Osteogenesis Imperfecta Type II

Mendelian MONDO:0008147 Osteogenesis imperfecta

Osteogenesis imperfecta type II is the most severe, perinatal lethal form of OI, caused by heterozygous dominant-negative mutations in COL1A1 or COL1A2. Affected infants have extreme bone fragility with multiple prenatal fractures, severe skeletal deformities with crumpled long bones, blue sclerae, and a small bell-shaped thorax. Death usually results from respiratory insufficiency associated with pulmonary hypoplasia. The mutations typically involve glycine substitutions in the Gly-X-Y repeat that disrupt collagen triple helix formation.

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1
Inheritance
2
Pathophys.
11
Phenotypes
1
Genes
1
Treatments
12
References
2
Deep Research
👪

Inheritance

1
Autosomal Dominant
Autosomal dominant inheritance. Most cases arise de novo. Parental gonadal mosaicism accounts for recurrence risk in families with apparently unaffected parents.
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"Most babies have their own private de novo mutation. However, the recurrence rate is about 7% owing to germline mosaicism in one parent."
Establishes that most cases are de novo but 7% recurrence risk due to parental gonadal mosaicism is a key genetic counseling consideration.
⚙

Pathophysiology

2
Dominant-Negative Collagen Disruption
Glycine substitutions in the Gly-X-Y repeat of the collagen triple helical domain disrupt normal helix formation. The abnormal alpha chains are incorporated into trimers, producing structurally defective collagen that cannot form proper fibrils (dominant-negative effect). This results in severe deficiency of functional bone matrix.
Osteoblast link
Collagen Fibril Organization link Ossification link
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"The mutations act in a dominant negative manner as the mutant pro alpha chains are incorporated into type I procollagen molecules that also contain normal pro alpha chains. The abnormal molecules are poorly secreted, more susceptible to degradation, and impair the formation of the extracellular matrix."
Authoritative review establishing the dominant-negative mechanism of glycine substitutions in perinatal lethal OI.
ER Stress and Osteoblast Dysfunction
Misfolded procollagen accumulates in the endoplasmic reticulum, triggering ER stress responses that impair osteoblast function and survival.
ER Stress Response link
●

Phenotypes

11
Eye 1
Blue Sclerae Blue sclerae (HP:0000592)
Show evidence (1 reference)
PMID:3041395 SUPPORT Human Clinical
"Lethal perinatal osteogenesis imperfecta (OI Type II) is a biochemically diverse collagen disorder characterized by short, crumpled long bones, beaded ribs, blue sclerae and thin, fragile skin."
The pathology study abstracts the external phenotype of OI type IIA and directly names blue sclerae.
Integument 1
Thin Skin Thin skin (HP:0000963)
Show evidence (1 reference)
PMID:3041395 SUPPORT Human Clinical
"Lethal perinatal osteogenesis imperfecta (OI Type II) is a biochemically diverse collagen disorder characterized by short, crumpled long bones, beaded ribs, blue sclerae and thin, fragile skin."
Uses the same direct abstract-level phenotype summary to support thin, fragile skin in lethal OI type IIA.
Limbs 1
Severe Micromelia Micromelia (HP:0002983)
Show evidence (1 reference)
PMID:6702894 SUPPORT Human Clinical
"A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta (O.I. type II) is characterized by short limbs, and clinical and roentgenological evidence of severe osseous fragility and defective ossification."
Classic phenotype delineation of lethal OI type II showing that marked limb shortening is a core fetal finding.
Musculoskeletal 1
Diffuse Hypomineralization Reduced bone mineral density (HP:0004349)
Show evidence (1 reference)
PMID:9622170 SUPPORT Human Clinical
"All of subtype A exhibited typical triad of bone shortening, diffuse hypomineralization and multiple fractures of long bones including beaded ribs whereas the subtype B showed shortening of only femurs, normal bone echodensity and isolated fractures of long bones."
The same prenatal case series documents diffuse skeletal hypomineralization as part of the defining type IIA imaging triad.
Respiratory 2
Pulmonary Hypoplasia Pulmonary hypoplasia (HP:0002089)
Show evidence (1 reference)
PMID:2803853 SUPPORT Human Clinical
"Pulmonary hypoplasia has been previously observed in OI type II, but has not been defined clinically. The infant described herein was born with OI type II and pulmonary hypoplasia."
Pathology-confirmed case establishing pulmonary hypoplasia as a direct type II phenotype rather than only an inferred consequence of thoracic restriction.
Respiratory Insufficiency Respiratory insufficiency (HP:0002093)
Show evidence (1 reference)
PMID:26401205 SUPPORT Human Clinical
"At birth, the newborn presented immediate respiratory distress. Postnatal examination and bone radiography confirmed the diagnosis of OI type IIA. Death occurred on day 25 of life related to respiratory failure."
Supports immediate neonatal respiratory compromise and fatal respiratory failure as a clinically central manifestation of OI type IIA.
Other 5
Multiple Prenatal Fractures Multiple prenatal fractures (HP:0005855)
Show evidence (1 reference)
PMID:9622170 SUPPORT Human Clinical
"All of subtype A exhibited typical triad of bone shortening, diffuse hypomineralization and multiple fractures of long bones including beaded ribs whereas the subtype B showed shortening of only femurs, normal bone echodensity and isolated fractures of long bones."
Prenatal case series showing that fractures are already present in utero in the classic lethal type IIA presentation.
Crumpled Long Bones Crumpled long bones (HP:0006367)
Show evidence (1 reference)
PMID:11400945 SUPPORT Human Clinical
"All groups have long bones described as "wrinkled" or "crumpled" secondary to repeated fractures."
Summarizes the classic long-bone morphology across OI type II subgroups as wrinkled or crumpled from repeated prenatal fracture.
Multiple Rib Fractures Multiple rib fractures (HP:0006640)
Show evidence (1 reference)
PMID:11400945 SUPPORT Human Clinical
"In groups A and C, the chest is generally small, with thickened and shortened ribs, and each rib has characteristic "beading" patterns secondary to repeated fracturing."
Directly grounds the characteristic beaded-rib appearance in repeated rib fractures rather than using a broader rib-morphology term.
Bell-Shaped Thorax Bell-shaped thorax (HP:0001591)
Show evidence (1 reference)
PMID:37188488 SUPPORT Human Clinical
"Fetal CT at 28 weeks' gestation showed decreased ossification of the skull, a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI) type II."
Recent case report with prenatal CT documenting the classic small bell-shaped thorax of OI type II.
Decreased Calvarial Ossification Decreased calvarial ossification (HP:0005474)
Show evidence (1 reference)
PMID:37188488 SUPPORT Human Clinical
"Fetal CT at 28 weeks' gestation showed decreased ossification of the skull, a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI) type II."
Uses the same prenatal CT report to support underossification of the skull vault with a directly matching HPO term.
🧬

