Osteogenesis Imperfecta Type XXI

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Recessive HP:0000007

Autosomal recessive inheritance from biallelic (homozygous or compound heterozygous) loss-of-function KDELR2 variants; heterozygous carriers are clinically unaffected.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33053334 SUPPORT Human Clinical

"We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families."

Establishes the autosomal recessive (biallelic) inheritance of OI type XXI from KDELR2 variants in four families.

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Discussions and Knowledge Gaps

1

Does the KDELR2-dependent GSK3-beta/beta-catenin osteoblast-differentiation arm demonstrated in mouse bone-marrow mesenchymal stromal cells actually operate in KDELR2-deficient human patients, or is human OI type XXI driven solely by the failure of HSP47 release from collagen type I? Concretely: do osteoblasts differentiated from OI type XXI patient cells show reduced active beta-catenin, reduced inhibitory phospho-GSK3-beta (Ser9), and impaired osteogenic differentiation independently of the collagen-quality defect — and if so, does that reclassify OI type XXI as a partly WNT-pathway OI alongside WNT1-related type XV and MESD-related type XX?

HUMAN MODEL MISMATCH OPEN gap_oi21_kdelr2_wnt_arm_human_translation

Attached to

pathophysiology#Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling pathophysiology#KDELR2 Loss Disables Retrograde Recycling of ER-Resident Chaperones

This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because evidence for the mechanism does exist — it is just entirely non-human. Wu et al. 2024 (PMID:38470494) show in mouse bone-marrow mesenchymal stromal cells and a mouse fracture model that KDELR2 level bidirectionally controls osteogenic differentiation through GSK3-beta/beta-catenin signaling, and explicitly motivate the work by noting that KDELR2 "has been found that involved in osteogenesis imperfecta. However, the exact mechanism is still unclear." The human defining study (van Dijk et al. 2020, PMID:33053334) instead localizes the lesion to failed KDELR2-mediated HSP47 retrieval, with HSP47 retained on secreted collagen disrupting fibril formation, and does not assay WNT signaling. The two accounts are not contradictory — a chaperone-recycling receptor could plausibly do both — but their relative contribution in patients is untested, and the translational risk is concrete: mouse BMSC osteogenic differentiation assays are a general osteogenesis readout that responds to many perturbations, and overexpression/knockdown of a Golgi receptor in a non-patient background need not reproduce the biallelic hypomorphic human genotype. Curating the WNT arm as an established human mechanism would therefore overstate the evidence, so it is modeled as an explicitly model-derived parallel arm with this mismatch recorded.

Proposed experiments

Canonical WNT signaling and osteogenic differentiation in KDELR2-deficient patient-derived human osteoblasts

patient-derived osteoblast differentiation and WNT reporter assay

exp_oi21_patient_osteoblast_wnt_readout

Differentiate osteoblasts from OI type XXI patient-derived cells (primary fibroblast-reprogrammed iPSCs, or CRISPR-engineered KDELR2-null human iPSCs with isogenic controls) and quantify active (non-phospho) beta-catenin, phospho-GSK3-beta (Ser9), TCF/LEF reporter activity, osteoblast markers (RUNX2, SP7, ALPL), and in-vitro mineralization. A positive result would confirm that the murine GSK3-beta/beta-catenin arm operates in human KDELR2 deficiency; a negative result would confine human OI type XXI to the HSP47-collagen mechanism and mark the mouse finding as species- or assay-specific.

Model systems

KDELR2-deficient human iPSC-derived osteoblast

Osteoblasts differentiated from OI type XXI patient-derived or CRISPR-edited KDELR2-null human iPSCs, compared with isogenic KDELR2-intact controls.

IPSC DERIVED MODEL

Separating the WNT-signaling arm from the HSP47-collagen arm in KDELR2-deficient cells

pathway-rescue epistasis assay

exp_oi21_wnt_vs_collagen_arm_separation

In KDELR2-deficient human osteoblasts, test whether pharmacological or genetic restoration of canonical WNT signaling (e.g., GSK3-beta inhibition) rescues osteogenic differentiation and mineralization while the secreted collagen fibril abnormality and HSP47 retention persist — and conversely whether forced HSP47 release corrects collagen quality without restoring WNT signaling. Dissociating the two readouts would establish whether the arms are independent contributors or whether the WNT readout is a downstream consequence of defective collagen matrix production.

Model systems

KDELR2-deficient patient primary fibroblast and derived osteoblast

Cultured OI type XXI patient fibroblasts (in which intracellular HSP47 and FKBP65 depletion and abnormal secreted collagen fibrils are already documented) and osteoblasts derived from them, used to test rescue of one arm without the other.

