Osteogenesis Imperfecta Type XXII

Mendelian MONDO:0030714 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XXII (OI type XXII) is a severe autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in CCDC134, the gene encoding a secreted, endoplasmic-reticulum-resident coiled-coil protein that regulates osteoblast differentiation and bone formation. CCDC134 is widely expressed and was originally implicated in the regulation of the mitogen-activated protein kinase (MAPK)/ERK signaling pathway; more recent work places it as an ER luminal specificity factor that, together with the oligosaccharyltransferase OST-A, protects the ER chaperone HSP90B1 (GRP94) during folding, and whose disruption impairs WNT and IGF1R receptor signaling. The defining human allele is a recurrent homozygous translation-start-site variant (c.2T>C) that abolishes CCDC134 protein, first identified in consanguineous families of Moroccan origin and subsequently in unrelated ancestries. Loss of CCDC134 dysregulates osteoblast signaling (increased ERK1/2 phosphorylation, reduced osteopontin and COL1A1 expression) and impairs bone matrix formation and mineralization, producing severe, progressively deforming OI with short stature, gracile long bones, recurrent fractures, and pseudarthroses (non-union), characteristically without dentinogenesis imperfecta, and with poor response to bisphosphonate therapy.

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1
Inheritance
3
Pathophys.
6
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
5
References
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from a biallelic (homozygous) loss-of-function CCDC134 variant; the recurrent allele is the homozygous translation-start-site variant c.2T>C.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta."
Establishes the autosomal recessive inheritance of OI type XXII from a biallelic (homozygous) CCDC134 loss-of-function variant in unrelated families.
⚙

Pathophysiology

3
CCDC134 Loss Eliminates a Secreted ER Regulator of Osteoblast Signaling
CCDC134 encodes a secreted, endoplasmic-reticulum-resident protein that is widely expressed and regulates osteoblast differentiation and bone formation. It was originally implicated in the regulation of the MAPK/ERK signaling pathway, and is now understood as an ER luminal specificity factor that, with the oligosaccharyltransferase OST-A, protects the ER chaperone HSP90B1 (GRP94) during folding. The recurrent OI type XXII allele is a homozygous translation-start-site variant (c.2T>C) that abolishes CCDC134 protein, as confirmed by the absence of CCDC134 in patient cells.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
MAPK cascade (ERK1/2 signaling) GO:0000165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased MAPK cascade (ERK1/2 signaling), annotated with MAPK cascade (GO:0000165). GO:0000165 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Dysregulated Osteoblast Signaling and Impaired Bone Matrix Formation Loss of CCDC134 dysregulates osteoblast MAPK/ERK and WNT/IGF1R signaling and reduces osteoblast matrix-protein expression and mineralization.
Show evidence (3 references)
PMID:32181939 SUPPORT Human Clinical
"CCDC134 encodes a secreted protein widely expressed and implicated in the regulation of some mitogen-activated protein kinases (MAPK) signaling pathway."
Defines CCDC134 as the secreted MAPK-regulating protein whose loss causes OI type XXII.
PMID:32181939 SUPPORT In Vitro
"Western blot and immunofluorescence analyses confirmed the absence of CCDC134 protein in patient cells compared with controls."
Documents that the c.2T>C variant eliminates CCDC134 protein, the proximal lesion of the disorder.
PMID:39509507 SUPPORT In Vitro
"Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane receptors, and CCDC134, an ER luminal protein."
Establishes CCDC134 as an ER luminal protein acting with OST-A and the ER chaperone HSP90B1, refining the ER-resident mechanism.
Dysregulated Osteoblast Signaling and Impaired Bone Matrix Formation
In CCDC134-deficient osteoblasts, ERK1/2 phosphorylation is increased while osteopontin (OPN) mRNA and COL1A1 expression and mineralization are reduced, indicating dysregulated osteoblast differentiation and bone-forming function. Independently, disruption of the CCDC134-HSP90B1-OST-A ER pathway impairs WNT and IGF1R receptor signaling, both osteogenic pathways, linking CCDC134 loss to the LRP5/6-WNT and MAPK/ERK axes that govern bone formation.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ↓ DECREASED regulation of canonical Wnt signaling pathway GO:0060828 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of canonical Wnt signaling pathway (GO:0060828). GO:0060828 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Defective Bone Matrix, Reduced Mineralization, and Skeletal Fragility Reduced collagen/matrix-protein expression and impaired mineralization yield a defective bone matrix with low bone mass and mechanical fragility.
Show evidence (2 references)
PMID:32181939 SUPPORT In Vitro
"we demonstrated that CCDC134 mutations are associated with increased Erk1/2 phosphorylation, decreased OPN mRNA and COL1A1 expression and reduced mineralization in patient osteoblasts compared with controls."
Documents the dysregulated osteoblast signaling (increased ERK1/2, reduced OPN/COL1A1, reduced mineralization) caused by CCDC134 loss.
PMID:39509507 SUPPORT In Vitro
"Disruption of this pathway impairs WNT and IGF1R signaling and causes the bone developmental disorder osteogenesis imperfecta."
Links CCDC134-pathway disruption to impaired WNT and IGF1R osteogenic signaling and to osteogenesis imperfecta, supporting the WNT/MAPK axis mechanism.
Defective Bone Matrix, Reduced Mineralization, and Skeletal Fragility
Impaired osteoblast bone-matrix synthesis (reduced COL1A1 and osteopontin) and reduced mineralization produce a defective bone extracellular matrix with low bone mass and mechanical fragility. Clinically this manifests as severe, progressively deforming OI with recurrent fractures, gracile long bones, pseudarthroses (non-union fractures), bone deformity, and growth deficiency.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:32181939 SUPPORT Human Clinical
"These data support that CCDC134 is a new gene involved in severe progressive deforming recessive osteogenesis imperfecta (type III)."
Establishes that CCDC134 loss causes severe, progressively deforming recessive OI with the fragile, deforming skeleton of this disorder.
PMID:38014644 SUPPORT In Vitro
"pro-α1(I) expression was very low in fibroblasts which had knockdown of IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134."
Cellular OI models show very low type I procollagen expression on CCDC134 knockdown, consistent with reduced collagen matrix output underlying the bone fragility.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Osteogenesis Imperfecta Type XXII Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Limbs 1
Bowing of the Long Bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone deformity (bowing of the long bones), annotated with Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"These data support that CCDC134 is a new gene involved in severe progressive deforming recessive osteogenesis imperfecta (type III)."
Documents the severe progressively deforming skeletal phenotype, which includes long-bone deformity such as bowing, in CCDC134-related OI.
Musculoskeletal 2
Recurrent Fractures HP:0002757 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fractures (HP:0002757). HP:0002757 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta."
Documents severe bone fragility with gracile long bones and pseudarthroses (non-union fractures) in CCDC134-related OI.
Reduced Bone Mineral Density HP:0004349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced bone mineral density (HP:0004349). HP:0004349 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35019224 SUPPORT Human Clinical
"Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian disorder characterized by bone fragility leading to bone fractures, with deformities and stunted growth in the more severe phenotypes."
Documents low bone mass as a defining feature of the severe OI phenotype caused by CCDC134, consistent with reduced bone mineral density.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta."
Documents short stature as part of the CCDC134-related OI phenotype.
Other 2
Pseudarthrosis (Fracture Non-Union) Pseudoarthrosis HP:0005864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pseudarthrosis (fracture non-union), annotated with Pseudoarthrosis (HP:0005864). HP:0005864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta"
Documents pseudarthroses (fracture non-union) of the gracile long bones as a defining feature of CCDC134-related OI type XXII in the original cohort.
Slender (Gracile) Long Bones Slender long bone HP:0003100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Slender (gracile) long bones, annotated with Slender long bone (HP:0003100). HP:0003100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta"
Documents the gracile (slender) long bones of CCDC134-related OI type XXII in the original cohort.
🧬

