis Imperfecta
creation_date: "2026-06-14T00:00:00Z"
description: >-
  A curated grouping of explicit osteogenesis imperfecta disease entries
  spanning classic COL1A1/COL1A2-related type I collagen quantitative and
  structural disorders, IFITM5-related type V disease, and CRTAP-related type
  VII disease. Members share intrinsic bone fragility with recurrent or prenatal
  fractures, low bone mass, abnormal bone matrix or mineralization, skeletal
  deformity, and variable extraskeletal connective-tissue manifestations.
grouping_basis:
- SHARED_MECHANISM
- SHARED_PHENOTYPE
grouping_rationale: >-
  Grouped as an explicit curated union of Disease entries that are named
  osteogenesis imperfecta subtypes, not as all skeletal dysplasias, all
  osteoporosis disorders, or every MONDO descendant. The shared boundary is
  intrinsic heritable brittle-bone disease caused by defects in type I collagen
  quantity or structure, collagen post-translational modification/folding, bone
  matrix mineralization, or osteoblast differentiation/signaling. Current
  members include the curated KB entries for types I, II, III, IV, V, VI, VII,
  and VIII; future batches can add high-value missing OI subtypes such as type
  IX, X, XI, XIII, WNT1-related OI, and other dyadic gene-defined OI entities.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0019019
      label: osteogenesis imperfecta
    mapping_predicate: skos:closeMatch
    mapping_source: MONDO
    mapping_justification: >-
      closeMatch: the grouping corresponds to the MONDO osteogenesis imperfecta
      class, but is implemented as an explicit curated subset of current
      dismech Disease entries rather than as an automatic ontology closure over
      all OI and OI-like disorders.
    consistency:
    - reference: MONDO
      consistent: CONSISTENT
      notes: >-
        Listed members are MONDO osteogenesis imperfecta type I, II, III, IV, V,
        VI, VII, and VIII entries currently available in the knowledge base. Additional
        MONDO OI subtypes should be added only when standalone Disease entries
        are curated.
membership_criteria:
- description: >-
    A member is an explicit osteogenesis imperfecta disease entry with intrinsic
    heritable bone fragility and at least one core OI manifestation such as
    recurrent fractures, multiple prenatal fractures, reduced bone mineral
    density, or osteoporosis.
  criteria_semantics: NECESSARY
  logic:
    operator: OR
    operands:
    - criterion_predicate: HAS_PHENOTYPE
      description: Recurrent fractures.
      phenotype_term:
        preferred_term: Recurrent fractures
        term:
          id: HP:0002757
          label: Recurrent fractures
    - criterion_predicate: HAS_PHENOTYPE
      description: Multiple prenatal fractures.
      phenotype_term:
        preferred_term: Multiple prenatal fractures
        term:
          id: HP:0005855
          label: Multiple prenatal fractures
    - criterion_predicate: HAS_PHENOTYPE
      description: Reduced bone mineral density.
      phenotype_term:
        preferred_term: Reduced bone mineral density
        term:
          id: HP:0004349
          label: Reduced bone mineral density
    - criterion_predicate: HAS_PHENOTYPE
      description: Osteoporosis.
      phenotype_term:
        preferred_term: Osteoporosis
        term:
          id: HP:0000939
          label: Osteoporosis
members:
- member: Osteogenesis Imperfecta Type I
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Mild non-deforming OI most often caused by COL1A1 haploinsufficiency,
      producing reduced quantity of otherwise normal type I collagen with
      recurrent fractures, blue sclerae, osteoporosis, and variable
      dentinogenesis imperfecta or hearing impairment.
    gene:
      preferred_term: COL1A1
      term:
        id: hgnc:2197
        label: COL1A1
- member: Osteogenesis Imperfecta Type II
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Perinatal-lethal OI caused by severe dominant-negative type I collagen
      structural defects, with multiple prenatal fractures, profound reduced
      bone mineral density, crumpled long bones, rib fractures, and respiratory
      compromise.