PRIMARY CELL CULTURE

Raised during the issue #5079 second-pass review of OI types IX-XXIII. If resolved in favor of the WNT arm, OI type XXI would additionally warrant consideration against the WNT/osteoblast mechanism shared with OI types XV (WNT1) and XX (MESD), and the `Osteogenesis_Imperfecta` grouping's differentiating-mechanism text for this member should be revisited.

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Pathophysiology

4

KDELR2 Loss Disables Retrograde Recycling of ER-Resident Chaperones

KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, a cis-Golgi/ERGIC receptor that binds ER-resident proteins carrying a KDEL-like C-terminal retrieval signal and recycles them back to the endoplasmic reticulum through COPI-mediated retrograde (Golgi-to-ER) transport. Biallelic loss-of-function KDELR2 variants map onto the receptor structure as inactivating, abolishing KDELR2-mediated Golgi-to-ER transport and the retrieval of ER-resident cargoes including the collagen-specific chaperone HSP47 (SERPINH1) and FKBP65.

osteoblast CL:0000062 fibroblast CL:0000057

retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (KDEL retrieval) GO:0006890 ↓ DECREASED

Downstream

Failure to Release and Recycle HSP47 from Procollagen Without functional KDELR2-mediated retrieval, HSP47 is not released from collagen type I and is not recycled to the ER, depleting intracellular HSP47.

Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling Loss of KDELR2 is additionally proposed, on the basis of murine bone-marrow-stromal-cell data, to lower canonical GSK3-beta/beta-catenin signaling and thereby impair osteoblastic differentiation. This arm is model-derived and has not been demonstrated in KDELR2-deficient human cells or patients; see discussion `gap_oi21_kdelr2_wnt_arm_human_translation`.

Show evidence (2 references)

PMID:33053334 SUPPORT Human Clinical

"KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport."

Defines the normal KDELR2 function (COPI retrograde recycling of ER-resident proteins from cis-Golgi to ER) that is lost in OI type XXI.

PMID:33053334 SUPPORT In Vitro

"Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport."

Documents that the OI type XXI KDELR2 variants inactivate the receptor and abolish Golgi-to-ER retrograde transport, the proximal lesion.

Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling

A candidate second, collagen-independent arm of KDELR2 bone pathology, established so far only in mouse bone-marrow mesenchymal stromal cells (mBMSCs). Lentiviral KDELR2 knockdown inhibited osteogenic differentiation of mBMSCs while KDELR2 overexpression enhanced it, and the levels of active beta-catenin and inhibitory phospho-GSK3-beta (Ser9) tracked KDELR2 dose in the same direction; mBMSCs overexpressing KDELR2 promoted healing in a mouse fracture model. The authors conclude that KDELR2 promotes osteogenesis by regulating GSK3-beta/beta-catenin signaling. If it operates in patients, this arm would place OI type XXI alongside the WNT-pathway OI types (notably WNT1-related OI type XV and MESD-related OI type XX, in which LRP5/6-mediated canonical WNT signaling to the osteoblast is the primary lesion) rather than positioning it purely as a chaperone-recycling collagen-quality disorder. It is modeled here as an explicitly model-derived, parallel arm and NOT as an established human mechanism: no KDELR2-deficient patient cell or patient cohort study has tested osteoblast WNT signaling, and the defining human report attributes the disease to failed HSP47 release from collagen type I.

bone marrow mesenchymal stromal cell CL:0000134 osteoblast CL:0000062

canonical Wnt signaling pathway (GSK3-beta/beta-catenin) GO:0060070 ↓ DECREASED osteoblast differentiation GO:0001649 ↓ DECREASED

Downstream

Defective Bone Collagen Matrix and Skeletal Fragility Reduced osteoblastic differentiation would lower bone formation and so compound, rather than replace, the collagen-quality defect in producing low bone mass and fragility. The edge is proposed on model-system grounds only.

Show evidence (3 references)

PMID:38470494 SUPPORT In Vitro

"KDELR2 knockdown inhibited the osteogenic differentiation of mBMSCs, whereas KDELR2 overexpression had the opposite effect."

Shows in cultured mouse bone-marrow mesenchymal stromal cells that KDELR2 is required for osteogenic differentiation, the cellular deficit proposed for this arm. Mouse cell culture, not human patient cells.

PMID:38470494 SUPPORT In Vitro

"the levels of active-β-catenin and phospho-GSK3β (Ser9) were upregulated by KDELR2 overexpression and downregulated by KDELR2 knockdown."

Identifies the GSK3-beta/beta-catenin axis as the signaling readout that tracks KDELR2 dose, the proposed molecular link between KDELR2 loss and impaired osteoblast differentiation.

