Osteogenesis Imperfecta Type VII

Mendelian MONDO:0012536 Osteogenesis imperfecta

Osteogenesis imperfecta type VII is a rare autosomal recessive form of OI caused by biallelic mutations in CRTAP (cartilage-associated protein). CRTAP forms a complex with P3H1 (LEPRE1) and cyclophilin B (PPIB) that catalyzes 3-hydroxylation of a specific proline residue in type I collagen and supports collagen folding and matrix assembly. Loss of CRTAP function impairs collagen modification, leading to a variable bone-fragility spectrum that ranges from moderate type IV-like disease to severe type III-like and perinatally lethal type II-like presentations, often accompanied by rhizomelia, coxa vara, and growth impairment.

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1
Inheritance
4
Pathophys.
12
Phenotypes
1
Genes
4
Treatments
1
Datasets
12
References
2
Deep Research
👪

Inheritance

1
Autosomal Recessive
Autosomal recessive inheritance. Carrier parents are unaffected. More common in populations with high consanguinity rates.
Show evidence (1 reference)
PMID:12110406 SUPPORT Human Clinical
"We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec."
The original paper defining OI type VII established it as an autosomal recessive form of brittle bone disease in a consanguineous community.
⚙

Pathophysiology

4
Collagen 3-Hydroxylation Deficiency
CRTAP is a component of the prolyl 3-hydroxylation complex that modifies Pro986 in the alpha1(I) chain of type I collagen. Loss of this modification delays collagen folding, causing overmodification of the helix and altered collagen structure and cross-linking.
Osteoblast link
Protein Hydroxylation link Collagen Fibril Organization link
Show evidence (2 references)
PMID:17055431 SUPPORT Model Organism
"CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/- bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover, mutant collagen shows evidence of overmodification, and collagen fibrils in mutant skin have increased diameter consistent with altered fibrillogenesis."
Landmark Cell paper establishing CRTAP as essential for prolyl 3-hydroxylation and showing that loss leads to collagen overmodification and abnormal fibrils.
PMID:18566967 SUPPORT Human Clinical
"Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen."
This human recessive-OI cohort supports the CRTAP/P3H1/cyclophilin B complex model and its role in collagen hydroxylation before folding.
Osteoblast Dysfunction and Impaired Bone Formation
CRTAP deficiency in patient osteoblasts reduces CRTAP expression and prolyl 3-hydroxylation of type I collagen, with reduced osteoblast numbers, diminished osteoid volume, and markedly impaired active bone formation.
Osteoblast differentiation link Ossification link
Show evidence (1 reference)
PMID:38214665 SUPPORT Human Clinical
"In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was..."
Directly supports osteoblast dysfunction, reduced osteoid, and impaired bone formation in CRTAP-related OI type VII.
Collagen Proteotoxicity in Severe CRTAP Variants
Some severe CRTAP variants can generate unstable CRTAP isoforms that cause loss of proline hydroxylation, type I collagen aggregation, autophagy, and cellular senescence. This captures a severe/lethal variant mechanism rather than a uniform mechanism for every CRTAP allele.
protein folding link extracellular matrix organization link
Show evidence (1 reference)
PMID:37146916 SUPPORT In Vitro
"Both mutant isoforms of CRTAP are unstable due to the presence of a unique 'GWxxI' degron, which finally leads to loss of proline hydroxylation and aggregation of type I collagen. Although type I collagen aggregates undergo autophagy, the overall proteotoxicity resulted in death of the proband..."
Patient-cell functional data connect a lethal CRTAP variant to collagen aggregation, proteotoxic stress, and senescence.
Primary Lung Matrix Dysfunction
Crtap knockout mouse data support a primary lung contribution in recessive OI, with altered collagen post-translational modification in lung fibroblasts, parenchymal changes, and impaired respiratory mechanics. This supports respiratory surveillance while remaining model-organism evidence.
fibroblast link
extracellular matrix organization link
Show evidence (1 reference)
PMID:32022592 SUPPORT Model Organism
"Here, we analyzed the lung phenotype of Crtap knockout (KO) mice, a mouse model of recessive OI. While we confirm changes in the lung parenchyma that are reminiscent of emphysema, we show that CrtapKO lung fibroblasts synthesize type I collagen with altered posttranslation modifications..."
This model-organism study links CRTAP deficiency to intrinsic lung parenchymal and collagen-matrix abnormalities, not only secondary chest wall effects.
●

Phenotypes

12
Eye 3
Blue Sclerae Blue sclerae (HP:0000592)
Show evidence (1 reference)
PMID:12110406 SUPPORT Human Clinical
"The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia."
The original Ward et al. OI type VII cohort explicitly identifies bluish sclerae as part of the defining phenotype.
High Myopia High myopia (HP:0011003)
Show evidence (1 reference)
PMID:41064055 SUPPORT Human Clinical
"Interestingly, 1 patient presented with high myopia and bilateral retinal detachment, which have not been previously reported in OI type VII."
This should be interpreted cautiously as a single-patient report, but it expands the reported extraskeletal phenotype of CRTAP-related OI.
Retinal Detachment Retinal detachment (HP:0000541)
Show evidence (1 reference)
PMID:41064055 SUPPORT Human Clinical
"Interestingly, 1 patient presented with high myopia and bilateral retinal detachment, which have not been previously reported in OI type VII."
This is a single-patient report rather than a core defining feature, but it is a clinically important ocular manifestation when present.
Head and Neck 1
Wormian Bones Wormian bones (HP:0002645)
Show evidence (1 reference)
PMID:35970273 SUPPORT Human Clinical
"Cone-beam computed tomography showed occipital bossing, platybasia and wormian bones."
Wormian bones were documented on craniofacial imaging in the more severe of two 11-year-old girls with CRTAP-related OI.
Limbs 1
Coxa Vara Coxa vara (HP:0002812)
Show evidence (1 reference)
PMID:12110406 SUPPORT Human Clinical
"The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia."
Coxa vara is listed as a defining phenotypic feature of OI type VII in the original characterization of the disorder.
Musculoskeletal 4
Recurrent Fractures Recurrent fractures (HP:0002757)
Show evidence (3 references)
PMID:38214665 SUPPORT Human Clinical
"Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities."
The 2024 CRTAP cohort directly identifies early-onset recurrent fractures as a prominent phenotype.
PMID:12110406 SUPPORT Human Clinical
"The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia."
The founding OI type VII cohort describes fractures at birth as part of the defining phenotype.
PMID:41064055 SUPPORT Human Clinical
"The phenotype varied extensively in terms of severity and clinical features, ranging from moderate (type IV) to severe (type III) and including cases with prenatal fractures as well as one case with a low number of fractures and no prenatal fractures."
This 2025 series shows that fracture onset is variable, including prenatal presentation as well as milder postnatal cases.
Low Bone Mineral Density Osteopenia (HP:0000938)
Show evidence (2 references)
PMID:12110406 SUPPORT Human Clinical
"The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia."
Osteopenia is listed as a defining feature in the founding OI type VII cohort.
PMID:18566967 SUPPORT Human Clinical
"Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density."
This expands the low-BMD phenotype to the severe neonatal presentation of CRTAP-related recessive OI.
Osteoporosis Osteoporosis (HP:0000939)
Show evidence (1 reference)
PMID:38214665 SUPPORT Human Clinical
"Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities."
The 2024 CRTAP case series explicitly reports severe osteoporosis.
Skeletal Deformities Abnormality of the skeletal system (HP:0000924)
Show evidence (2 references)
PMID:38214665 SUPPORT Human Clinical
"Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities."
The 2024 CRTAP cohort directly identifies bone deformities as a prominent phenotype.
PMID:12110406 SUPPORT Human Clinical
"The phenotype is moderate to severe, characterized by fractures at birth, bluish sclerae, early deformity of the lower extremities, coxa vara, and osteopenia."
The founding cohort documents early lower-extremity deformity as part of the phenotype.
Growth 2
Rhizomelia Rhizomelia (HP:0008905)
Show evidence (1 reference)
PMID:12110406 SUPPORT Human Clinical
"Rhizomelia is a prominent clinical feature."
The original OI type VII paper identifies rhizomelia as a prominent and distinguishing clinical feature.
Growth Delay Growth delay (HP:0001510)
Show evidence (1 reference)
PMID:19895918 SUPPORT Human Clinical
"patients have fractures at birth, deformities of the lower extremities and impaired growth"
This human cohort supports impaired growth, but not a uniform claim of severe short stature across all OI type VII patients.
Other 1
Platybasia Platybasia (HP:0002691)
Show evidence (1 reference)
PMID:35970273 SUPPORT Human Clinical
"Cone-beam computed tomography showed occipital bossing, platybasia and wormian bones."
Platybasia was documented on craniofacial imaging in the more severe of two 11-year-old girls with CRTAP-related OI.
🧬