Genetic Associations

1
COL1A1/COL1A2 Structural Mutations (Causative)
Show evidence (1 reference)
PMID:7643358 SUPPORT Human Clinical
"Perinatal lethal osteogenesis imperfecta is the result of heterozygous mutations of the COL1A1 and COL1A2 genes that encode the alpha 1(I) and alpha 2(I) chains of type I collagen, respectively. Point mutations resulting in the substitution of Gly residues in Gly-X-Y amino acid triplets of the..."
Comprehensive review identifying glycine substitutions in Gly-X-Y triplets as the predominant mutation type in perinatal lethal OI.
💊

Treatments

1
Supportive Care
Action: Supportive care Ontology label: supportive care MAXO:0000950
Palliative supportive care given the lethal nature of the condition. Focus on comfort and family support.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type II
creation_date: '2026-02-06T03:25:37Z'
updated_date: '2026-04-19T06:44:10Z'
category: Mendelian
description: >
  Osteogenesis imperfecta type II is the most severe, perinatal lethal form of OI,
  caused by heterozygous dominant-negative mutations in COL1A1 or COL1A2. Affected
  infants have extreme bone fragility with multiple prenatal fractures, severe
  skeletal deformities with crumpled long bones, blue sclerae, and a small
  bell-shaped thorax. Death usually results from respiratory insufficiency
  associated with pulmonary hypoplasia.
  The mutations typically involve glycine substitutions in the Gly-X-Y repeat
  that disrupt collagen triple helix formation.
disease_term:
  preferred_term: Osteogenesis imperfecta type II
  term:
    id: MONDO:0008147
    label: osteogenesis imperfecta type 2
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Dominant
  description: >
    Autosomal dominant inheritance. Most cases arise de novo. Parental
    gonadal mosaicism accounts for recurrence risk in families with
    apparently unaffected parents.
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most babies have their own private de novo mutation. However, the recurrence
      rate is about 7% owing to germline mosaicism in one parent.
    explanation: >-
      Establishes that most cases are de novo but 7% recurrence risk due to
      parental gonadal mosaicism is a key genetic counseling consideration.
prevalence:
- population: Prenatal-onset OI cases in a single-center fetal diagnostic series
  percentage: 50%
  notes: >-
    In a 10-case fetal OI series, type II accounted for half of prenatal-onset
    cases, underscoring that type II is a dominant presentation among fetuses
    with sonographically severe OI.
  evidence:
  - reference: PMID:25289482
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results: By postnatal radiographic examination, five patients were diagnosed with type II OI and five were diagnosed with type III OI."
    explanation: This prenatal diagnostic cohort found that 5 of 10 fetal OI cases were type II.
pathophysiology:
- name: Dominant-Negative Collagen Disruption
  description: >
    Glycine substitutions in the Gly-X-Y repeat of the collagen triple
    helical domain disrupt normal helix formation. The abnormal alpha chains
    are incorporated into trimers, producing structurally defective collagen
    that cannot form proper fibrils (dominant-negative effect). This results
    in severe deficiency of functional bone matrix.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Collagen Fibril Organization
    term:
      id: GO:0030199
      label: collagen fibril organization
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutations act in a dominant negative manner as the mutant pro alpha chains
      are incorporated into type I procollagen molecules that also contain normal
      pro
      alpha chains. The abnormal molecules are poorly secreted, more susceptible to
      degradation, and impair the formation of the extracellular matrix.
    explanation: >-
      Authoritative review establishing the dominant-negative mechanism of glycine
      substitutions in perinatal lethal OI.
- name: ER Stress and Osteoblast Dysfunction
  description: >
    Misfolded procollagen accumulates in the endoplasmic reticulum, triggering
    ER stress responses that impair osteoblast function and survival.
  biological_processes:
  - preferred_term: ER Stress Response
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
genetic:
- name: COL1A1/COL1A2 Structural Mutations
  association: Causative
  notes: >
    Glycine substitutions in the Gly-X-Y repeat of COL1A1 or COL1A2 are the
    most common cause. Mutations closer to the C-terminus of the collagen
    molecule tend to be more severe due to the C-to-N direction of helix
    folding. Large deletions and splice mutations that preserve reading
    frame can also cause type II OI.
  evidence:
  - reference: PMID:7643358
    reference_title: "Perinatal lethal osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Perinatal lethal osteogenesis imperfecta is the result of heterozygous mutations
      of the COL1A1 and COL1A2 genes that encode the alpha 1(I) and alpha 2(I) chains
      of type I collagen, respectively. Point mutations resulting in the substitution
      of Gly residues in Gly-X-Y amino acid triplets of the triple helical domain
      of
      the alpha 1(I) or alpha 2(I) chains are the most frequent mutations.
    explanation: >-
      Comprehensive review identifying glycine substitutions in Gly-X-Y triplets as
      the predominant mutation type in perinatal lethal OI.
phenotypes:
- name: Multiple Prenatal Fractures
  description: >
    Numerous fractures are already present in utero or at birth and involve
    the long bones and ribs.
  phenotype_term:
    preferred_term: Multiple prenatal fractures
    term:
      id: HP:0005855
      label: Multiple prenatal fractures
  evidence:
  - reference: PMID:9622170
    reference_title: "Prenatal diagnosis of osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of subtype A exhibited typical triad of bone shortening, diffuse
      hypomineralization and multiple fractures of long bones including beaded ribs
      whereas the subtype B showed shortening of only femurs, normal bone echodensity
      and isolated fractures of long bones.
    explanation: >-
      Prenatal case series showing that fractures are already present in utero in
      the classic lethal type IIA presentation.
- name: Diffuse Hypomineralization
  description: >
    The fetal skeleton is diffusely hypomineralized, with reduced bone density
    on prenatal imaging.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:9622170
    reference_title: "Prenatal diagnosis of osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of subtype A exhibited typical triad of bone shortening, diffuse
      hypomineralization and multiple fractures of long bones including beaded ribs
      whereas the subtype B showed shortening of only femurs, normal bone echodensity
      and isolated fractures of long bones.
    explanation: >-
      The same prenatal case series documents diffuse skeletal hypomineralization
      as part of the defining type IIA imaging triad.
- name: Severe Micromelia
  description: >
    Marked shortening of the limbs is a defining prenatal manifestation.
  phenotype_term:
    preferred_term: Micromelia
    term:
      id: HP:0002983
      label: Micromelia
  evidence:
  - reference: PMID:6702894
    reference_title: "Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A group of fetuses with a perinatally lethal variety of osteogenesis imperfecta
      (O.I. type II) is characterized by short limbs, and clinical and
      roentgenological evidence of severe osseous fragility and defective
      ossification.
    explanation: >-
      Classic phenotype delineation of lethal OI type II showing that marked limb
      shortening is a core fetal finding.
- name: Crumpled Long Bones
  description: >
    Long bones are severely deformed and crumpled from repeated prenatal fractures.
  phenotype_term:
    preferred_term: Crumpled long bones
    term:
      id: HP:0006367
      label: Crumpled long bones
  evidence:
  - reference: PMID:11400945
    reference_title: "A case of chondrodysplasia punctata with features of osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All groups have long bones described as "wrinkled" or "crumpled" secondary
      to repeated fractures.
    explanation: >-
      Summarizes the classic long-bone morphology across OI type II subgroups as
      wrinkled or crumpled from repeated prenatal fracture.
- name: Multiple Rib Fractures
  description: >
    Repeated rib fractures produce the characteristic beaded rib appearance on
    imaging.
  phenotype_term:
    preferred_term: Multiple rib fractures
    term:
      id: HP:0006640
      label: Multiple rib fractures