PMID:38470494 SUPPORT Model Organism

"In the fracture model, mBMSCs overexpressing KDELR2 promoted healing."

In vivo mouse fracture-model evidence that KDELR2 level influences bone formation, supporting relevance of this arm to bone biology while leaving the human OI type XXI question open.

Failure to Release and Recycle HSP47 from Procollagen

Normally HSP47 binds the type I procollagen triple helix in the ER and is released from procollagen in the lower-pH cis-Golgi/ERGIC, then retrieved to the ER by KDELR2 for reuse. When KDELR2 is inactive, HSP47 cannot bind KDELR2 and therefore cannot dissociate from collagen type I; it remains bound to monomeric and multimeric collagen molecules. Patient fibroblasts show an intracellular decrease of HSP47 (and FKBP65) with reduced procollagen type I in culture media, and electron microscopy shows abnormal secreted collagen fibrils with increased HSP47 bound to collagen. This is the mechanistic mirror of OI type X, in which HSP47 (SERPINH1) is itself lost.

fibroblast CL:0000057 osteoblast CL:0000062

protein folding (HSP47 procollagen chaperoning/release) GO:0006457 ⚠ ABNORMAL collagen biosynthetic process GO:0032964 ⚠ ABNORMAL

Downstream

Defective Bone Collagen Matrix and Skeletal Fragility Persistent HSP47 bound to secreted collagen disrupts fibril formation, yielding a defective bone matrix that fails to mineralize normally.

Show evidence (2 references)

PMID:33053334 SUPPORT In Vitro

"Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media."

Documents intracellular HSP47/FKBP65 depletion and reduced secreted procollagen in KDELR2-deficient patient fibroblasts.

PMID:33053334 SUPPORT In Vitro

"in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I."

Establishes the core mechanism: loss of KDELR2 prevents HSP47 release from collagen type I, the defining pathophysiology of OI type XXI.

Defective Bone Collagen Matrix and Skeletal Fragility

Because HSP47 remains bound to collagen molecules extracellularly, normal fiber formation is disrupted and the secreted collagen is of abnormal quality. The resulting defective bone extracellular matrix fails to assemble and mineralize normally, producing low bone mineral density and severe bone fragility that manifests clinically as recurrent fractures, bone deformity, and growth deficiency. Cellular OI models confirm abnormal pro-alpha1(I) handling on KDELR2 loss, with intracellular pro-alpha1(I) aggregation.

osteoblast CL:0000062 fibroblast CL:0000057

bone mineralization GO:0030282 ↓ DECREASED ossification GO:0001503 ⚠ ABNORMAL

Show evidence (2 references)

PMID:33053334 SUPPORT In Vitro

"Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation."

Documents that retained HSP47 on secreted collagen disrupts fibril formation, the matrix defect underlying OI type XXI bone fragility.

PMID:38014644 SUPPORT In Vitro

"Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and KDELR2"

Cellular OI model shows abnormal pro-alpha1(I) aggregation upon KDELR2 knockdown, supporting the defective collagen handling of OI type XXI.

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Pathograph

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Phenotypes

4

Limbs 1

Bone Deformity Bowing of the long bones HP:0006487

Show evidence (1 reference)

PMID:33053334 SUPPORT Human Clinical

"Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation."

Documents bone deformation (manifesting as long-bone bowing) as part of the OI phenotype caused by KDELR2 deficiency.

Musculoskeletal 2

Recurrent Fractures HP:0002757

Show evidence (1 reference)

PMID:33053334 SUPPORT Human Clinical

"Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation."

Documents susceptibility to fractures as the cardinal feature of the OI phenotype caused by KDELR2 deficiency.

Reduced Bone Mineral Density HP:0004349

Show evidence (1 reference)

PMID:39127989 SUPPORT Human Clinical

"Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects."

OI is characterized by bone fragility; the defective KDELR2-related collagen matrix produces the low bone mineral density underlying that fragility.

Growth 1

Growth Deficiency Growth delay HP:0001510

Show evidence (1 reference)

PMID:39127989 SUPPORT Human Clinical

"Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects."

Documents growth deficiency as part of the OI phenotype that includes the KDELR2-related recessive forms.

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Genetic Associations

1

KDELR2 Loss-of-Function Mutations (Causative)

Gene: KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) hgnc:6305

Show evidence (2 references)

PMID:33053334 SUPPORT Human Clinical

"We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families."

Identifies biallelic KDELR2 variants as the cause of OI type XXI in the defining cohort of four families.

PMID:39127989 SUPPORT Human Clinical

"There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established"

A 2024 genetics review confirms recessive KDELR2 mutations as the established cause of OI type XXI (the CCDC134/type XXII numbering in the source list is a typographical error for type XXII).