Genetic Associations

1
CRTAP Mutations (Causative)
Show evidence (2 references)
PMID:17055431 SUPPORT Human Clinical
"In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms. Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective tissue disease."
Original paper identifying CRTAP mutations as cause of recessive OI types, establishing a new mechanism for OI distinct from collagen structural mutations.
PMID:41064055 SUPPORT Human Clinical
"INTRODUCTION: CRTAP-related osteogenesis imperfecta (OI) is a form of OI that ranges from moderate (type IV) to extremely severe (type II) and is caused by biallelic variants in the CRTAP gene."
This contemporary molecularly confirmed series frames the CRTAP-related severity spectrum from moderate through extremely severe OI.
💊

Treatments

4
Bisphosphonate Therapy
Action: Bisphosphonate therapy Ontology label: bisphosphonate agent therapy MAXO:0000954
Bisphosphonates to improve bone density, though response may differ from classical OI due to distinct pathophysiology.
Show evidence (1 reference)
PMID:32797291 SUPPORT Human Clinical
"Management of patients with OI involves medical treatment by bisphosphonates as the most promising therapy to inhibit bone resorption and thereby facilitate bone formation."
Review describes bisphosphonates as the standard medical treatment for OI to inhibit bone resorption and facilitate bone formation.
Orthopedic Management
Action: Orthopedic surgery Ontology label: surgical procedure MAXO:0000004
Fracture management and corrective surgery for deformities. Rodding procedures for long bone stabilization.
Show evidence (1 reference)
PMID:32797291 SUPPORT Human Clinical
"Surgical treatment ensures pain reduction and healing without an increase of deformities."
Review describes surgical treatment as part of OI management for pain reduction and preventing deformity progression.
Physical Therapy
Action: Physical therapy Ontology label: physical therapy MAXO:0000011
Careful rehabilitation to maintain mobility while minimizing fracture risk.
Show evidence (1 reference)
PMID:32797291 SUPPORT Human Clinical
"Timely remobilization and regular strengthening of the muscles by physiotherapy are crucial to improve mobility, prevent muscle wasting and avoid bone resorption caused by immobilization."
Review describes physiotherapy as crucial for maintaining mobility and preventing complications in OI patients.
Genetic Counseling
Action: Genetic counseling Ontology label: genetic counseling MAXO:0000079
Genetic counseling for families regarding recurrence risk and carrier testing for at-risk relatives.
Show evidence (1 reference)
PMID:18566967 SUPPORT Human Clinical
"testing for those mutations is essential to distinguish the mode of inheritance, prediction of recurrence risk, and facilitate testing for parental mosaicism when mutations occur in the collagen genes"
Emphasizes the importance of genetic testing to distinguish recessive inheritance from germline mosaicism in dominant OI, informing recurrence risk counseling for families.
📊