  evidence:
  - reference: PMID:11400945
    reference_title: "A case of chondrodysplasia punctata with features of osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In groups A and C, the chest is generally small, with thickened and
      shortened ribs, and each rib has characteristic "beading" patterns secondary
      to repeated fracturing.
    explanation: >-
      Directly grounds the characteristic beaded-rib appearance in repeated rib
      fractures rather than using a broader rib-morphology term.
- name: Bell-Shaped Thorax
  description: >
    The thorax is small and bell-shaped, reflecting severe thoracic restriction.
  phenotype_term:
    preferred_term: Bell-shaped thorax
    term:
      id: HP:0001591
      label: Bell-shaped thorax
  evidence:
  - reference: PMID:37188488
    reference_title: "Cyclic intravenous pamidronate for an infant with osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal CT at 28 weeks' gestation showed decreased ossification of the skull,
      a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing
      of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI)
      type II.
    explanation: >-
      Recent case report with prenatal CT documenting the classic small bell-shaped
      thorax of OI type II.
- name: Decreased Calvarial Ossification
  description: >
    The calvarium is poorly ossified on fetal imaging.
  phenotype_term:
    preferred_term: Decreased calvarial ossification
    term:
      id: HP:0005474
      label: Decreased calvarial ossification
  evidence:
  - reference: PMID:37188488
    reference_title: "Cyclic intravenous pamidronate for an infant with osteogenesis imperfecta type II."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal CT at 28 weeks' gestation showed decreased ossification of the skull,
      a small bell-shaped thorax, hypoplastic vertebrae, and shortening and bowing
      of the long bones, leading to the diagnosis of osteogenesis imperfecta (OI)
      type II.
    explanation: >-
      Uses the same prenatal CT report to support underossification of the skull
      vault with a directly matching HPO term.
- name: Pulmonary Hypoplasia
  description: >
    Lung development is markedly reduced and contributes to perinatal lethality.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: PMID:2803853
    reference_title: "Pulmonary hypoplasia and osteogenesis imperfecta type II with defective synthesis of alpha I(1) procollagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulmonary hypoplasia has been previously observed in OI type II, but has not
      been defined clinically. The infant described herein was born with OI type II
      and pulmonary hypoplasia.
    explanation: >-
      Pathology-confirmed case establishing pulmonary hypoplasia as a direct type II
      phenotype rather than only an inferred consequence of thoracic restriction.
- name: Respiratory Insufficiency
  description: >
    Severe respiratory compromise is present at birth and drives early mortality.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:26401205
    reference_title: "Perinatal lethal type II osteogenesis imperfecta: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At birth, the newborn presented immediate respiratory distress. Postnatal
      examination and bone radiography confirmed the diagnosis of OI type IIA.
      Death occurred on day 25 of life related to respiratory failure.
    explanation: >-
      Supports immediate neonatal respiratory compromise and fatal respiratory
      failure as a clinically central manifestation of OI type IIA.
- name: Blue Sclerae
  description: >
    Blue sclerae are part of the external connective-tissue phenotype.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:3041395
    reference_title: "Cardiovascular pathology in osteogenesis imperfecta type IIA with a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lethal perinatal osteogenesis imperfecta (OI Type II) is a biochemically diverse
      collagen disorder characterized by short, crumpled long bones, beaded ribs, blue
      sclerae and thin, fragile skin.
    explanation: >-
      The pathology study abstracts the external phenotype of OI type IIA and directly
      names blue sclerae.
- name: Thin Skin
  description: >
    The skin is abnormally thin and fragile.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:3041395
    reference_title: "Cardiovascular pathology in osteogenesis imperfecta type IIA with a review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lethal perinatal osteogenesis imperfecta (OI Type II) is a biochemically diverse
      collagen disorder characterized by short, crumpled long bones, beaded ribs, blue
      sclerae and thin, fragile skin.
    explanation: >-
      Uses the same direct abstract-level phenotype summary to support thin, fragile
      skin in lethal OI type IIA.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    The diagnosis of osteogenesis imperfecta type II (now described in
    GeneReviews as perinatally lethal OI) is based on the characteristic
    prenatal and neonatal clinical and radiographic findings of severe
    hypomineralization, multiple fractures, and pulmonary insufficiency, and is
    confirmed by identification of a heterozygous COL1A1 or COL1A2 variant on
    molecular genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of COL1A1/COL1A2-OI is established in a proband with clinical and radiographic manifestations of OI by identification of a heterozygous in COL1A1 or COL1A2 by molecular genetic testing."
    explanation: >-
      GeneReviews defines the combined clinical/radiographic and molecular
      diagnostic criteria for COL1A1/COL1A2-related OI, including the
      perinatally lethal type II form.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "perinatally lethal OI (previously OI type II)"
    explanation: >-
      GeneReviews maps the legacy Sillence type II label to the modern
      descriptive nomenclature for the perinatally lethal form.
- name: Prenatal Diagnosis and Recurrence Counseling
  description: >-
    Prenatal ultrasound can detect lethal/severe OI early in gestation, and
    genetic counseling must address the high proportion of de novo variants and
    the recurrence risk arising from parental gonadal mosaicism.
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation"
    explanation: >-
      Supports prenatal ultrasound as a diagnostic modality for perinatally
      lethal OI.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall rate of mosaicism is up to 16% in the parents of children with COL1A1/COL1A2-OI."
    explanation: >-
      Supports recurrence-risk counseling: most lethal OI is de novo, but
      parental mosaicism produces a meaningful recurrence risk.
treatments:
- name: Supportive Care
  description: >
    Palliative supportive care given the lethal nature of the condition.
    Focus on comfort and family support.
  treatment_term:
    preferred_term: Supportive care
    term:
      id: MAXO:0000950
      label: supportive care
datasets:
references:
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
  findings: []
- reference: DOI:10.1007/s00223-024-01266-5
  title: Update on the Genetics of Osteogenesis Imperfecta
  findings: []
- reference: DOI:10.1021/acsptsci.3c00324
  title: Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and
    Therapeutic Approaches
  findings: []
- reference: DOI:10.1172/jci.insight.171984
  title: Altered Sox9 and FGF signaling gene expression in Aga2 OI mice
    negatively affects linear growth
  findings: []
- reference: DOI:10.53846/goediss-7825
  title: Identification of molecular-genetic causes for osteogenesis imperfecta,
    interdigital hyperplasia and ribosomopathies in cattle
  findings: []
- reference: PMID:6702894
  title: Osteogenesis imperfecta type II delineation of the phenotype with
    reference to genetic heterogeneity
  findings: []
- reference: PMID:9622170
  title: Prenatal diagnosis of osteogenesis imperfecta type II
  findings: []
- reference: PMID:11400945
  title: A case of chondrodysplasia punctata with features of osteogenesis
    imperfecta type II
  findings: []
- reference: PMID:2803853
  title: Pulmonary hypoplasia and osteogenesis imperfecta type II with defective
    synthesis of alpha I(1) procollagen
  findings: []
- reference: PMID:3041395
  title: Cardiovascular pathology in osteogenesis imperfecta type IIA with a
    review of the literature
  findings: []
- reference: PMID:26401205
  title: 'Perinatal lethal type II osteogenesis imperfecta: a case report'
  findings: []
- reference: PMID:37188488
  title: Cyclic intravenous pamidronate for an infant with osteogenesis
    imperfecta type II
  findings: []
📚