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Medical Actions

3

Bisphosphonate Therapy

Action: Bisphosphonate Therapy NCIT:C198585

Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of severe OI, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying KDELR2/HSP47 chaperone-recycling defect.

Show evidence (1 reference)

PMID:20301472 SUPPORT Human Clinical

"Bisphosphonates continue to be used most extensively in those with vertebral fractures, frequent long bone fractures, or more severe OI."

GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for severe OI, the management category that applies to OI type XXI.

Orthopedic Surgery and Intramedullary Rodding

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed long bones; spinal surgery addresses progressive deformity.

Show evidence (1 reference)

PMID:20301472 SUPPORT Human Clinical

"intramedullary rodding when indicated to provide anatomic positioning of limbs"

GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity.

Physical Therapy and Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical and occupational therapy improve mobility and muscle strength and reduce fracture risk; early physical therapy follows brief post-fracture immobilization.

Show evidence (1 reference)

PMID:20301472 SUPPORT Human Clinical

"short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed"

GeneReviews documents early physical therapy and brief immobilization as part of standard OI fracture rehabilitation.

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Diagnosis

1

Molecular Genetic Diagnosis

OI type XXI is suspected in an infant or child with severe recessive OI (recurrent fractures, low bone mineral density, deformity) when COL1A1/COL1A2 and other recessive OI genes are negative. Diagnosis is confirmed by identifying biallelic KDELR2 loss-of-function variants by gene-panel or exome sequencing. Supportive cellular findings include intracellular HSP47/FKBP65 depletion with abnormal secreted collagen fibrils.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:33053334 SUPPORT Human Clinical

"We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families."

Molecular identification of biallelic KDELR2 variants establishes the diagnosis of OI type XXI.