Related Datasets

1
Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. PMID:12110406
Foundational clinical, radiological, and histological cohort describing eight individuals with osteogenesis imperfecta type VII from an isolated First Nations community in northern Quebec.
human PHENOPACKETS n=8
Conditions: Osteogenesis imperfecta type VII
PMID:12110406
Show evidence (2 references)
PMID:12110406 SUPPORT Human Clinical
"We report the clinical, radiological, and histological features of four children (age 3.9-8.6 years at last follow-up; all girls) and four adults (age 28-33 years; two women) with a novel form of autosomal recessive OI living in an isolated First Nations community in northern Quebec."
Supports this publication as the defining eight-person human phenotype cohort for OI type VII.
PMID:12110406 SUPPORT Human Clinical
"Histomorphometric analyses of iliac crest bone samples revealed findings similar to OI type I, with decreased cortical width and trabecular number, increased bone turnover, and preservation of the birefringent pattern of lamellar bone."
Confirms that the cohort includes structured bone histology data in addition to clinical and radiographic characterization.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type VII
creation_date: '2026-02-06T03:25:37Z'
updated_date: '2026-04-19T07:26:23Z'
category: Mendelian
description: >
  Osteogenesis imperfecta type VII is a rare autosomal recessive form of OI
  caused by biallelic mutations in CRTAP (cartilage-associated protein). CRTAP
  forms a complex with P3H1 (LEPRE1) and cyclophilin B (PPIB) that catalyzes
  3-hydroxylation of a specific proline residue in type I collagen and supports
  collagen folding and matrix assembly. Loss of CRTAP function impairs collagen
  modification, leading to a variable bone-fragility spectrum that ranges from
  moderate type IV-like disease to severe type III-like and perinatally lethal
  type II-like presentations, often accompanied by rhizomelia, coxa vara, and
  growth impairment.
disease_term:
  preferred_term: Osteogenesis imperfecta type VII
  term:
    id: MONDO:0012536
    label: osteogenesis imperfecta type 7
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >
    Autosomal recessive inheritance. Carrier parents are unaffected.
    More common in populations with high consanguinity rates.
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the clinical, radiological, and histological features of four
      children (age 3.9-8.6 years at last follow-up; all girls) and four adults
      (age 28-33 years; two women) with a novel form of autosomal recessive OI
      living in an isolated First Nations community in northern Quebec.
    explanation: >-
      The original paper defining OI type VII established it as an autosomal
      recessive form of brittle bone disease in a consanguineous community.
prevalence:
- population: 283-patient severe osteogenesis imperfecta cohort
  percentage: 4 of 283 (~1.4%)
  notes: >-
    Population prevalence for type VII is not well established, but this large
    clinical OI cohort identified four type VII patients among 283 total cases.
  evidence:
  - reference: PMID:16439896
    reference_title: "High prevalence of coxa vara in patients with severe osteogenesis imperfecta"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients were classified according to the Sillence classification modified by Glorieux: 94 type I, 90 type IV, 67 type III, 18 type V, 10 type VI, and 4 type VII."
    explanation: The abstract reports 4 type VII patients among 283 OI patients, corresponding to approximately 1.4% of the cohort.
pathophysiology:
- name: Collagen 3-Hydroxylation Deficiency
  description: >
    CRTAP is a component of the prolyl 3-hydroxylation complex that modifies
    Pro986 in the alpha1(I) chain of type I collagen. Loss of this modification
    delays collagen folding, causing overmodification of the helix and altered
    collagen structure and cross-linking.
  cell_types:
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Protein Hydroxylation
    term:
      id: GO:0018126
      label: protein hydroxylation
  - preferred_term: Collagen Fibril Organization
    term:
      id: GO:0030199
      label: collagen fibril organization
  evidence:
  - reference: PMID:17055431
    reference_title: "CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CRTAP can form a complex with P3H1 and cyclophilin B (CYPB), and Crtap-/-
      bone and cartilage collagens show decreased prolyl 3-hydroxylation. Moreover,
      mutant collagen shows evidence of overmodification, and collagen fibrils in
      mutant skin have increased diameter consistent with altered fibrillogenesis.
    explanation: >-
      Landmark Cell paper establishing CRTAP as essential for prolyl 3-hydroxylation
      and showing that loss leads to collagen overmodification and abnormal fibrils.
  - reference: PMID:18566967
    reference_title: "CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two proteins, cartilage-associated protein (CRTAP) and
      prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex
      that performs the hydroxylation and brings the prolyl cis-trans isomerase
      cyclophilin-B (CYPB) to the unfolded collagen.
    explanation: >-
      This human recessive-OI cohort supports the CRTAP/P3H1/cyclophilin B
      complex model and its role in collagen hydroxylation before folding.
- name: Osteoblast Dysfunction and Impaired Bone Formation
  description: >
    CRTAP deficiency in patient osteoblasts reduces CRTAP expression and prolyl
    3-hydroxylation of type I collagen, with reduced osteoblast numbers,
    diminished osteoid volume, and markedly impaired active bone formation.
  biological_processes:
  - preferred_term: Osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
  - preferred_term: Ossification
    term:
      id: GO:0001503
      label: ossification
  evidence:
  - reference: PMID:38214665
    reference_title: "Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP,
      the mRNA and protein levels of CRTAP in osteoblasts were significantly
      decreased and the osteoid volume and osteoblast numbers were markedly
      reduced compared with those in the normal control individual. This was
      simultaneously accompanied by significantly reduced prolyl 3-hydroxylation
      at Pro986 in the α1 chain of type I collagen and invisible active bone
      formation in bone.
    explanation: >-
      Directly supports osteoblast dysfunction, reduced osteoid, and impaired
      bone formation in CRTAP-related OI type VII.
- name: Collagen Proteotoxicity in Severe CRTAP Variants
  description: >
    Some severe CRTAP variants can generate unstable CRTAP isoforms that cause
    loss of proline hydroxylation, type I collagen aggregation, autophagy, and
    cellular senescence. This captures a severe/lethal variant mechanism rather
    than a uniform mechanism for every CRTAP allele.
  biological_processes:
  - preferred_term: protein folding
    term:
      id: GO:0006457
      label: protein folding
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:37146916
    reference_title: "Deep intronic mutation in CRTAP results in unstable isoforms of the protein to induce type I collagen aggregation in a lethal type of osteogenesis imperfecta type VII."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Both mutant isoforms of CRTAP are unstable due to the presence of a unique
      'GWxxI' degron, which finally leads to loss of proline hydroxylation and
      aggregation of type I collagen. Although type I collagen aggregates undergo
      autophagy, the overall proteotoxicity resulted in death of the proband
      cells by senescence.
    explanation: >-
      Patient-cell functional data connect a lethal CRTAP variant to collagen
      aggregation, proteotoxic stress, and senescence.
- name: Primary Lung Matrix Dysfunction
  description: >
    Crtap knockout mouse data support a primary lung contribution in recessive
    OI, with altered collagen post-translational modification in lung
    fibroblasts, parenchymal changes, and impaired respiratory mechanics. This
    supports respiratory surveillance while remaining model-organism evidence.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:32022592
    reference_title: "Respiratory defects in the CrtapKO mouse model of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we analyzed the lung phenotype of Crtap knockout (KO) mice, a mouse
      model of recessive OI. While we confirm changes in the lung parenchyma
      that are reminiscent of emphysema, we show that CrtapKO lung fibroblasts
      synthesize type I collagen with altered posttranslation modifications
      consistent with those observed in bone and skin.
    explanation: >-
      This model-organism study links CRTAP deficiency to intrinsic lung
      parenchymal and collagen-matrix abnormalities, not only secondary chest
      wall effects.
genetic:
- name: CRTAP Mutations
  association: Causative
  notes: >
    Biallelic loss-of-function mutations in CRTAP cause type VII OI. A
    common founder mutation (IVS1+1G>A) is found in West African populations.
    The phenotype spans moderate type IV-like disease, severe type III-like
    disease, and extremely severe or lethal type II-like presentations.
  evidence:
  - reference: PMID:17055431
    reference_title: "CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans, CRTAP mutations are associated with the clinical spectrum of
      recessive osteogenesis imperfecta, including the type II and VII forms.
      Hence, dysregulation of prolyl 3-hydroxylation is a mechanism for connective
      tissue disease.
    explanation: >-
      Original paper identifying CRTAP mutations as cause of recessive OI types,
      establishing a new mechanism for OI distinct from collagen structural mutations.
  - reference: PMID:41064055
    reference_title: "CRTAP-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      INTRODUCTION: CRTAP-related osteogenesis imperfecta (OI) is a form of OI
      that ranges from moderate (type IV) to extremely severe (type II) and is
      caused by biallelic variants in the CRTAP gene.
    explanation: >-
      This contemporary molecularly confirmed series frames the CRTAP-related
      severity spectrum from moderate through extremely severe OI.
phenotypes:
- name: Recurrent Fractures
  description: >
    Bone fragility typically manifests with recurrent fractures beginning
    prenatally, at birth, or in early childhood.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:38214665
    reference_title: "Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with OI type VII had early-onset recurrent fractures, severe
      osteoporosis, and bone deformities.
    explanation: >-
      The 2024 CRTAP cohort directly identifies early-onset recurrent fractures
      as a prominent phenotype.
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype is moderate to severe, characterized by fractures at birth,
      bluish sclerae, early deformity of the lower extremities, coxa vara, and
      osteopenia.
    explanation: >-
      The founding OI type VII cohort describes fractures at birth as part of
      the defining phenotype.
  - reference: PMID:41064055
    reference_title: "CRTAP-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype varied extensively in terms of severity and clinical
      features, ranging from moderate (type IV) to severe (type III) and
      including cases with prenatal fractures as well as one case with a low
      number of fractures and no prenatal fractures.
    explanation: >-
      This 2025 series shows that fracture onset is variable, including prenatal
      presentation as well as milder postnatal cases.
- name: Rhizomelia
  description: >
    Characteristic shortening of the proximal limb segments (humerus, femur),
    which helps distinguish recessive OI from dominant forms.
  phenotype_term:
    preferred_term: Rhizomelia
    term:
      id: HP:0008905
      label: Rhizomelia
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rhizomelia is a prominent clinical feature.
    explanation: >-
      The original OI type VII paper identifies rhizomelia as a prominent and
      distinguishing clinical feature.
- name: Growth Delay
  description: >
    Impaired growth is reported in childhood survivors and contributes to short
    stature in more severely affected individuals.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:19895918
    reference_title: "CRTAP deficiency leads to abnormally high bone matrix mineralization in a murine model and in children with osteogenesis imperfecta type VII."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      patients have fractures at birth, deformities of the lower extremities
      and impaired growth
    explanation: >-
      This human cohort supports impaired growth, but not a uniform claim of
      severe short stature across all OI type VII patients.
- name: Blue Sclerae
  description: >
    Bluish sclerae are part of the original clinical description of OI type VII.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype is moderate to severe, characterized by fractures at birth,
      bluish sclerae, early deformity of the lower extremities, coxa vara, and
      osteopenia.
    explanation: >-
      The original Ward et al. OI type VII cohort explicitly identifies bluish
      sclerae as part of the defining phenotype.
- name: Coxa Vara
  description: >
    Abnormal angle of the femoral neck contributing to hip dysfunction.
  phenotype_term:
    preferred_term: Coxa vara
    term:
      id: HP:0002812
      label: Coxa vara
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype is moderate to severe, characterized by fractures at birth,
      bluish sclerae, early deformity of the lower extremities, coxa vara, and
      osteopenia.
    explanation: >-
      Coxa vara is listed as a defining phenotypic feature of OI type VII in
      the original characterization of the disorder.
- name: Low Bone Mineral Density
  description: >
    Reduced bone mineral density ranges from osteopenia in the founding cohort
    to extremely low bone mineral density in more severe cases.
  phenotype_term:
    preferred_term: Low bone mineral density
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype is moderate to severe, characterized by fractures at birth,
      bluish sclerae, early deformity of the lower extremities, coxa vara, and
      osteopenia.
    explanation: >-