    gene:
      preferred_term: COL1A1
      term:
        id: hgnc:2197
        label: COL1A1
  - description: >-
      COL1A2 structural variants can produce the same lethal type II collagen
      matrix phenotype with severely abnormal bone formation and prenatal
      fractures.
    gene:
      preferred_term: COL1A2
      term:
        id: hgnc:2198
        label: COL1A2
- member: Osteogenesis Imperfecta Type III
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Severe progressively deforming OI caused by dominant-negative COL1A1 or
      COL1A2 collagen structural variants, with recurrent fractures, severe
      short stature, scoliosis, dentinogenesis imperfecta, reduced bone mineral
      density, and loss of ambulation in severe cases.
    gene:
      preferred_term: COL1A1
      term:
        id: hgnc:2197
        label: COL1A1
  - description: >-
      COL1A2 dominant-negative variants can drive the type III progressive
      deforming phenotype through abnormal type I collagen fibril organization
      and bone development.
    gene:
      preferred_term: COL1A2
      term:
        id: hgnc:2198
        label: COL1A2
- member: Osteogenesis Imperfecta Type IV
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      Moderate OI caused by COL1A1 or COL1A2 collagen defects, with recurrent
      fractures, reduced bone mineral density, bowing of the long bones,
      scoliosis, dentinogenesis imperfecta, and variable scleral color.
    gene:
      preferred_term: COL1A1
      term:
        id: hgnc:2197
        label: COL1A1
  - description: >-
      COL1A2 variants contribute to the genetically heterogeneous type IV
      spectrum through impaired collagen folding, fibril organization, and bone
      mineralization.
    gene:
      preferred_term: COL1A2
      term:
        id: hgnc:2198
        label: COL1A2
- member: Osteogenesis Imperfecta Type V
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      IFITM5-related non-collagen OI, usually driven by the recurrent 5' UTR
      gain-of-function variant, with recurrent fractures plus distinctive
      hyperplastic callus formation, interosseous membrane calcification,
      radial-head dislocation, dense metaphyseal bands, and abnormal osteoblast
      differentiation/signaling.
    gene:
      preferred_term: IFITM5
      term:
        id: hgnc:16644
        label: IFITM5
- member: Osteogenesis Imperfecta Type VI
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SERPINF1-related recessive OI with structurally normal type I collagen and
      a unique primary mineralization defect: loss of secreted PEDF causes
      accumulation of unmineralized osteoid with a pathognomonic "fish-scale"
      lamellation pattern and increased RANKL-driven osteoclastic resorption.
      Distinguished by post-natal fracture onset, white/faintly blue sclerae,
      absent dentinogenesis imperfecta and hearing loss, elevated childhood serum
      alkaline phosphatase, and a characteristic responsiveness to anti-RANKL
      denosumab rather than bisphosphonates.
    gene:
      preferred_term: SERPINF1
      term:
        id: hgnc:8824
        label: SERPINF1
    module: osteoporosis_bone_resorption
- member: Osteogenesis Imperfecta Type VII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CRTAP-related recessive OI caused by impaired collagen prolyl
      3-hydroxylation and collagen folding/post-translational modification,
      with recurrent fractures, rhizomelia, growth delay, severe osteoporosis,
      and skeletal deformity.
    gene:
      preferred_term: CRTAP
      term:
        id: hgnc:2379
        label: CRTAP
- member: Osteogenesis Imperfecta Type VIII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      P3H1 (LEPRE1)-related recessive OI; the closest sibling of type VII,
      caused by loss of the same ER prolyl 3-hydroxylation complex (P3H1 is the
      enzymatic subunit that mutually stabilizes CRTAP). Loss leaves alpha1(I)
      Pro986 unmodified, delays collagen folding, and causes overmodification
      and a defective, extremely undermineralized bone matrix. Severe-to-lethal
      with white sclerae and rhizomelia; relatively frequent in West African and
      African American populations through the c.1080+1G>T founder allele.