{ }

Source YAML

click to show

name: Osteogenesis Imperfecta Type XXI
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 21
  term:
    id: MONDO:0030861
    label: osteogenesis imperfecta, type 21
description: >-
  Osteogenesis imperfecta type XXI (OI type XXI) is a severe autosomal recessive
  brittle bone disease caused by biallelic loss-of-function variants in KDELR2,
  the gene encoding KDEL endoplasmic reticulum protein retention receptor 2.
  KDELR2 is a cis-Golgi/ERGIC transmembrane receptor that captures soluble
  ER-resident proteins bearing a C-terminal KDEL-like retrieval signal and
  returns them to the endoplasmic reticulum via COPI-coated retrograde
  transport. A key cargo is HSP47 (SERPINH1), the collagen-specific molecular
  chaperone whose own loss causes the mechanistically linked OI type X. HSP47
  binds the type I procollagen triple helix in the ER and must dissociate from
  procollagen as the cargo reaches the lower-pH cis-Golgi/ERGIC; KDELR2-mediated
  retrieval is required to release HSP47 from procollagen and recycle it to the
  ER. When KDELR2 is inactive, HSP47 cannot be released and instead remains bound
  to collagen type I molecules, is depleted intracellularly, and is carried out
  with the secreted collagen, where persistent HSP47 binding disrupts normal
  collagen fibril formation. Patient fibroblasts show intracellular decrease of
  HSP47 and FKBP65 with reduced procollagen type I in the culture media and
  abnormal secreted collagen fibrils. The resulting defective bone collagen
  matrix fails to mineralize and assemble normally, producing severe skeletal
  fragility with recurrent fractures, reduced bone mineral density, growth
  deficiency, and bone deformity. OI type XXI was defined in 2020 (van Dijk
  et al.) in four families with biallelic KDELR2 variants; a second group
  reported additional biallelic KDELR2 missense variants with associated
  neurodevelopmental features.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous or compound
    heterozygous) loss-of-function KDELR2 variants; heterozygous carriers are
    clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in
      four families.
    explanation: >-
      Establishes the autosomal recessive (biallelic) inheritance of OI type XXI
      from KDELR2 variants in four families.
classifications:
  isds_skeletal_category:
  - classification_value: osteogenesis_imperfecta_and_decreased_bone_density
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 25 "Osteogenesis
      Imperfecta and decreased bone density group"; this entry corresponds to the
      phenotypic osteogenesis imperfecta entries (OI types 1-5), which the
      nosology lists by clinical severity rather than by the gene-numbered OI type
      used for this entry.
pathophysiology:
- name: KDELR2 Loss Disables Retrograde Recycling of ER-Resident Chaperones
  description: >-
    KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, a
    cis-Golgi/ERGIC receptor that binds ER-resident proteins carrying a
    KDEL-like C-terminal retrieval signal and recycles them back to the
    endoplasmic reticulum through COPI-mediated retrograde (Golgi-to-ER)
    transport. Biallelic loss-of-function KDELR2 variants map onto the receptor
    structure as inactivating, abolishing KDELR2-mediated Golgi-to-ER transport
    and the retrieval of ER-resident cargoes including the collagen-specific
    chaperone HSP47 (SERPINH1) and FKBP65.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum (KDEL retrieval)
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    modifier: DECREASED
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2,
      which recycles ER-resident proteins with a KDEL-like peptide from the
      cis-Golgi to the ER through COPI retrograde transport.
    explanation: >-
      Defines the normal KDELR2 function (COPI retrograde recycling of
      ER-resident proteins from cis-Golgi to ER) that is lost in OI type XXI.
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mapping the identified KDELR2 variants onto the crystal structure of G.
      gallus KDELR2 indicated that these lead to an inactive receptor resulting
      in impaired KDELR2-mediated Golgi-ER transport.
    explanation: >-
      Documents that the OI type XXI KDELR2 variants inactivate the receptor and
      abolish Golgi-to-ER retrograde transport, the proximal lesion.
  downstream:
  - target: Failure to Release and Recycle HSP47 from Procollagen
    description: >-
      Without functional KDELR2-mediated retrieval, HSP47 is not released from
      collagen type I and is not recycled to the ER, depleting intracellular
      HSP47.
  - target: Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling
    description: >-
      Loss of KDELR2 is additionally proposed, on the basis of murine
      bone-marrow-stromal-cell data, to lower canonical GSK3-beta/beta-catenin
      signaling and thereby impair osteoblastic differentiation. This arm is
      model-derived and has not been demonstrated in KDELR2-deficient human
      cells or patients; see discussion
      `gap_oi21_kdelr2_wnt_arm_human_translation`.
- name: Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling
  biological_scale: CELLULAR
  description: >-
    A candidate second, collagen-independent arm of KDELR2 bone pathology,
    established so far only in mouse bone-marrow mesenchymal stromal cells
    (mBMSCs). Lentiviral KDELR2 knockdown inhibited osteogenic differentiation of
    mBMSCs while KDELR2 overexpression enhanced it, and the levels of
    active beta-catenin and inhibitory phospho-GSK3-beta (Ser9) tracked KDELR2
    dose in the same direction; mBMSCs overexpressing KDELR2 promoted healing in
    a mouse fracture model. The authors conclude that KDELR2 promotes osteogenesis
    by regulating GSK3-beta/beta-catenin signaling. If it operates in patients,
    this arm would place OI type XXI alongside the WNT-pathway OI types (notably
    WNT1-related OI type XV and MESD-related OI type XX, in which LRP5/6-mediated
    canonical WNT signaling to the osteoblast is the primary lesion) rather than
    positioning it purely as a chaperone-recycling collagen-quality disorder.