      Osteopenia is listed as a defining feature in the founding OI type VII
      cohort.
  - reference: PMID:18566967
    reference_title: "CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infants in both groups had multiple fractures, decreased bone modeling
      (affecting especially the femurs), and extremely low bone mineral density.
    explanation: >-
      This expands the low-BMD phenotype to the severe neonatal presentation of
      CRTAP-related recessive OI.
- name: Osteoporosis
  description: >
    Severe osteoporosis is part of the more severe CRTAP-related OI type VII
    phenotype spectrum.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:38214665
    reference_title: "Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with OI type VII had early-onset recurrent fractures, severe
      osteoporosis, and bone deformities.
    explanation: >-
      The 2024 CRTAP case series explicitly reports severe osteoporosis.
- name: Skeletal Deformities
  description: >
    Long-bone and other skeletal deformities arise early and contribute to
    clinical severity.
  phenotype_term:
    preferred_term: Skeletal deformity
    term:
      id: HP:0000924
      label: Abnormality of the skeletal system
  evidence:
  - reference: PMID:38214665
    reference_title: "Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by CRTAP Variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with OI type VII had early-onset recurrent fractures, severe
      osteoporosis, and bone deformities.
    explanation: >-
      The 2024 CRTAP cohort directly identifies bone deformities as a prominent
      phenotype.
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The phenotype is moderate to severe, characterized by fractures at birth,
      bluish sclerae, early deformity of the lower extremities, coxa vara, and
      osteopenia.
    explanation: >-
      The founding cohort documents early lower-extremity deformity as part of
      the phenotype.
- name: Wormian Bones
  description: >
    Wormian bones have been reported in severe craniofacial involvement.
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:35970273
    reference_title: "Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cone-beam computed tomography showed occipital bossing, platybasia and
      wormian bones.
    explanation: >-
      Wormian bones were documented on craniofacial imaging in the more severe
      of two 11-year-old girls with CRTAP-related OI.
- name: Platybasia
  description: >
    Platybasia has been reported as part of the craniofacial phenotype in severe
    childhood OI type VII.
  phenotype_term:
    preferred_term: Platybasia
    term:
      id: HP:0002691
      label: Platybasia
  evidence:
  - reference: PMID:35970273
    reference_title: "Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cone-beam computed tomography showed occipital bossing, platybasia and
      wormian bones.
    explanation: >-
      Platybasia was documented on craniofacial imaging in the more severe of
      two 11-year-old girls with CRTAP-related OI.
- name: High Myopia
  description: >
    High myopia has been reported in an adult with CRTAP-related OI, suggesting
    that ocular involvement can occur outside the skeleton.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: PMID:41064055
    reference_title: "CRTAP-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, 1 patient presented with high myopia and bilateral retinal
      detachment, which have not been previously reported in OI type VII.
    explanation: >-
      This should be interpreted cautiously as a single-patient report, but it
      expands the reported extraskeletal phenotype of CRTAP-related OI.
- name: Retinal Detachment
  description: >
    Bilateral retinal detachment has been reported in an adult with
    CRTAP-related OI type VII.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:41064055
    reference_title: "CRTAP-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in CRTAP."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, 1 patient presented with high myopia and bilateral retinal
      detachment, which have not been previously reported in OI type VII.
    explanation: >-
      This is a single-patient report rather than a core defining feature, but
      it is a clinically important ocular manifestation when present.
diagnosis:
- name: Clinical, Radiographic, and Molecular Diagnosis
  description: >-
    Osteogenesis imperfecta type VII is an autosomal recessive form of brittle
    bone disease diagnosed from clinical and radiographic features of OI and
    confirmed by identification of biallelic CRTAP variants. Because CRTAP
    deficiency overlaps clinically with other recessive OI forms, molecular
    testing should distinguish CRTAP from LEPRE1/P3H1, PPIB/cyclophilin B, and
    COL1A1/COL1A2-related OI or parental mosaicism in apparently recurrent
    severe OI.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:17055431
    reference_title: "CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In humans, CRTAP mutations are associated with the clinical spectrum of recessive osteogenesis imperfecta, including the type II and VII forms."
    explanation: >-
      Directly connects CRTAP mutations to the clinical spectrum of recessive
      OI including the type VII form, supporting CRTAP molecular genetic testing
      as the basis of diagnosis.
  - reference: PMID:18566967
    reference_title: "CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results expand the range of CRTAP/LEPRE1 mutations that result in
      recessive OI and emphasize the importance of distinguishing recurrence of
      severe OI of recessive inheritance from those that result from parental
      germline mosaicism for COL1A1 or COL1A2 mutations.
    explanation: >-
      Supports using molecular testing to separate CRTAP/P3H1-complex recessive
      OI from recurrent dominant collagen-gene disease caused by parental
      mosaicism.
- name: General OI Multisystem Surveillance
  description: >-
    General multisystem OI surveillance applies, including growth, mobility,
    pain, bone-density, craniovertebral, dental, hearing, respiratory, sleep,
    feeding/nutrition, and psychosocial assessment tailored to severity.
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assess growth at each visit throughout childhood and adolescence. Physical
      and rehabilitation medicine and physical and occupational therapy
      evaluation in infancy for those with motor delays and as needed in older
      individuals. Assessment of pain at each visit.
    explanation: >-
      GeneReviews supports general OI follow-up for growth, mobility, and pain,
      which applies to CRTAP-related OI type VII according to individual
      severity.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DXA scans beginning at age five years with follow-up scan based on severity of OI, initial results, and pharmacologic treatment status."
    explanation: >-
      GeneReviews bone-density surveillance is part of general OI care
      applicable across OI types, including recessive type VII.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CT and/or MRI with views across the base of the skull to evaluate for
      basilar impression in those with platybasia, moderate-to-severe OI, or
      concerning signs or symptoms.
    explanation: >-
      Supports craniovertebral imaging surveillance in moderate-to-severe OI
      or when platybasia is present, which is relevant to reported OI type VII
      craniofacial involvement.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dental examination every six months beginning in early childhood or
      infancy for those with (or at risk for) DI. Annual dental exams in those
      without DI. Hearing evaluation every three years from age five years until
      hearing loss is identified, then as indicated based on the nature and
      degree of hearing loss and associated interventions.
    explanation: >-
      Supports dental and audiology surveillance as part of general OI care.
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Assess for pulmonary issues at each visit; consider pulmonary evaluation
      in those with lung disease; pulmonary function tests every one to two
      years in adults; sleep study in those with symptoms of sleep apnea.
    explanation: >-
      Supports respiratory and sleep-related monitoring, reinforced for type VII
      by CRTAP model data showing primary lung-matrix defects.
treatments:
- name: Bisphosphonate Therapy
  description: >
    Bisphosphonates to improve bone density, though response may differ
    from classical OI due to distinct pathophysiology.
  treatment_term:
    preferred_term: Bisphosphonate therapy
    term:
      id: MAXO:0000954
      label: bisphosphonate agent therapy
  evidence:
  - reference: PMID:32797291
    reference_title: "Osteogenesis imperfecta-pathophysiology and therapeutic options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Management of patients with OI involves medical treatment by
      bisphosphonates as the most promising therapy to inhibit bone resorption
      and thereby facilitate bone formation.
    explanation: >-
      Review describes bisphosphonates as the standard medical treatment for OI
      to inhibit bone resorption and facilitate bone formation.
- name: Orthopedic Management
  description: >
    Fracture management and corrective surgery for deformities. Rodding
    procedures for long bone stabilization.
  treatment_term:
    preferred_term: Orthopedic surgery
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:32797291
    reference_title: "Osteogenesis imperfecta-pathophysiology and therapeutic options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical treatment ensures pain reduction and healing without an increase
      of deformities.
    explanation: >-
      Review describes surgical treatment as part of OI management for pain
      reduction and preventing deformity progression.
- name: Physical Therapy
  description: >
    Careful rehabilitation to maintain mobility while minimizing fracture risk.
  treatment_term:
    preferred_term: Physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:32797291
    reference_title: "Osteogenesis imperfecta-pathophysiology and therapeutic options."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Timely remobilization and regular strengthening of the muscles by
      physiotherapy are crucial to improve mobility, prevent muscle wasting and
      avoid bone resorption caused by immobilization.
    explanation: >-
      Review describes physiotherapy as crucial for maintaining mobility and
      preventing complications in OI patients.
- name: Genetic Counseling
  description: >
    Genetic counseling for families regarding recurrence risk and carrier
    testing for at-risk relatives.
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:18566967
    reference_title: "CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      testing for those mutations is essential to distinguish the mode of
      inheritance, prediction of recurrence risk, and facilitate testing for
      parental mosaicism when mutations occur in the collagen genes
    explanation: >-
      Emphasizes the importance of genetic testing to distinguish recessive
      inheritance from germline mosaicism in dominant OI, informing recurrence
      risk counseling for families.
datasets:
- accession: PMID:12110406
  title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
  description: >-
    Foundational clinical, radiological, and histological cohort describing
    eight individuals with osteogenesis imperfecta type VII from an isolated
    First Nations community in northern Quebec.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: PHENOPACKETS
  sample_count: 8
  conditions:
  - Osteogenesis imperfecta type VII
  publication: PMID:12110406
  evidence:
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the clinical, radiological, and histological features of four
      children (age 3.9-8.6 years at last follow-up; all girls) and four adults
      (age 28-33 years; two women) with a novel form of autosomal recessive OI
      living in an isolated First Nations community in northern Quebec.
    explanation: >-
      Supports this publication as the defining eight-person human phenotype
      cohort for OI type VII.
  - reference: PMID:12110406
    reference_title: "Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histomorphometric analyses of iliac crest bone samples revealed findings
      similar to OI type I, with decreased cortical width and trabecular
      number, increased bone turnover, and preservation of the birefringent
      pattern of lamellar bone.
    explanation: >-
      Confirms that the cohort includes structured bone histology data in
      addition to clinical and radiographic characterization.
references:
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1295/
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta - GeneReviews® - NCBI Bookshelf"
  findings: []
  tags:
  - GeneReviews
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  findings: []
- reference: DOI:10.1007/s00223-024-01266-5
  title: Update on the Genetics of Osteogenesis Imperfecta
  findings: []
- reference: DOI:10.1007/s00441-009-0872-0
  title: Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta
  findings: []
- reference: DOI:10.1038/nm.3544
  title: Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta
  findings: []
- reference: DOI:10.1056/nejmoa063804
  title: Deficiency of Cartilage-Associated Protein in Recessive Lethal Osteogenesis Imperfecta
  findings: []
- reference: DOI:10.1111/j.1399-0004.2011.01794.x
  title: Deficiency of <i>CRTAP</i> in non‐lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix
  findings: []
- reference: DOI:10.1152/ajplung.00313.2019
  title: Respiratory defects in the <i>Crtap</i>KO mouse model of osteogenesis imperfecta
  findings: []
- reference: DOI:10.1210/clinem/dgae025
  title: Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by <i>CRTAP</i> Variants
  findings: []
- reference: DOI:10.1016/j.bone.2022.116516
  title: Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in <i>CRTAP</i>
  findings: []
- reference: DOI:10.1002/humu.20799
  title: <i>CRTAP</i> and <i>LEPRE1</i> mutations in recessive osteogenesis imperfecta
  findings: []
- reference: DOI:10.1159/000547923
  title: "<i>CRTAP</i>-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in <i>CRTAP</i>"
  findings: []
📚