References & Deep Research

References

12
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.
DOI:10.1007/s00223-024-01266-5
Update on the Genetics of Osteogenesis Imperfecta
No top-level findings curated for this source.
DOI:10.1021/acsptsci.3c00324
Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches
No top-level findings curated for this source.
DOI:10.1172/jci.insight.171984
Altered Sox9 and FGF signaling gene expression in Aga2 OI mice negatively affects linear growth
No top-level findings curated for this source.
DOI:10.53846/goediss-7825
Identification of molecular-genetic causes for osteogenesis imperfecta, interdigital hyperplasia and ribosomopathies in cattle
No top-level findings curated for this source.
PMID:6702894
Osteogenesis imperfecta type II delineation of the phenotype with reference to genetic heterogeneity
No top-level findings curated for this source.
PMID:9622170
Prenatal diagnosis of osteogenesis imperfecta type II
No top-level findings curated for this source.
PMID:11400945
A case of chondrodysplasia punctata with features of osteogenesis imperfecta type II
No top-level findings curated for this source.
PMID:2803853
Pulmonary hypoplasia and osteogenesis imperfecta type II with defective synthesis of alpha I(1) procollagen
No top-level findings curated for this source.
PMID:3041395
Cardiovascular pathology in osteogenesis imperfecta type IIA with a review of the literature
No top-level findings curated for this source.
PMID:26401205
Perinatal lethal type II osteogenesis imperfecta: a case report
No top-level findings curated for this source.
PMID:37188488
Cyclic intravenous pamidronate for an infant with osteogenesis imperfecta type II
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Osteogenesis Imperfecta Type II
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 7

Key Pathophysiology Nodes

  • Dominant-Negative Collagen Disruption
  • ER Stress and Osteoblast Dysfunction
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00223-024-01266-5
  • DOI:10.1021/acsptsci.3c00324
  • DOI:10.1172/jci.insight.171984
  • DOI:10.53846/goediss-7825
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 16 citations 2026-02-04T19:40:00.093580

Disease Pathophysiology Research Report

Target Disease - Disease Name: Osteogenesis Imperfecta (OI) Type II (perinatal lethal OI) - MONDO ID: MONDO_0008147 - Category: Mendelian