    It is modeled here as an explicitly model-derived, parallel arm and NOT as an
    established human mechanism: no KDELR2-deficient patient cell or patient
    cohort study has tested osteoblast WNT signaling, and the defining human
    report attributes the disease to failed HSP47 release from collagen type I.
  cell_types:
  - preferred_term: bone marrow mesenchymal stromal cell
    term:
      id: CL:0000134
      label: mesenchymal stem cell
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway (GSK3-beta/beta-catenin)
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:38470494
    reference_title: "KDELR2 promotes bone marrow mesenchymal stem cell osteogenic differentiation via GSK3β/β-catenin signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      KDELR2 knockdown inhibited the osteogenic differentiation of
      mBMSCs, whereas KDELR2 overexpression had the opposite effect.
    explanation: >-
      Shows in cultured mouse bone-marrow mesenchymal stromal cells that KDELR2
      is required for osteogenic differentiation, the cellular deficit proposed
      for this arm. Mouse cell culture, not human patient cells.
  - reference: PMID:38470494
    reference_title: "KDELR2 promotes bone marrow mesenchymal stem cell osteogenic differentiation via GSK3β/β-catenin signaling pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the levels of active-β-catenin and phospho-GSK3β (Ser9) were upregulated by
      KDELR2 overexpression and downregulated by KDELR2 knockdown.
    explanation: >-
      Identifies the GSK3-beta/beta-catenin axis as the signaling readout that
      tracks KDELR2 dose, the proposed molecular link between KDELR2 loss and
      impaired osteoblast differentiation.
  - reference: PMID:38470494
    reference_title: "KDELR2 promotes bone marrow mesenchymal stem cell osteogenic differentiation via GSK3β/β-catenin signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the fracture model, mBMSCs overexpressing KDELR2 promoted healing.
    explanation: >-
      In vivo mouse fracture-model evidence that KDELR2 level influences bone
      formation, supporting relevance of this arm to bone biology while leaving
      the human OI type XXI question open.
  downstream:
  - target: Defective Bone Collagen Matrix and Skeletal Fragility
    description: >-
      Reduced osteoblastic differentiation would lower bone formation and so
      compound, rather than replace, the collagen-quality defect in producing low
      bone mass and fragility. The edge is proposed on model-system grounds only.
- name: Failure to Release and Recycle HSP47 from Procollagen
  description: >-
    Normally HSP47 binds the type I procollagen triple helix in the ER and is
    released from procollagen in the lower-pH cis-Golgi/ERGIC, then retrieved to
    the ER by KDELR2 for reuse. When KDELR2 is inactive, HSP47 cannot bind KDELR2
    and therefore cannot dissociate from collagen type I; it remains bound to
    monomeric and multimeric collagen molecules. Patient fibroblasts show an
    intracellular decrease of HSP47 (and FKBP65) with reduced procollagen type I
    in culture media, and electron microscopy shows abnormal secreted collagen
    fibrils with increased HSP47 bound to collagen. This is the mechanistic
    mirror of OI type X, in which HSP47 (SERPINH1) is itself lost.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: protein folding (HSP47 procollagen chaperoning/release)
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  - preferred_term: collagen biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of patient primary fibroblasts showed intracellular decrease of
      HSP47 and FKBP65 along with reduced procollagen type I in culture media.
    explanation: >-
      Documents intracellular HSP47/FKBP65 depletion and reduced secreted
      procollagen in KDELR2-deficient patient fibroblasts.
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      in KDELR2-deficient individuals, OI most likely occurs because of the
      inability of HSP47 to bind KDELR2 and dissociate from collagen type I.
    explanation: >-
      Establishes the core mechanism: loss of KDELR2 prevents HSP47 release from
      collagen type I, the defining pathophysiology of OI type XXI.
  downstream:
  - target: Defective Bone Collagen Matrix and Skeletal Fragility
    description: >-
      Persistent HSP47 bound to secreted collagen disrupts fibril formation,
      yielding a defective bone matrix that fails to mineralize normally.
- name: Defective Bone Collagen Matrix and Skeletal Fragility
  description: >-
    Because HSP47 remains bound to collagen molecules extracellularly, normal
    fiber formation is disrupted and the secreted collagen is of abnormal
    quality. The resulting defective bone extracellular matrix fails to assemble
    and mineralize normally, producing low bone mineral density and severe bone
    fragility that manifests clinically as recurrent fractures, bone deformity,
    and growth deficiency. Cellular OI models confirm abnormal pro-alpha1(I)
    handling on KDELR2 loss, with intracellular pro-alpha1(I) aggregation.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Instead, HSP47 remains bound to collagen molecules extracellularly,
      disrupting fiber formation.
    explanation: >-
      Documents that retained HSP47 on secreted collagen disrupts fibril
      formation, the matrix defect underlying OI type XXI bone fragility.
  - reference: PMID:38014644
    reference_title: "Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Cell phenotypic assays of pro-α1(I) in OI-related gene knocked down
      fibroblasts revealed aggregates of pro-α1(I) in conditions with knockdown
      of SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, TMEM38B, MESD, and
      KDELR2
    explanation: >-
      Cellular OI model shows abnormal pro-alpha1(I) aggregation upon KDELR2
      knockdown, supporting the defective collagen handling of OI type XXI.
discussions:
- discussion_id: gap_oi21_kdelr2_wnt_arm_human_translation
  prompt: >-
    Does the KDELR2-dependent GSK3-beta/beta-catenin osteoblast-differentiation
    arm demonstrated in mouse bone-marrow mesenchymal stromal cells actually