References & Deep Research

References

12
url:https://www.ncbi.nlm.nih.gov/books/NBK1295/
COL1A1- and COL1A2-Related Osteogenesis Imperfecta - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
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:10.1007/s00441-009-0872-0
Null mutations in LEPRE1 and CRTAP cause severe recessive osteogenesis imperfecta
No top-level findings curated for this source.
DOI:10.1038/nm.3544
Excessive transforming growth factor-β signaling is a common mechanism in osteogenesis imperfecta
No top-level findings curated for this source.
DOI:10.1056/nejmoa063804
Deficiency of Cartilage-Associated Protein in Recessive Lethal Osteogenesis Imperfecta
No top-level findings curated for this source.
DOI:10.1111/j.1399-0004.2011.01794.x
Deficiency of <i>CRTAP</i> in non‐lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix
No top-level findings curated for this source.
DOI:10.1152/ajplung.00313.2019
Respiratory defects in the <i>Crtap</i>KO mouse model of osteogenesis imperfecta
No top-level findings curated for this source.
DOI:10.1210/clinem/dgae025
Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare Osteogenesis Imperfecta Caused by <i>CRTAP</i> Variants
No top-level findings curated for this source.
DOI:10.1016/j.bone.2022.116516
Craniofacial and dental phenotype of two girls with osteogenesis imperfecta due to mutations in <i>CRTAP</i>
No top-level findings curated for this source.
DOI:10.1002/humu.20799
<i>CRTAP</i> and <i>LEPRE1</i> mutations in recessive osteogenesis imperfecta
No top-level findings curated for this source.
DOI:10.1159/000547923
<i>CRTAP</i>-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in <i>CRTAP</i>
No top-level findings curated for this source.

Deep Research

2
Disorder ▸

Disorder

  • Name: Osteogenesis Imperfecta Type VII
  • Category: Mendelian
  • Existing deep-research providers: falcon
  • Existing evidence reference count in YAML: 9

Key Pathophysiology Nodes

  • Collagen 3-Hydroxylation Deficiency
  • ER Stress from Abnormal Collagen Folding
  • Deep research literature mapping

Citation Inventory (for evidence mapping)

  • DOI:10.1007/s00223-024-01266-5
  • DOI:10.1007/s00441-009-0872-0
  • DOI:10.1038/nm.3544
  • DOI:10.1056/nejmoa063804
  • DOI:10.1111/j.1399-0004.2011.01794.x
  • DOI:10.1152/ajplung.00313.2019
  • DOI:10.1210/clinem/dgae025
Falcon ▸
Disease Pathophysiology Research Report
Edison Scientific Literature 30 citations 2026-02-04T19:43:40.924086

Disease Pathophysiology Research Report

Target Disease

  • Disease Name: Osteogenesis Imperfecta Type VII (OI type VII; CRTAP-related)
  • MONDO ID: Not explicitly stated in cited texts; OI as a group is represented in MONDO. Nosology assigns CRTAP-related OI as Type VII in 2024 ISDS framework (dyadic nosology). (jovanovic2024updateonthe pages 8-9)
  • Category: Mendelian, autosomal recessive

Pathophysiology Description (Narrative)

Osteogenesis imperfecta type VII is a recessive collagen-processing disorder caused by biallelic variants in CRTAP that disrupt an endoplasmic reticulum (ER) prolyl 3‑hydroxylation complex composed of P3H1/LEPRE1 (catalytic subunit), CRTAP (stabilizing/helper subunit), and cyclophilin B/PPIB (prolyl isomerase/chaperone). This complex 3‑hydroxylates Pro986 on each α1(I) chain of type I collagen and supports procollagen folding. Loss of CRTAP destabilizes the complex, reduces or abolishes α1(I) Pro986 3‑hydroxyproline, delays helix folding with “over‑modification,” impairs collagen secretion and matrix deposition, alters fibril structure and crosslinking, and ultimately weakens bone. Mouse and human studies show resultant osteoblast dysfunction with reduced osteoid, growth‑plate cartilage disorganization causing rhizomelia, and extraskeletal involvement such as primary lung parenchymal defects; excessive TGF‑β signaling is implicated as a shared downstream mechanism linking matrix abnormalities to cell signaling. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, marini2010nullmutationsin pages 2-4, valli2012deficiencyofcrtap pages 1-2, barnes2006deficiencyofcartilageassociated pages 1-2, dimori2020respiratorydefectsin pages 1-6)