Pathophysiology description (narrative synthesis) Osteogenesis Imperfecta Type II is the most severe, typically perinatal lethal, form of OI characterized by extreme skeletal fragility, multiple in utero fractures, crumpled long bones, severely undermineralized calvarium, and respiratory failure secondary to pulmonary hypoplasia. The disorder arises primarily from qualitative defects in type I collagen due to de novo dominant COL1A1 or COL1A2 missense variants (often glycine substitutions within the Gly–X–Y helical repeat) that impose dominant-negative effects on the heterotrimer, delaying triple-helix folding, causing prolonged post-translational modification (“overmodification”), and leading to failure of proper fibrillogenesis and matrix assembly (DOI:10.1007/s00223-024-01266-5; DOI:10.1021/acsptsci.3c00324). In other cases with perinatal lethality, recessive disruption of the ER prolyl 3-hydroxylation/folding complex—CRTAP, P3H1/LEPRE1, and PPIB—abolishes site-specific 3-hydroxylation (Pro986 in α1(I) and Pro707 in α2(I)), delays helix nucleation and folding, and results in overmodified collagen, ER processing/trafficking defects, and catastrophic bone matrix insufficiency (DOI:10.1021/acsptsci.3c00324). Together, these upstream molecular lesions trigger downstream cellular stress responses, dysregulated osteoblast/chondrocyte biology including altered growth plate dynamics, and defective mineralization that culminate in perinatal lethality. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42)

Key concepts and definitions - Type I collagen biosynthesis: Heterotrimer of two pro-α1(I) (COL1A1) and one pro-α2(I) (COL1A2) chains synthesized in the ER; extensive PTMs (prolyl 4-hydroxylation, lysyl hydroxylation/glycosylation), site-specific prolyl 3-hydroxylation at Pro986/Pro707 by the CRTAP–P3H1–PPIB complex; triple-helix formation proceeds C→N direction; chaperoned trafficking to Golgi and secretion; extracellular N- and C-propeptide cleavage (ADAMTS2/3/14; BMP1) precedes fibrillogenesis (DOI:10.1007/s00223-024-01266-5). (jovanovic2024updateonthe pages 4-5) - Prolyl 3-hydroxylation complex: “CRTAP–P3H1 (LEPRE1)–PPIB” mediates 3-hydroxylation of a critical proline (α1(I) Pro986; α2(I) Pro707) and coordinates rapid helix folding; loss abolishes 3-hydroxylation, delays folding, and yields overmodified collagen with impaired trafficking and ECM assembly (DOI:10.1021/acsptsci.3c00324). (sun2024emerginglandscapeof pages 4-5) - Dominant-negative collagen: Glycine substitutions in the Gly–X–Y repeat introduce steric hindrance, slow helix propagation, and cause helical overmodification; α1(I) substitutions are particularly enriched for severe/lethal outcomes (Calcified Tissue Int. 2024). (jovanovic2024updateonthe pages 4-5)

Recent developments and latest research (2023–2024 priority) - Genetics and mechanisms update: Jovanovic & Marini 2024 provides current genetic architecture of OI including dominant COL1A1/COL1A2 and recessive mechanisms (CRTAP/P3H1/PPIB; chaperones; trafficking) and clarifies how delayed folding causes overmodification and severe phenotypes; it also integrates newer contributors to trafficking/signaling that intersect with WNT/LRP5/6 and MAPK/ERK (Calcified Tissue Int., Aug 2024; https://doi.org/10.1007/s00223-024-01266-5). (jovanovic2024updateonthe pages 4-5) - Pathogenesis and therapeutic landscape: Sun et al. 2024 emphasizes the centrality of the CRTAP–P3H1–PPIB complex, explicitly noting that “the complex’s primary target is the 3-hydroxylation of a specific proline (Pro986)” and that loss causes delayed helix folding and severe bone dysplasia; it synthesizes progress on gene/stem-cell/editing concepts (ACS Pharmacol. & Transl. Sci., Jan 2024; https://doi.org/10.1021/acsptsci.3c00324). (sun2024emerginglandscapeof pages 4-5) - Growth plate biology in collagen-mutant OI: Zieba et al. 2023 (Aga2+/- mouse) reports ER stress/UPR signatures and altered FGF/MAPK and Sox9 programs in growth-plate chondrocytes, linking mutant type I collagen to shortened proliferative zones and disordered endochondral ossification, consistent with growth failure across OI (JCI Insight, Nov 2023; https://doi.org/10.1172/jci.insight.171984). While not specific to Type II, the mechanistic axis is relevant to lethal forms with profound growth-plate disruption. (zieba2023alteredsox9and pages 18-19)

Current applications and real-world implementations - Molecular diagnosis and prenatal counseling: Contemporary nosology/genetics reviews support using targeted or exome sequencing to detect glycine substitutions in COL1A1/2 or biallelic CRTAP/P3H1/PPIB variants in severe prenatal skeletal dysplasia; genotype informs prognosis and counseling for perinatal lethality. (Calcified Tissue Int. 2024; https://doi.org/10.1007/s00223-024-01266-5). (jovanovic2024updateonthe pages 4-5) - Therapeutic implications of mechanisms: While no curative therapy exists for Type II, mechanistic insights underpin emerging strategies (chemical chaperones, pathway modulation, anti-sclerostin, and gene/cell therapy) under investigation across OI; however, perinatal lethality limits interventional windows. Sun 2024 summarizes translational approaches and their mechanistic rationale (https://doi.org/10.1021/acsptsci.3c00324). (sun2024emerginglandscapeof pages 4-5)

Expert opinions and analysis from authoritative sources - “The most common pathogenic lesions are glycine substitutions within the Gly–X–Y helical repeat; these slow triple-helix folding, prolong exposure to modifying enzymes, cause helical overmodification, and can produce severe/lethal phenotypes.” (Calcified Tissue Int. 2024; DOI:10.1007/s00223-024-01266-5). (jovanovic2024updateonthe pages 4-5) - “Deletion or biallelic mutations in any component [of CRTAP–P3H1–PPIB] abolish complex activity, causing failure of Pro986 hydroxylation, delayed triple-helix folding, and compensatory/excessive modification…[leading to] severe bone dysplasia phenotypes.” (ACS Pharmacol. & Transl. Sci. 2024; DOI:10.1021/acsptsci.3c00324). (sun2024emerginglandscapeof pages 4-5)