    operate in KDELR2-deficient human patients, or is human OI type XXI driven
    solely by the failure of HSP47 release from collagen type I? Concretely: do
    osteoblasts differentiated from OI type XXI patient cells show reduced active
    beta-catenin, reduced inhibitory phospho-GSK3-beta (Ser9), and impaired
    osteogenic differentiation independently of the collagen-quality defect — and
    if so, does that reclassify OI type XXI as a partly WNT-pathway OI alongside
    WNT1-related type XV and MESD-related type XX?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired GSK3-beta/Beta-Catenin Osteoblast Differentiation Signaling
  - pathophysiology#KDELR2 Loss Disables Retrograde Recycling of ER-Resident Chaperones
  rationale: >-
    This is a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because evidence
    for the mechanism does exist — it is just entirely non-human. Wu et al. 2024
    (PMID:38470494) show in mouse bone-marrow mesenchymal stromal cells and a
    mouse fracture model that KDELR2 level bidirectionally controls osteogenic
    differentiation through GSK3-beta/beta-catenin signaling, and explicitly
    motivate the work by noting that KDELR2 "has been found that involved in
    osteogenesis imperfecta. However, the exact mechanism is still unclear." The
    human defining study (van Dijk et al. 2020, PMID:33053334) instead localizes
    the lesion to failed KDELR2-mediated HSP47 retrieval, with HSP47 retained on
    secreted collagen disrupting fibril formation, and does not assay WNT
    signaling. The two accounts are not contradictory — a chaperone-recycling
    receptor could plausibly do both — but their relative contribution in patients
    is untested, and the translational risk is concrete: mouse BMSC osteogenic
    differentiation assays are a general osteogenesis readout that responds to many
    perturbations, and overexpression/knockdown of a Golgi receptor in a
    non-patient background need not reproduce the biallelic hypomorphic human
    genotype. Curating the WNT arm as an established human mechanism would
    therefore overstate the evidence, so it is modeled as an explicitly
    model-derived parallel arm with this mismatch recorded.
  proposed_experiments:
  - experiment_id: exp_oi21_patient_osteoblast_wnt_readout
    name: >-
      Canonical WNT signaling and osteogenic differentiation in KDELR2-deficient
      patient-derived human osteoblasts
    description: >-
      Differentiate osteoblasts from OI type XXI patient-derived cells (primary
      fibroblast-reprogrammed iPSCs, or CRISPR-engineered KDELR2-null human iPSCs
      with isogenic controls) and quantify active (non-phospho) beta-catenin,
      phospho-GSK3-beta (Ser9), TCF/LEF reporter activity, osteoblast markers
      (RUNX2, SP7, ALPL), and in-vitro mineralization. A positive result would
      confirm that the murine GSK3-beta/beta-catenin arm operates in human
      KDELR2 deficiency; a negative result would confine human OI type XXI to the
      HSP47-collagen mechanism and mark the mouse finding as species- or
      assay-specific.
    experiment_type:
      preferred_term: patient-derived osteoblast differentiation and WNT reporter assay
    model_systems:
    - name: KDELR2-deficient human iPSC-derived osteoblast
      description: >-
        Osteoblasts differentiated from OI type XXI patient-derived or
        CRISPR-edited KDELR2-null human iPSCs, compared with isogenic
        KDELR2-intact controls.
      experimental_model_type: IPSC_DERIVED_MODEL
  - experiment_id: exp_oi21_wnt_vs_collagen_arm_separation
    name: >-
      Separating the WNT-signaling arm from the HSP47-collagen arm in
      KDELR2-deficient cells
    description: >-
      In KDELR2-deficient human osteoblasts, test whether pharmacological or
      genetic restoration of canonical WNT signaling (e.g., GSK3-beta inhibition)
      rescues osteogenic differentiation and mineralization while the secreted
      collagen fibril abnormality and HSP47 retention persist — and conversely
      whether forced HSP47 release corrects collagen quality without restoring
      WNT signaling. Dissociating the two readouts would establish whether the
      arms are independent contributors or whether the WNT readout is a downstream
      consequence of defective collagen matrix production.
    experiment_type:
      preferred_term: pathway-rescue epistasis assay
    model_systems:
    - name: KDELR2-deficient patient primary fibroblast and derived osteoblast
      description: >-
        Cultured OI type XXI patient fibroblasts (in which intracellular HSP47 and
        FKBP65 depletion and abnormal secreted collagen fibrils are already
        documented) and osteoblasts derived from them, used to test rescue of one
        arm without the other.
      experimental_model_type: PRIMARY_CELL_CULTURE
  notes: >-
    Raised during the issue #5079 second-pass review of OI types IX-XXIII. If
    resolved in favor of the WNT arm, OI type XXI would additionally warrant
    consideration against the WNT/osteoblast mechanism shared with OI types XV
    (WNT1) and XX (MESD), and the `Osteogenesis_Imperfecta` grouping's
    differentiating-mechanism text for this member should be revisited.
genetic:
- name: KDELR2 Loss-of-Function Mutations
  association: Causative
  gene_term:
    preferred_term: KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2)
    term:
      id: hgnc:6305
      label: KDELR2
  notes: >-
    OI type XXI is caused by biallelic (homozygous or compound heterozygous)
    loss-of-function variants in KDELR2. The defining report (van Dijk et al.
    2020, PMID:33053334) identified bi-allelic pathogenic KDELR2 variants in four
    families; the variants map onto the KDELR2 structure as inactivating,
    abolishing receptor-mediated Golgi-to-ER retrograde transport. A second cohort
    (Efthymiou et al. 2021, PMID:33964184) reported two additional biallelic
    KDELR2 missense variants (a homozygous R5W substitution in two Pakistani
    siblings and a homozygous Y162C substitution in a Turkish boy) in children
    with progressively deforming recessive OI, expanding the phenotypic spectrum
    to include neurodevelopmental features (motor delay and speech delay) alongside