    gene:
      preferred_term: P3H1
      term:
        id: hgnc:19316
        label: P3H1
- member: Osteogenesis Imperfecta Type IX
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      PPIB-related recessive OI; the third member of the same ER prolyl
      3-hydroxylation complex (cyclophilin B, the peptidyl-prolyl cis-trans
      isomerase subunit). Unlike CRTAP/P3H1, CyPB stability is independent of
      the other subunits, and the biochemical consequences of its loss are
      heterogeneous — some severe cases show reduced alpha1(I)Pro986
      3-hydroxylation with overmodification, while moderate cases retain normal
      3-hydroxylation and folding. The phenotype spans perinatally lethal to
      moderate disease; rhizomelia is variable and severity-dependent (typically
      absent in moderate cases, with a rhizomelic trend reported in severe cases,
      unlike its consistent presence in types VII/VIII), implicating loss of the
      CyPB folding and chain-association function rather than loss of
      3-hydroxylation per se.
    gene:
      preferred_term: PPIB
      term:
        id: hgnc:9255
        label: PPIB
- member: Osteogenesis Imperfecta Type X
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SERPINH1-related recessive OI. SERPINH1 encodes HSP47, the collagen-specific
      ER molecular chaperone; loss impairs procollagen folding/quality control and
      secretion, producing a defective, undermineralized bone matrix. A
      collagen-chaperone OI distinct from the prolyl 3-hydroxylation-complex types.
    gene:
      preferred_term: SERPINH1
      term:
        id: hgnc:1546
        label: SERPINH1
- member: Osteogenesis Imperfecta Type XI
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      FKBP10-related recessive OI. FKBP10 encodes FKBP65, an ER peptidyl-prolyl
      isomerase/chaperone required for collagen telopeptide lysyl hydroxylation
      (via LH2/PLOD2) and intermolecular cross-linking; loss yields defective
      collagen cross-linking. Spans the OI–Bruck syndrome (type II) continuum
      (OI with congenital joint contractures).
    gene:
      preferred_term: FKBP10
      term:
        id: hgnc:18169
        label: FKBP10
- member: Osteogenesis Imperfecta Type XII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SP7-related recessive OI. SP7 (Osterix) is an osteoblast-specific
      transcription factor acting downstream of RUNX2; loss-of-function impairs
      osteoblast differentiation and bone formation — a transcription-factor OI
      distinct from the collagen-structural and collagen-modification types.
    gene:
      preferred_term: SP7
      term:
        id: hgnc:17321
        label: SP7
- member: Osteogenesis Imperfecta Type XIII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      BMP1-related recessive OI. BMP1 is the procollagen C-proteinase that cleaves
      the C-propeptide of type I procollagen; defective processing impairs collagen
      fibril maturation. Distinctively associated with high/increased bone mineral
      density in most patients (bisphosphonate caution).
    gene:
      preferred_term: BMP1
      term:
        id: hgnc:1067
        label: BMP1
- member: Osteogenesis Imperfecta Type XIV
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TMEM38B-related recessive OI. TMEM38B encodes TRIC-B, an ER-membrane
      monovalent-cation channel that balances ER Ca2+ release; loss disrupts
      intracellular Ca2+ flux required for osteoblast collagen synthesis,
      secretion, and mineralization — a Ca2+-homeostasis OI.
    gene:
      preferred_term: TMEM38B
      term:
        id: hgnc:25535
        label: TMEM38B
- member: Osteogenesis Imperfecta Type XV
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      WNT1-related recessive OI. WNT1 is a Wnt ligand driving canonical
      WNT/beta-catenin signaling essential for osteoblast differentiation and bone
      formation; biallelic loss → low bone mass and fragility (a signaling-pathway
      OI), with CNS involvement in the severe subset. Heterozygous WNT1 variants
      cause early-onset osteoporosis.
    gene:
      preferred_term: WNT1
      term:
        id: hgnc:12774
        label: WNT1
- member: Osteogenesis Imperfecta Type XVI
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CREB3L1-related recessive OI. CREB3L1 encodes OASIS, an ER-stress-induced
      bZIP transcription factor (activated by regulated intramembrane proteolysis)
      that transcriptionally activates COL1A1 in osteoblasts; loss reduces type I
      collagen synthesis. Mechanistically linked to MBTPS2 (type XIX).