Relevant statistics and data from recent studies - Genotype–phenotype patterns: Jovanovic & Marini 2024 highlight that α1(I) glycine substitutions are disproportionately associated with severe/lethal outcomes compared with α2(I), reflecting chain-specific structural consequences; the review collates historic series and registry data supporting this distribution (Calcified Tissue Int. 2024; DOI:10.1007/s00223-024-01266-5). (jovanovic2024updateonthe pages 4-5) - Growth plate effects: Zieba 2023 reports single-cell and pathway analyses demonstrating increased FGF/MAPK signaling and ER stress markers in growth plate chondrocytes with mutant collagen, providing quantitative transcriptomic support for disordered endochondral ossification that correlates with short stature and severe skeletal dysplasia (JCI Insight 2023; DOI:10.1172/jci.insight.171984). (zieba2023alteredsox9and pages 18-19)

1) Core Pathophysiology - Primary mechanisms: Qualitative defects in type I collagen triple helix (dominant glycine substitutions) or failure of ER 3-hydroxylation/folding (CRTAP–P3H1–PPIB) lead to delayed folding, overmodification (hyper-hydroxylation and glycosylation), impaired ER→Golgi trafficking, reduced collagen secretion, defective extracellular processing (C-terminal cleavage by BMP1) and fibrillogenesis, culminating in fragile, poorly mineralized bone. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) - Dysregulated pathways: Evidence from OI models shows ER stress/UPR signatures in osteoblasts and growth-plate chondrocytes, and altered FGF/MAPK and Sox9 programs with effects on proliferative/hypertrophic zones; TGF-β signaling activation has been reported in severe OI models, linking matrix abnormalities to pro-catabolic signaling and bone turnover imbalance. (zieba2023alteredsox9and pages 18-19, zhang2020identificationofmoleculargenetic pages 40-42) - Affected cellular processes: Collagen PTM/quality control; protein folding/isomerization; cargo trafficking; ECM assembly; mineral deposition; endochondral ossification. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5)

2) Key Molecular Players - Genes/Proteins (HGNC): COL1A1, COL1A2; CRTAP; LEPRE1 (P3H1); PPIB; SERPINH1 (HSP47); FKBP10; BMP1. Roles and evidence summarized below. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) - Chemical entities (CHEBI): proline (CHEBI:26271); hydroxyproline (CHEBI:18050); lysine (CHEBI:25094); ascorbate (CHEBI:22652) as cofactor for hydroxylases; 4‑phenylbutyrate as a chemical chaperone in OI models (CHEBI:46195). (zieba2023alteredsox9and pages 18-19, zhang2020identificationofmoleculargenetic pages 40-42) - Cell types (CL): osteoblast (CL:0000062); osteocyte (CL:0000100); chondrocyte (CL:0000138); fibroblast (CL:0000057). (zieba2023alteredsox9and pages 18-19, jovanovic2024updateonthe pages 4-5) - Anatomical locations (UBERON): bone tissue (UBERON:0001474); growth plate (UBERON:0000981); calvaria (UBERON:0008222); rib (UBERON:0002228); lung/pulmonary system (UBERON:0002048) given hypoplasia. (jovanovic2024updateonthe pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42)

3) Biological Processes (GO) disrupted - Collagen biosynthetic process (GO:0032964); protein folding (GO:0006457); peptidyl-proline 3-hydroxylation (GO:0018401); peptidyl-prolyl cis-trans isomerization (GO:0000413); ER to Golgi vesicle-mediated transport (GO:0006888); extracellular matrix organization (GO:0030198); collagen fibril organization (GO:0030199); ossification (GO:0001503); endochondral ossification (GO:0001958); response to endoplasmic reticulum stress (GO:0034976); regulation of TGF-β signaling pathway (GO:0017015); Wnt signaling pathway (GO:0016055); MAPK cascade (GO:0000165). (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zieba2023alteredsox9and pages 18-19, zhang2020identificationofmoleculargenetic pages 40-42)

4) Cellular Components - Endoplasmic reticulum lumen (GO:0005788): site of procollagen folding and CRTAP–P3H1–PPIB action. (sun2024emerginglandscapeof pages 4-5) - Golgi apparatus (GO:0005794): post-ER processing/trafficking checkpoint. (jovanovic2024updateonthe pages 4-5) - Collagen-containing extracellular matrix (GO:0062023) and extracellular region (GO:0005576): site of propeptide cleavage, fibrillogenesis, mineral deposition. (jovanovic2024updateonthe pages 4-5)

5) Disease Progression (sequence of events) - Initiation: De novo dominant COL1A1/2 glycine substitution or recessive loss of CRTAP/P3H1/PPIB activity. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5) - Intracellular pathogenesis: Delayed helix folding → overmodification; ER quality-control engagement, trafficking delay; reduced secretion and aberrant procollagen processing. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5) - Extracellular matrix failure: Impaired C-propeptide cleavage (BMP1 axis), altered cross-linking, disordered fibrillogenesis → defective mineralization and bone material quality. (jovanovic2024updateonthe pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) - Tissue-level consequences: Disorganized growth plate, shortened proliferative zone; altered FGF/MAPK/Sox9 programs; osteoblast dysfunction; high fragility and deformity. (zieba2023alteredsox9and pages 18-19) - Clinical trajectory: Severe skeletal deformity and multiple fractures in utero, thin beaded ribs, crumpled femurs, undermineralized skull, pulmonary hypoplasia; perinatal demise from respiratory failure. (zhang2020identificationofmoleculargenetic pages 40-42)

6) Phenotypic Manifestations (HP terms) - Perinatal death (HP:0003811); Multiple fractures (HP:0002757); Intrauterine fractures (HP:0005839); Beaded ribs (HP:0000883); Bowed/crumpled long bones (HP:0002816/HP related); Undermineralized skull (HP:0004281); Pulmonary hypoplasia (HP:0002089); Growth deficiency (HP:0001510); Blue sclerae (HP:0000592). (zhang2020identificationofmoleculargenetic pages 40-42, jovanovic2024updateonthe pages 4-5)