Category Entity (ontology) Mechanism / Role Key Findings Source (Year, DOI/URL) Citation ID
Gene / Protein CRTAP (HGNC:2387) ER-resident cofactor that stabilizes P3H1 in the prolyl 3‑hydroxylation complex Biallelic CRTAP loss → markedly reduced CRTAP mRNA/protein, loss/reduction of Pro986 3‑hydroxylation on COL1A1, impaired collagen folding/secretion, reduced osteoid and osteoblast numbers, severe osteoporosis and deformity in patients 2024, Zhou et al., J Clin Endocrinol Metab, DOI: 10.1210/clinem/dgae025; 2006, Barnes et al., NEJM, DOI: 10.1056/NEJMoa063804 (zhou2024geneticanalysisphenotypic pages 1-1, barnes2006deficiencyofcartilageassociated pages 1-2)
Gene / Protein LEPRE1 / P3H1 (HGNC:18684) Catalytic subunit of the P3H1–CRTAP–CyPB complex performing Pro986 3‑hydroxylation Loss/null mutations abolish Pro986 3‑hydroxylation, produce recessive OI phenotypes (growth deficiency, osteopenia, cartilage disorganization) 2010, Marini et al., Cell Tissue Res, DOI: 10.1007/s00441-009-0872-0; 2024, Jovanovic & Marini review, DOI: 10.1007/s00223-024-01266-5 (marini2010nullmutationsin pages 4-5, jovanovic2024updateonthe pages 8-9)
Gene / Protein PPIB / Cyclophilin B (HGNC:9250) Peptidyl‑prolyl isomerase / chaperone in the complex that aids procollagen folding Participates in complex with P3H1 and CRTAP; loss or dysfunction perturbs folding/isomerization contributing to overmodified collagen and matrix defects 2010, Marini et al., DOI: 10.1007/s00441-009-0872-0; 2012, Valli et al., Clin Genet, DOI: 10.1111/j.1399-0004.2011.01794.x (marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2)
Substrate / Structural Type I collagen COL1A1 (HGNC:2197) Major fibrillar collagen; Pro986 in α1(I) is 3‑hydroxylated by the complex Lack of Pro986 3‑hydroxylation → delayed helix formation, helical overmodification, altered crosslinking and fibril diameter, poor matrix deposition → weaker bone 2024, Zhou et al., DOI: 10.1210/clinem/dgae025; 2012, Valli et al., DOI: 10.1111/j.1399-0004.2011.01794.x; 2006, Barnes et al., DOI: 10.1056/NEJMoa063804 (zhou2024geneticanalysisphenotypic pages 1-1, valli2012deficiencyofcrtap pages 1-2, barnes2006deficiencyofcartilageassociated pages 1-2)
Cell type Osteoblast (CL:0000062) Primary cell synthesizing type I collagen and mineralizing matrix CRTAP-deficient osteoblasts: ↓CRTAP expression, ↓osteoid volume and osteoblast numbers, impaired matrix formation; some CRTAP-null cells show altered proliferation/protein secretion (functional perturbation of osteoblast biology) 2024, Zhou et al., J Clin Endocrinol Metab, DOI: 10.1210/clinem/dgae025; 2006, Barnes et al., NEJM, DOI: 10.1056/NEJMoa063804 (zhou2024geneticanalysisphenotypic pages 1-1, barnes2006deficiencyofcartilageassociated pages 1-2)
Cell type Chondrocyte (CL:0000138) Growth‑plate cartilage cells reliant on properly modified collagen Crtap−/− mice: disorganized proliferative chondrocytes, metaphyseal/growth‑plate abnormalities and rhizomelic shortening → contributes to short stature / limb deformities in type VII OI 2010, Marini et al., DOI: 10.1007/s00441-009-0872-0 (marini2010nullmutationsin pages 4-5)
Tissue / Cell Lung fibroblast (CL:0002553) / Lung (UBERON:0002048) Synthesis of interstitial collagen in lung parenchyma CrtapKO mice show altered collagen PTMs in lung fibroblasts, emphysema‑like parenchymal changes, abnormal lung mechanics; increased TGF‑β signaling seen and anti‑TGF‑β partially rescues phenotype 2020, Dimori et al., Am J Physiol Lung Cell Mol Physiol, DOI: 10.1152/ajplung.00313.2019; 2024, Zhou et al. (discussion of lung findings) DOI: 10.1210/clinem/dgae025 (dimori2020respiratorydefectsin pages 1-6, zhou2024geneticanalysisphenotypic pages 1-1)
Tissue Growth plate cartilage (UBERON:0002429) Site of endochondral growth dependent on ECM integrity Patient and mouse data: metaphyseal enlargement, 'popcorn' epiphyses, femoral/tibial deformities indicating growth‑plate disruption from abnormal collagen matrix 2024, Zhou et al., DOI: 10.1210/clinem/dgae025; 2010, Marini et al., DOI: 10.1007/s00441-009-0872-0 (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5)
Cellular component / ECM ECM / Collagen fibril (GO:0005583 / GO:0030199) Extracellular assembly of collagen fibrils that determine bone matrix quality CRTAP deficiency → markedly reduced collagen deposition into matrix, disorganized fibrils, altered fibril diameter and crosslinking → compromised bone mechanical properties 2012, Valli et al., Clin Genet, DOI: 10.1111/j.1399-0004.2011.01794.x; 2006, Barnes et al., NEJM, DOI: 10.1056/NEJMoa063804; 2024, Zhou et al., DOI: 10.1210/clinem/dgae025 (valli2012deficiencyofcrtap pages 1-2, barnes2006deficiencyofcartilageassociated pages 1-2, zhou2024geneticanalysisphenotypic pages 1-1)
Organelle / Compartment Endoplasmic reticulum (GO:0005783) Location of the CRTAP–P3H1–CyPB complex and collagen PTMs/folding CRTAP/P3H1 complex loss → delayed procollagen folding (overmodification), ER perturbation/UPR signals; chemical chaperone (4‑phenylbutyrate) shown to reduce ER stress/overmodified collagen in models 2012, Valli et al., DOI: 10.1111/j.1399-0004.2011.01794.x; 2024, Zhou et al., DOI: 10.1210/clinem/dgae025 (valli2012deficiencyofcrtap pages 1-2, zhou2024geneticanalysisphenotypic pages 9-9)
Pathway / Process Prolyl 3‑hydroxylation (GO:0019794) Post‑translational hydroxylation of Pro986 on α1(I) by P3H1 within complex Essential PTM for correct helix assembly; absent/reduced in CRTAP or P3H1 nulls → biochemical signature of recessive OI type VII/VIII 2010, Marini et al., DOI: 10.1007/s00441-009-0872-0; 2006, Barnes et al., NEJM, DOI: 10.1056/NEJMoa063804; 2024, Zhou et al., DOI: 10.1210/clinem/dgae025 (marini2010nullmutationsin pages 4-5, barnes2006deficiencyofcartilageassociated pages 1-2, zhou2024geneticanalysisphenotypic pages 1-1)
Pathway / Process Protein folding / chaperone activity (GO:0006457) CyPB isomerase + ER chaperones assist procollagen folding; folding rate influences extent of other PTMs Delayed folding (due to complex loss) → helical overmodification; chemical chaperones partially correct aberrant modifications in models (e.g., 4‑PBA) 2012, Valli et al., DOI: 10.1111/j.1399-0004.2011.01794.x; 2024, Zhou et al., DOI: 10.1210/clinem/dgae025 (valli2012deficiencyofcrtap pages 1-2, zhou2024geneticanalysisphenotypic pages 9-9)
Pathway / Process Collagen biosynthetic process (GO:0032964) Encompasses PTMs, folding, secretion and matrix assembly Disruption at PTM/folding step reduces matrix deposition and mineralized bone, causing fragility; phenotype connects molecular defect → cellular dysfunction → clinical fractures 2010, Marini et al., DOI: 10.1007/s00441-009-0872-0; 2012, Valli et al., DOI: 10.1111/j.1399-0004.2011.01794.x (marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2)
Pathway / Process TGF‑β signaling (GO:0007179) Matrix‑cell signaling axis modulated by collagen–proteoglycan interactions Excessive TGF‑β signaling observed in Crtap−/− models and contributes to bone (and lung) pathology; anti‑TGF‑β antibodies improve bone phenotype in mice (preclinical rationale) 2014 (mechanistic landmark cited in reviews), and 2020/2024 model data showing elevated TGF‑β and partial rescue via anti‑TGF‑β (see Dimori 2020; Zhou 2024) DOI: 10.1152/ajplung.00313.2019; DOI: 10.1210/clinem/dgae025 (dimori2020respiratorydefectsin pages 1-6, zhou2024geneticanalysisphenotypic pages 10-11, jovanovic2024updateonthe pages 8-9)
Pathway / Process Bone mineralization (GO:0030282) Downstream outcome of osteoblast function and matrix quality CRTAP deficiency → low bone mass/osteoporosis and deformity; preclinical sclerostin antibody improves bone microarchitecture in Crtap−/− mice; clinical bisphosphonate use reported with vertebral reshaping and fracture reduction in small CRTAP case series 2024, Zhou et al. (patient response to zoledronic acid) DOI: 10.1210/clinem/dgae025; preclinical sclerostin antibody cited in Zhou (2024) DOI: 10.1210/clinem/dgae025 (zhou2024geneticanalysisphenotypic pages 4-5, zhou2024geneticanalysisphenotypic pages 10-11)

Table: A concise evidence‑mapping table summarizing molecular players, cells, compartments and pathways implicated in CRTAP‑related (Type VII) osteogenesis imperfecta, with key mechanistic findings and primary sources (2020–2024) for quick reference.

Structured Sections Aligned to Research Objectives

1. Core Pathophysiology

  • Primary mechanisms: Loss of CRTAP disrupts the ER prolyl 3‑hydroxylation complex (P3H1–CRTAP–PPIB), eliminating or severely reducing 3‑hydroxylation of α1(I) Pro986; this leads to delayed procollagen folding (helical over‑modification), impaired secretion, and defective extracellular matrix (ECM) assembly with reduced collagen deposition and disorganized fibrils. (marini2010nullmutationsin pages 4-5, marini2010nullmutationsin pages 2-4, valli2012deficiencyofcrtap pages 1-2, barnes2006deficiencyofcartilageassociated pages 1-2)
  • Dysregulated pathways: Collagen biosynthesis/processing (prolyl 3‑hydroxylation, protein folding), ECM organization, and TGF‑β signaling become aberrant. Excessive TGF‑β signaling was demonstrated as a common mechanism in OI, including Crtap−/− models, with anti‑TGF‑β antibodies rescuing bone and partially improving lung abnormalities in mice. (dimori2020respiratorydefectsin pages 1-6)
  • Affected cellular processes: Osteoblast matrix production and osteoid formation are reduced in human CRTAP‑mutant bone; growth‑plate chondrocyte organization is disrupted in Crtap−/− mice; lung fibroblasts synthesize abnormally modified collagen leading to parenchymal and mechanical defects. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, dimori2020respiratorydefectsin pages 1-6)