    gene:
      preferred_term: CREB3L1
      term:
        id: hgnc:18856
        label: CREB3L1
- member: Osteogenesis Imperfecta Type XVII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      SPARC-related recessive OI. SPARC encodes osteonectin, a collagen-binding
      matricellular glycoprotein regulating collagen fibril assembly, matrix
      maturation, and mineralization; loss yields a defective bone ECM — an
      extracellular matricellular-protein OI.
    gene:
      preferred_term: SPARC
      term:
        id: hgnc:11219
        label: SPARC
- member: Osteogenesis Imperfecta Type XVIII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      TENT5A (FAM46A)-related recessive OI. TENT5A is a non-canonical cytoplasmic
      poly(A) polymerase that polyadenylates and stabilizes mRNAs encoding
      osteoblast secretory/ECM proteins (including type I collagen); loss
      destabilizes these transcripts, reducing bone matrix protein output.
    gene:
      preferred_term: TENT5A
      term:
        id: hgnc:18345
        label: TENT5A
- member: Osteogenesis Imperfecta Type XIX
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MBTPS2-related OI — the only X-linked recessive OI type. MBTPS2 encodes
      site-2 protease (S2P), which performs regulated intramembrane proteolysis
      activating OASIS/CREB3L1 (type XVI) and SREBP; hypomorphic loss impairs
      OASIS-driven COL1A1 transcription and collagen synthesis in affected males.
    gene:
      preferred_term: MBTPS2
      term:
        id: hgnc:15455
        label: MBTPS2
- member: Osteogenesis Imperfecta Type XX
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      MESD-related recessive OI. MESD is an ER chaperone required for folding and
      trafficking of the Wnt co-receptors LRP5/LRP6; hypomorphic loss impairs
      WNT/beta-catenin signaling (the same osteoanabolic axis as WNT1, type XV) →
      reduced osteoblast bone formation. Complete loss is lethal.
    gene:
      preferred_term: MESD
      term:
        id: hgnc:13520
        label: MESD
- member: Osteogenesis Imperfecta Type XXI
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      KDELR2-related recessive OI. KDELR2 is a KDEL ER-retrieval receptor required
      to release the collagen chaperone HSP47 (SERPINH1, type X) from procollagen
      in the cis-Golgi/ERGIC; loss traps HSP47 on procollagen, disrupting collagen
      secretion. Mechanistically linked to SERPINH1.
    gene:
      preferred_term: KDELR2
      term:
        id: hgnc:6305
        label: KDELR2
- member: Osteogenesis Imperfecta Type XXII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      CCDC134-related recessive OI. CCDC134 is a secreted ER-resident protein that
      regulates osteoblast differentiation/bone formation (modulating MAPK and
      WNT/beta-catenin signaling); biallelic loss impairs bone formation.
    gene:
      preferred_term: CCDC134
      term:
        id: hgnc:26185
        label: CCDC134
- member: Osteogenesis Imperfecta Type XXIII
  member_type: DISEASE
  differentiating_mechanisms:
  - description: >-
      PHLDB1-related recessive OI — a recently described, mild-type entity
      (recurrent fractures, osteopenia, platyspondyly, short bowed long bones with
      regressive spondylometaphyseal changes). The molecular mechanism linking
      PHLDB1 loss-of-function to bone fragility is not yet established.
    gene:
      preferred_term: PHLDB1
      term:
        id: hgnc:23697
        label: PHLDB1
notes: >-
  Exclude isolated osteoporosis, hypophosphatasia, achondrogenesis,
  atelosteogenesis, Ehlers-Danlos syndrome, and broad skeletal dysplasia entries
  unless the standalone Disease entry is explicitly curated as osteogenesis
  imperfecta or as a clearly labeled OI/brittle-bone boundary entity.