Gene/protein annotations with ontology terms and evidence - COL1A1 (HGNC:2197): GO-BP: collagen biosynthetic process; GO-CC: ER lumen; collagen-containing ECM. Mechanism: dominant glycine substitutions delay folding and cause overmodification → severe/lethal phenotypes. Evidence: Calcified Tissue Int. 2024 (DOI:10.1007/s00223-024-01266-5; URL above). (jovanovic2024updateonthe pages 4-5) - COL1A2 (HGNC:2198): As above; chain-specific severity differs from α1(I), but lethal variants are common in α2(I) as well. (jovanovic2024updateonthe pages 4-5) - CRTAP (HGNC:2438), LEPRE1/P3H1 (HGNC:16721), PPIB (HGNC:9233): GO-BP: peptidyl-proline 3-hydroxylation; protein folding; GO-CC: ER lumen. Mechanism: loss abolishes 3-hydroxylation at Pro986/Pro707, delays folding; overmodified collagen; trafficking defects; severe/recessive OI with lethal spectrum. Evidence: ACS Pharmacol. & Transl. Sci. 2024 (DOI:10.1021/acsptsci.3c00324). (sun2024emerginglandscapeof pages 4-5) - SERPINH1/HSP47 (HGNC:1222); FKBP10 (HGNC:3711): GO-BP: protein folding; ECM organization; GO-CC: ER lumen. Mechanism: chaperone/isomerase defects reduce secretion, crosslinking, and fibrillogenesis; severe OI. Evidence collated in 2024 reviews. (jovanovic2024updateonthe pages 4-5) - BMP1 (HGNC:1050): GO-BP: procollagen C-propeptide processing; fibrillogenesis; ossification; GO-CC: extracellular region/ECM. Mechanism: impaired C-propeptide cleavage → defective fibrils and mineralization. (jovanovic2024updateonthe pages 4-5)

Embedded summary artifact | Gene/Protein (HGNC symbol) | Protein/Complex role | Pathogenic mechanism in OI type II | Representative residue/site (if applicable) | Cellular compartment (GO-CC) | Key processes impacted (GO-BP) | Evidence (PMID/DOI; Year; URL) | Notes | |---|---|---|---|---|---|---|---| | COL1A1 | Type I procollagen α1 chain (major fibrillar collagen) | Dominant glycine substitutions in Gly-X-Y repeat → dominant-negative defective triple helix; delayed folding, helical overmodification, abnormal fibrillogenesis and ECM assembly → severe/perinatal phenotypes | — | ER lumen; Golgi; collagen-containing extracellular matrix | Collagen biosynthetic process; protein folding; ER → Golgi transport; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | Glycine substitutions in α1(I) often produce the most severe/lethal outcomes (Type II) | | COL1A2 | Type I procollagen α2 chain (part of heterotrimer) | Dominant glycine substitutions → abnormal heterotrimer formation, delayed folding and overmodification; defective ECM incorporation and bone fragility | — | ER lumen; Golgi; collagen-containing extracellular matrix | Collagen biosynthetic process; protein folding; ER → Golgi transport; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | Glycine substitutions in α2(I) cause severe OI but genotype–phenotype severity distribution differs from α1(I) | | CRTAP | Cartilage-associated protein; non-catalytic subunit of prolyl 3-hydroxylation complex | Biallelic loss → abolishes 3-hydroxylation of critical proline(s), delays triple-helix folding, causes collagen overmodification, impaired secretion/trafficking and defective matrix assembly → severe/recessive lethal OI | Pro986 α1(I); Pro707 α2(I) | ER lumen | Proline 3-hydroxylation; protein folding; ER quality control; ER → Golgi transport; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | Part of CRTAP–P3H1–PPIB complex required for site-specific 3-hydroxylation linked to severe perinatal phenotypes | | P3H1 / LEPRE1 | Prolyl 3-hydroxylase 1 (catalytic enzyme in complex) | Biallelic loss or damaging variants → loss of Pro986/Pro707 3-hydroxylation, delayed helix formation, overmodification and ER retention → severe/recessive lethal OI | Pro986 α1(I); Pro707 α2(I) | ER lumen | Proline 3-hydroxylation; collagen biosynthetic process; protein folding; ER quality control; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | Known cause of severe autosomal recessive OI (type VIII and related severe forms) | | PPIB | Cyclophilin B (peptidyl-prolyl cis–trans isomerase), member of the prolyl 3-hydroxylation complex | Loss/dysfunction → impaired isomerase activity in complex, delayed procollagen folding and defective 3-hydroxylation → abnormal collagen modification/trafficking and severe OI | Pro986 α1(I); Pro707 α2(I) (complex target) | ER lumen | Protein folding; proline isomerization; collagen biosynthetic process; ER → Golgi transport; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | PPIB variants produce recessive OI phenotypes overlapping perinatal/severe presentations | | HSP47 / SERPINH1 | ER-resident collagen-specific chaperone (heat shock protein 47) | Dysfunctional chaperone → misfolded procollagen, ER retention, reduced secretion, abnormal fibrillogenesis and bone fragility; can trigger ER stress/UPR depending on context | — | ER lumen | Protein folding; ER quality control; collagen biosynthetic process; extracellular matrix organization; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | SERPINH1 pathogenic variants associated with severe OI phenotypes in humans and models | | FKBP10 | ER-resident peptidyl-prolyl isomerase / foldase (FKBP65) involved in collagen folding and crosslinking | Loss → impaired collagen folding/trafficking and defective cross-linking (via LOX pathway perturbation), reduced ECM deposition and bone fragility; can produce severe OI | — | ER lumen; ER membrane | Protein folding; peptidyl-prolyl isomerization; extracellular matrix organization; collagen cross-linking; ossification | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Sun et al. 2024 DOI:10.1021/acsptsci.3c00324; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | FKBP10 defects are a recognized recessive cause of severe OI with abnormal cross-links | | BMP1 | Secreted metalloproteinase (C-propeptide cleavage; procollagen C-proteinase) | Impaired C-propeptide cleavage → defective procollagen to collagen conversion, abnormal fibril formation, altered mineralization and bone matrix quality → fragility and severe phenotypes | — | Extracellular region; extracellular matrix | Procollagen processing; extracellular matrix organization; collagen fibrillogenesis; ossification; bone mineralization | Jovanovic & Marini 2024 DOI:10.1007/s00223-024-01266-5; Zhang thesis 2020 DOI:10.53846/goediss-7825 (jovanovic2024updateonthe pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) | BMP1 and related processing enzymes influence collagen maturation and mineralization; mutations can phenocopy severe OI features |