Direct quotes supporting key claims: - “This is the first evidence that collagen defects in OI cause primary changes in lung parenchyma and several respiratory parameters and thus negatively impact lung function.” (Dimori et al., 2020; Am J Physiol Lung Cell Mol Physiol; https://doi.org/10.1152/ajplung.00313.2019) (dimori2020respiratorydefectsin pages 1-6) - “Deficiency of cartilage‑associated protein [CRTAP]… [leads to] complete loss of Pro986 hydroxylation in α1(I)” with severe skeletal pathology in mouse and human recessive OI. (Barnes et al., 2006; N Engl J Med; https://doi.org/10.1056/NEJMoa063804) (barnes2006deficiencyofcartilageassociated pages 1-2) - In patient bone: “significantly reduced prolyl 3‑hydroxylation at Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone,” with decreased CRTAP mRNA/protein and reduced osteoid volume/osteoblast numbers. (Zhou et al., 2024; J Clin Endocrinol Metab; https://doi.org/10.1210/clinem/dgae025) (zhou2024geneticanalysisphenotypic pages 1-1)

2. Key Molecular Players

  • Genes/Proteins (HGNC):
  • CRTAP (HGNC:2387): ER complex subunit stabilizing P3H1; loss causes OI type VII. (barnes2006deficiencyofcartilageassociated pages 1-2, zhou2024geneticanalysisphenotypic pages 1-1)
  • LEPRE1/P3H1 (HGNC:18684): catalytic prolyl 3‑hydroxylase 1 for α1(I) Pro986; null alleles cause recessive OI. (marini2010nullmutationsin pages 4-5)
  • PPIB/Cyclophilin B (HGNC:9250): peptidyl‑prolyl isomerase aiding procollagen folding; complex member. (marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2)
  • COL1A1 (HGNC:2197): type I collagen α1 chain carrying the Pro986 3‑Hyp site; aberrant PTMs when complex is lost. (valli2012deficiencyofcrtap pages 1-2, zhou2024geneticanalysisphenotypic pages 1-1)
  • Chemical entities (CHEBI; selected): 4‑phenylbutyrate (CHEBI:46195) as ER chemical chaperone rescue in models; zoledronic acid (CHEBI:46550) and denosumab (CHEBI:68481) in clinical management. (zhou2024geneticanalysisphenotypic pages 10-11, zhou2024geneticanalysisphenotypic pages 4-5)
  • Cell types (CL): osteoblast (CL:0000062), chondrocyte (CL:0000138), lung fibroblast (CL:0002553). (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, dimori2020respiratorydefectsin pages 1-6)
  • Anatomical locations (UBERON): bone (UBERON:0001474), lung (UBERON:0002048), growth plate cartilage (UBERON:0002429). (dimori2020respiratorydefectsin pages 1-6, marini2010nullmutationsin pages 4-5)

3. Biological Processes (for GO annotation)

  • Prolyl 3‑hydroxylation (GO:0019794): modification of α1(I) Pro986 by P3H1 complex; absent/reduced in CRTAP or P3H1 loss. (marini2010nullmutationsin pages 4-5, barnes2006deficiencyofcartilageassociated pages 1-2)
  • Protein folding (GO:0006457): CyPB‑assisted isomerization/folding; delayed folding underlies over‑modification. (valli2012deficiencyofcrtap pages 1-2)
  • Collagen biosynthetic process (GO:0032964): includes PTMs, folding, secretion; impaired in CRTAP deficiency. (marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2)
  • TGF‑β receptor signaling pathway (GO:0007179): elevated activity contributes to bone/lung phenotypes; neutralization improves bone in models. (dimori2020respiratorydefectsin pages 1-6)
  • Bone mineralization (GO:0030282): reduced due to impaired osteoblast matrix; improved in mice with sclerostin antibody; improved BMD/vertebral remodeling in human case on antiresorptives. (zhou2024geneticanalysisphenotypic pages 10-11, zhou2024geneticanalysisphenotypic pages 4-5)

4. Cellular Components

  • Endoplasmic reticulum (GO:0005783): site of the P3H1–CRTAP–PPIB complex and procollagen PTMs/folding. (marini2010nullmutationsin pages 4-5)
  • Extracellular matrix / collagen fibril (GO:0005583/GO:0030199): reduced collagen deposition and abnormal fibrillogenesis in CRTAP deficiency. (valli2012deficiencyofcrtap pages 1-2)

5. Disease Progression

  • Initiation: Biallelic CRTAP variants reduce CRTAP expression/protein and destabilize the P3H1–CRTAP–PPIB complex. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5)
  • Molecular consequence: Loss of α1(I) Pro986 3‑hydroxylation; delayed triple‑helix folding; helical over‑modification and abnormal crosslinking/fibril size. (marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2)
  • Cellular/tissue effects: Impaired secretion and ECM deposition; reduced osteoid and osteoblast numbers; growth‑plate disorganization; excess TGF‑β signaling; lung parenchymal defects and abnormal mechanics in CrtapKO mice. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, dimori2020respiratorydefectsin pages 1-6)
  • Clinical manifestation: Early‑onset recurrent fractures, severe osteoporosis, deformities, rhizomelia, metaphyseal enlargement/‘popcorn’ epiphyses; extraskeletal features variable (some series without dentinogenesis imperfecta/blue sclera). (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5)

6. Phenotypic Manifestations (HPO terms)

  • Recurrent fractures (HP:0002757) and osteopenia/low BMD (HP:0000938), severe osteoporosis with deformities. (zhou2024geneticanalysisphenotypic pages 1-1)
  • Rhizomelia/proximal limb shortening (HP:0008915) and short stature (HP:0004322). (marini2010nullmutationsin pages 4-5)
  • Metaphyseal widening/“popcorn” epiphyses (HP:0100660). (zhou2024geneticanalysisphenotypic pages 1-1)
  • Variable extraskeletal features: absent dentinogenesis imperfecta and blue sclera in some CRTAP cases in 2024 series. (zhou2024geneticanalysisphenotypic pages 4-5)

Recent Developments and Applications (2023–2024 priority)

  • Genetics and nosology: 2024 updates emphasize CRTAP/P3H1/PPIB as the 3‑hydroxylation complex underlying recessive OI types VII–IX and integrate these into ISDS dyadic nosology. (Calcified Tissue Int 2024; https://doi.org/10.1007/s00223-024-01266-5) (jovanovic2024updateonthe pages 8-9)
  • Human bone mechanistic study: 2024 bone‑specimen evidence links CRTAP loss to reduced α1(I) Pro986 3‑hyp, decreased osteoblast numbers/osteoid, and no active bone formation; novel CRTAP splice variant described. (J Clin Endocrinol Metab 2024; https://doi.org/10.1210/clinem/dgae025) (zhou2024geneticanalysisphenotypic pages 1-1)
  • Clinical management signals (2024 case data): zoledronic acid associated with vertebral body reshaping and 3‑year fracture freedom; sequential zoledronic acid→teriparatide→denosumab increased femoral neck BMD in a CRTAP patient. (J Clin Endocrinol Metab 2024; https://doi.org/10.1210/clinem/dgae025) (zhou2024geneticanalysisphenotypic pages 4-5)
  • Preclinical therapeutics: anti‑TGF‑β rescues bone (and partially lung) in Crtap−/−; sclerostin antibody improves bone microarchitecture in Crtap−/−; 4‑phenylbutyrate reduces ER stress/over‑modification in models. (Nature Med 2014; https://doi.org/10.1038/nm.3544; AJPLung 2020; https://doi.org/10.1152/ajplung.00313.2019; citations within 2024 JCEM) (dimori2020respiratorydefectsin pages 1-6, zhou2024geneticanalysisphenotypic pages 10-11)

Expert Opinions/Quotes

  • “Excessive transforming growth factor‑β signaling is a common mechanism in osteogenesis imperfecta,” with anti‑TGF‑β normalizing bone phenotypes in both dominant and recessive OI murine models, including Crtap−/−. (Nature Med 2014; https://doi.org/10.1038/nm.3544) (dimori2020respiratorydefectsin pages 1-6)
  • “CRTAP is required for prolyl 3‑hydroxylation… [and] Prolyl 3‑hydroxylase 1 and CRTAP are mutually stabilizing” in the ER complex, explaining why CRTAP loss leads to loss of the collagen 3‑hyp mark and folding delays. (Synthesized from Marini 2010 and Zhou 2024; URLs: https://doi.org/10.1007/s00441-009-0872-0; https://doi.org/10.1210/clinem/dgae025) (marini2010nullmutationsin pages 4-5, zhou2024geneticanalysisphenotypic pages 9-10)
  • “This is the first evidence that collagen defects in OI cause primary changes in lung parenchyma…” highlighting extraskeletal primary pathology in Crtap deficiency. (AJPLung 2020; https://doi.org/10.1152/ajplung.00313.2019) (dimori2020respiratorydefectsin pages 1-6)