    the recessive OI signs (short stature, wormian bones, bowed limbs, chest
    deformity, hypotonia, joint hypermobility, blue sclerae, and dentinogenesis
    imperfecta). Those extended phenotype descriptors are recorded here as notes
    rather than as separately modeled phenotype evidence because the Efthymiou et
    al. 2021 report has no PubMed abstract and its phenotype detail resides only in
    the figures/full text, so an exact-quote snippet cannot be validated against
    the cached reference (per the CLAUDE.md evidence SOP).
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in
      four families.
    explanation: >-
      Identifies biallelic KDELR2 variants as the cause of OI type XXI in the
      defining cohort of four families.
  - reference: PMID:39127989
    reference_title: "Update on the Genetics of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a special emphasis on discoveries of recessive mutations in
      TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI
      and XXI, respectively, is now established
    explanation: >-
      A 2024 genetics review confirms recessive KDELR2 mutations as the
      established cause of OI type XXI (the CCDC134/type XXII numbering in the
      source list is a typographical error for type XXII).
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent fractures, the cardinal feature of OI
    type XXI.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is characterized primarily by susceptibility
      to fractures with or without bone deformation.
    explanation: >-
      Documents susceptibility to fractures as the cardinal feature of the OI
      phenotype caused by KDELR2 deficiency.
- name: Bone Deformity
  description: >-
    Bone deformity accompanies the fragility and fractures in OI type XXI,
    reflecting the structurally defective, mechanically weak bone.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is characterized primarily by susceptibility
      to fractures with or without bone deformation.
    explanation: >-
      Documents bone deformation (manifesting as long-bone bowing) as part of
      the OI phenotype caused by KDELR2 deficiency.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mineral density and skeletal undermineralization reflecting the
    defective collagen matrix and impaired mineralization in OI type XXI.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:39127989
    reference_title: "Update on the Genetics of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal
      dysplasia characterized by bone fragility and deformity, growth
      deficiency, and other secondary connective tissue defects.
    explanation: >-
      OI is characterized by bone fragility; the defective KDELR2-related
      collagen matrix produces the low bone mineral density underlying that
      fragility.
- name: Growth Deficiency
  description: >-
    Growth deficiency with short stature, part of the severe OI phenotype in
    KDELR2-related OI type XXI.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:39127989
    reference_title: "Update on the Genetics of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal
      dysplasia characterized by bone fragility and deformity, growth
      deficiency, and other secondary connective tissue defects.
    explanation: >-
      Documents growth deficiency as part of the OI phenotype that includes the
      KDELR2-related recessive forms.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XXI is suspected in an infant or child with severe recessive OI
    (recurrent fractures, low bone mineral density, deformity) when COL1A1/COL1A2
    and other recessive OI genes are negative. Diagnosis is confirmed by
    identifying biallelic KDELR2 loss-of-function variants by gene-panel or exome
    sequencing. Supportive cellular findings include intracellular HSP47/FKBP65
    depletion with abnormal secreted collagen fibrils.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:33053334
    reference_title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in
      four families.
    explanation: >-
      Molecular identification of biallelic KDELR2 variants establishes the
      diagnosis of OI type XXI.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of severe OI, increasing bone mineral density and
    reducing fracture frequency. They are antiresorptive and do not correct the
    underlying KDELR2/HSP47 chaperone-recycling defect.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bisphosphonates continue to be used most extensively in those with
      vertebral fractures, frequent long bone fractures, or more severe OI.
    explanation: >-
      GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for
      severe OI, the management category that applies to OI type XXI.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery addresses progressive
    deformity.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy improve mobility and muscle strength and
    reduce fracture risk; early physical therapy follows brief post-fracture
    immobilization.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short a period of immobility as is practical, small and lightweight casts, and
      physical therapy as soon as casts are removed
    explanation: >-
      GeneReviews documents early physical therapy and brief immobilization as
      part of standard OI fracture rehabilitation.
datasets: []
references:
- reference: PMID:33053334
  title: "Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2."
- reference: PMID:33964184
  title: "Two novel bi-allelic KDELR2 missense variants cause osteogenesis imperfecta with neurodevelopmental features."
- reference: PMID:38014644
  title: "Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta."
- reference: PMID:38470494
  title: "KDELR2 promotes bone marrow mesenchymal stem cell osteogenic differentiation via GSK3β/β-catenin signaling pathway."
- reference: PMID:39127989
  title: "Update on the Genetics of Osteogenesis Imperfecta."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews

📚

References & Deep Research

References

6

PMID:33053334

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.