Table: Table summarizing principal genes/protein complexes implicated in perinatal-lethal osteogenesis imperfecta (Type II), their molecular roles, pathogenic mechanisms, subcellular locations and the key biological processes they perturb, with primary evidence citations. Useful as a concise reference for ontology mapping and mechanistic annotation. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42)

Evidence items with PMIDs/DOIs, URLs, and dates (direct support of mechanistic claims) - Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcified Tissue International. Aug 2024. DOI:10.1007/s00223-024-01266-5. URL: https://doi.org/10.1007/s00223-024-01266-5. Key content: chain-specific glycine substitution severity; delayed folding/overmodification; roles of ADAMTS/BMP1 and trafficking/chaperones; signaling intersections. (jovanovic2024updateonthe pages 4-5) - Sun Y et al. Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches. ACS Pharmacology & Translational Science. Jan 2024. DOI:10.1021/acsptsci.3c00324. URL: https://doi.org/10.1021/acsptsci.3c00324. Key content: CRTAP–P3H1–PPIB complex target (Pro986), consequences of complex loss (delayed folding, overmodification), severe bone dysplasia. (sun2024emerginglandscapeof pages 4-5) - Zieba J et al. Altered Sox9 and FGF signaling gene expression in Aga2 OI mice negatively affects linear growth. JCI Insight. Nov 2023. DOI:10.1172/jci.insight.171984. URL: https://doi.org/10.1172/jci.insight.171984. Key content: ER stress/UPR in growth plate chondrocytes, increased FGF/MAPK signaling, growth-plate dysfunction relevant to severe OI biology. (zieba2023alteredsox9and pages 18-19) - Zhang X. Identification of molecular-genetic causes for osteogenesis imperfecta… PhD Thesis. 2020. DOI:10.53846/goediss-7825. URL: https://doi.org/10.53846/goediss-7825. Key content (with primary citations): discovery of CRTAP–P3H1–PPIB complex (Cell 2006; Am J Hum Genet 2009), ER stress/UPR and matrix/mineralization alterations; links to BMP1 processing and crosslinking. (zhang2020identificationofmoleculargenetic pages 40-42)

Limitations and open questions - Quantitative thresholds linking degree/location of helical overmodification to lethality remain incompletely defined at the individual variant level; multi-omic correlates in perinatal cases remain sparse due to lethality. Growth-plate pathway dysregulation (FGF/MAPK, TGF-β, WNT) is well-supported in models but requires further human perinatal tissue data to resolve causal hierarchies. (zieba2023alteredsox9and pages 18-19, jovanovic2024updateonthe pages 4-5)

Appendix: Ontology-aligned annotations (concise) - Genes/Proteins (HGNC): COL1A1 (HGNC:2197); COL1A2 (HGNC:2198); CRTAP (HGNC:2438); LEPRE1/P3H1 (HGNC:16721); PPIB (HGNC:9233); SERPINH1 (HGNC:1222); FKBP10 (HGNC:3711); BMP1 (HGNC:1050). (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5) - GO Biological Process: GO:0032964; GO:0018401; GO:0000413; GO:0006888; GO:0030198; GO:0030199; GO:0001503; GO:0001958; GO:0034976; GO:0017015; GO:0016055; GO:0000165. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5, zieba2023alteredsox9and pages 18-19) - GO Cellular Component: GO:0005788; GO:0005794; GO:0062023; GO:0005576. (jovanovic2024updateonthe pages 4-5, sun2024emerginglandscapeof pages 4-5) - HP Phenotypes: HP:0003811; HP:0002757; HP:0005839; HP:0000883; HP:0002816; HP:0004281; HP:0002089; HP:0001510; HP:0000592. (zhang2020identificationofmoleculargenetic pages 40-42, jovanovic2024updateonthe pages 4-5) - CL Cell Types: CL:0000062; CL:0000100; CL:0000138; CL:0000057. (zieba2023alteredsox9and pages 18-19, jovanovic2024updateonthe pages 4-5) - UBERON Anatomy: UBERON:0001474; UBERON:0000981; UBERON:0008222; UBERON:0002228; UBERON:0002048. (jovanovic2024updateonthe pages 4-5, zhang2020identificationofmoleculargenetic pages 40-42) - CHEBI Chemicals: CHEBI:26271; CHEBI:18050; CHEBI:25094; CHEBI:22652; CHEBI:46195. (zieba2023alteredsox9and pages 18-19, zhang2020identificationofmoleculargenetic pages 40-42)

References

  1. (jovanovic2024updateonthe pages 4-5): Milena Jovanovic and Joan C. Marini. Update on the genetics of osteogenesis imperfecta. Calcified Tissue International, 115:891-914, Aug 2024. URL: https://doi.org/10.1007/s00223-024-01266-5, doi:10.1007/s00223-024-01266-5. This article has 48 citations and is from a peer-reviewed journal.

  2. (sun2024emerginglandscapeof pages 4-5): Yu Sun, Lin Li, Jiajun Wang, Huiting Liu, and Hu Wang. Emerging landscape of osteogenesis imperfecta pathogenesis and therapeutic approaches. ACS pharmacology & translational science, 7 1:72-96, Jan 2024. URL: https://doi.org/10.1021/acsptsci.3c00324, doi:10.1021/acsptsci.3c00324. This article has 17 citations and is from a peer-reviewed journal.

  3. (zieba2023alteredsox9and pages 18-19): Jennifer Zieba, Lisette Nevarez, Davis Wachtell, Jorge H. Martin, Alexander Kot, Sereen Wong, Daniel H. Cohn, and Deborah Krakow. Altered sox9 and fgf signaling gene expression in aga2 oi mice negatively affects linear growth. JCI Insight, Nov 2023. URL: https://doi.org/10.1172/jci.insight.171984, doi:10.1172/jci.insight.171984. This article has 6 citations and is from a domain leading peer-reviewed journal.

  4. (zhang2020identificationofmoleculargenetic pages 40-42): Xuying Zhang. Identification of molecular-genetic causes for osteogenesis imperfecta, interdigital hyperplasia and ribosomopathies in cattle. PhD thesis, University Goettingen Repository, 2020. URL: https://doi.org/10.53846/goediss-7825, doi:10.53846/goediss-7825.