Statistics/Data Points

  • Human bone from CRTAP‑mutant patient: significantly reduced CRTAP mRNA/protein; markedly reduced prolyl 3‑hydroxylation at α1(I) Pro986; reduced osteoid volume and osteoblast numbers; no active bone formation. (JCEM 2024; https://doi.org/10.1210/clinem/dgae025) (zhou2024geneticanalysisphenotypic pages 1-1)
  • ECM deposition: CRTAP‑deficient fibroblasts deposit only ~10–15% of normal collagen into matrix with disorganized fibrils; 3‑hyp at Pro986 as low as ~5% in a non‑lethal CRTAP case. (Clin Genet 2012; https://doi.org/10.1111/j.1399-0004.2011.01794.x) (valli2012deficiencyofcrtap pages 1-2)
  • Lung mechanics in CrtapKO: increased elastance, decreased compliance, altered breathing cycle parameters, and emphysema‑like parenchymal changes; partial rescue with anti‑TGF‑β. (AJPLung 2020; https://doi.org/10.1152/ajplung.00313.2019) (dimori2020respiratorydefectsin pages 1-6)
  • Clinical response (2024 case): vertebral body reshaping after zoledronic acid; no new fractures during 3 years; increased femoral neck BMD after sequential zoledronic acid→teriparatide→denosumab in CRTAP case. (JCEM 2024; https://doi.org/10.1210/clinem/dgae025) (zhou2024geneticanalysisphenotypic pages 4-5)

Gene/Protein Annotations with Ontologies

  • CRTAP (HGNC:2387): collagen prolyl‑3‑hydroxylation complex subunit; GO:0019794, GO:0005783; disease: OI type VII. (marini2010nullmutationsin pages 4-5, barnes2006deficiencyofcartilageassociated pages 1-2)
  • LEPRE1/P3H1 (HGNC:18684): prolyl 3‑hydroxylase; GO:0019794, GO:0005783. (marini2010nullmutationsin pages 4-5)
  • PPIB (HGNC:9250): peptidyl‑prolyl cis‑trans isomerase; GO:0003755, GO:0005783. (marini2010nullmutationsin pages 4-5)
  • COL1A1 (HGNC:2197): structural ECM protein; GO:0030199, GO:0005583. (valli2012deficiencyofcrtap pages 1-2)

Phenotype Associations (HPO)

  • HP:0002757 Recurrent fractures; HP:0000938 Osteopenia; HP:0008915 Rhizomelia; HP:0004322 Short stature; HP:0100660 Metaphyseal widening/“popcorn” epiphyses. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5)

Cell Type Involvement (CL) and Anatomical Locations (UBERON)

  • CL:0000062 Osteoblast; CL:0000138 Chondrocyte; CL:0002553 Lung fibroblast. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, dimori2020respiratorydefectsin pages 1-6)
  • UBERON:0001474 Bone; UBERON:0002048 Lung; UBERON:0002429 Growth plate cartilage. (dimori2020respiratorydefectsin pages 1-6, marini2010nullmutationsin pages 4-5)

Chemical Entities (CHEBI)

  • 4‑Phenylbutyrate (CHEBI:46195): ER chemical chaperone shown to reduce over‑modification/ER stress in models of collagen 3‑hydroxylation complex impairment. (zhou2024geneticanalysisphenotypic pages 10-11)
  • Zoledronic acid (CHEBI:46550) and Denosumab (CHEBI:68481): antiresorptives with reported structural/BMD benefits in a CRTAP case. (zhou2024geneticanalysisphenotypic pages 4-5)

Evidence Items (PMIDs/DOIs/URLs)

  • Zhou et al., 2024, J Clin Endocrinol Metab, “Genetic Analysis, Phenotypic Spectrum and Functional Study of Rare OI Caused by CRTAP Variants.” DOI: 10.1210/clinem/dgae025; URL: https://doi.org/10.1210/clinem/dgae025 (zhou2024geneticanalysisphenotypic pages 1-1, zhou2024geneticanalysisphenotypic pages 9-10, zhou2024geneticanalysisphenotypic pages 9-9, zhou2024geneticanalysisphenotypic pages 4-5, zhou2024geneticanalysisphenotypic pages 10-11)
  • Jovanovic & Marini, 2024, Calcified Tissue Int, “Update on the Genetics of OI.” DOI: 10.1007/s00223-024-01266-5; URL: https://doi.org/10.1007/s00223-024-01266-5 (jovanovic2024updateonthe pages 8-9)
  • Barnes et al., 2006, N Engl J Med, “Deficiency of cartilage‑associated protein in recessive lethal OI.” DOI: 10.1056/NEJMoa063804; URL: https://doi.org/10.1056/NEJMoa063804 (barnes2006deficiencyofcartilageassociated pages 1-2)
  • Marini et al., 2010, Cell Tissue Res, “Null mutations in LEPRE1 and CRTAP cause severe recessive OI.” DOI: 10.1007/s00441-009-0872-0; URL: https://doi.org/10.1007/s00441-009-0872-0 (marini2010nullmutationsin pages 4-5, marini2010nullmutationsin pages 2-4)
  • Valli et al., 2012, Clin Genet, “Deficiency of CRTAP … reduces collagen deposition into matrix.” DOI: 10.1111/j.1399-0004.2011.01794.x; URL: https://doi.org/10.1111/j.1399-0004.2011.01794.x (valli2012deficiencyofcrtap pages 1-2)
  • Dimori et al., 2020, Am J Physiol Lung Cell Mol Physiol, “Respiratory defects in CrtapKO.” DOI: 10.1152/ajplung.00313.2019; URL: https://doi.org/10.1152/ajplung.00313.2019 (dimori2020respiratorydefectsin pages 1-6)

Current Applications and Real‑World Implementations

  • Diagnostics: Genetic testing targeting COL1A1/2 and known recessive OI genes including CRTAP is recommended in modern practice; dyadic nosology aids classification (ISDS 2024). (jovanovic2024updateonthe pages 8-9)
  • Pharmacologic management: Bisphosphonates (e.g., zoledronic acid) can improve vertebral morphology and reduce fractures; sequential antiresorptive/anabolic regimens (including teriparatide and denosumab) may increase BMD in individual CRTAP cases. Larger OI cohorts underlie these practices; CRTAP‑specific data remain limited to case level. (zhou2024geneticanalysisphenotypic pages 4-5)
  • Emerging therapeutics: Anti‑TGF‑β and sclerostin‑neutralizing antibodies show preclinical efficacy in Crtap−/− mice; chemical chaperones (4‑phenylbutyrate) alleviate ER stress/over‑modification in models. As of the sources reviewed, no CRTAP‑targeted gene therapy trials were identified in 2023–2024. (zhou2024geneticanalysisphenotypic pages 10-11, dimori2020respiratorydefectsin pages 1-6)

Limitations and Gaps

  • Human, CRTAP‑specific therapeutic evidence is limited to case reports/series with surrogate endpoints (BMD, vertebral shape). Controlled trials in OI often mix genotypes, limiting CRTAP‑specific inference. Preclinical anti‑TGF‑β and sclerostin antibody data are promising but not yet translated to CRTAP‑specific clinical trials. (zhou2024geneticanalysisphenotypic pages 4-5, dimori2020respiratorydefectsin pages 1-6)

Conclusion

CRTAP‑related OI type VII is a prototypical recessive collagen‑processing disorder. The central pathogenic axis is loss of α1(I) Pro986 3‑hydroxylation and impaired procollagen folding in the ER, culminating in ECM failure and aberrant matrix–cell signaling (notably TGF‑β). Human bone evidence from 2024 links CRTAP loss directly to reduced osteoblast numbers/osteoid and to absent active bone formation; murine and cellular models extend the pathology to growth plate cartilage and lung. Current management follows OI standards with antiresorptives; targeted pathways (anti‑TGF‑β, sclerostin inhibition, chemical chaperones) are supported preclinically but require CRTAP‑focused clinical evaluation. (zhou2024geneticanalysisphenotypic pages 1-1, marini2010nullmutationsin pages 4-5, valli2012deficiencyofcrtap pages 1-2, barnes2006deficiencyofcartilageassociated pages 1-2, dimori2020respiratorydefectsin pages 1-6, jovanovic2024updateonthe pages 8-9)

References

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