Genetic Associations

1
CCDC134 Loss-of-Function Mutation (Causative)
Gene: CCDC134 (secreted ER regulator of osteoblast signaling) hgnc:26185 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CCDC134 (secreted ER regulator of osteoblast signaling), annotated with CCDC134 (hgnc:26185). hgnc:26185 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:32181939 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta."
Identifies the causative homozygous CCDC134 translation-start-site variant (c.2T>C) defining OI type XXII.
PMID:35019224 SUPPORT Human Clinical
"We report on a 9-year-old Brazilian boy, harboring the same homozygous variant in CCDC134, also presenting severe bone involvement."
Confirms the recurrent homozygous CCDC134 variant in an unrelated ancestry, reinforcing CCDC134 as the causative OI type XXII gene.
💊

Medical Actions

3
Bisphosphonate Therapy
Action: Bisphosphonate TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. NCIT:C198585
Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of severe OI, but CCDC134-related OI type XXII is characteristically poorly responsive to bisphosphonate treatment, and pathway-targeted (e.g., RAS/MAPK-directed) therapies have been proposed as alternatives.
Show evidence (1 reference)
PMID:35019224 SUPPORT Human Clinical
"A poor response to bisphosphonate therapy was observed in these individuals."
Documents that bisphosphonate therapy, the standard OI pharmacotherapy, is poorly effective in CCDC134-related OI type XXII.
Orthopedic Surgery and Intramedullary Rodding
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed gracile long bones; surgical management also addresses pseudarthroses (non-union fractures) common in this disorder.
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, applicable to OI type XXII.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. 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
"Fractures are treated with as 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, applicable to OI type XXII.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XXII is suspected in a child with severe, progressively deforming recessive OI (recurrent fractures, gracile long bones, pseudarthroses, short stature, poor bisphosphonate response, typically without dentinogenesis imperfecta) when COL1A1/COL1A2 and other recessive OI genes are negative. Diagnosis is confirmed by identifying a biallelic CCDC134 loss-of-function variant (typically the recurrent c.2T>C translation-start-site allele) by gene-panel or exome sequencing.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32181939 SUPPORT Human Clinical
"By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in CCDC134 gene in three patients from two unrelated families with severe bone fragility that did not respond to bisphosphonate treatment, short stature, and gracile long bones with pseudarthroses but no dentinogenesis imperfecta."
Molecular identification of a biallelic CCDC134 variant by exome sequencing establishes the diagnosis of OI type XXII.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XXII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 22
  term:
    id: MONDO:0030714
    label: osteogenesis imperfecta, IIA 22
description: >-
  Osteogenesis imperfecta type XXII (OI type XXII) is a severe autosomal
  recessive brittle bone disease caused by biallelic loss-of-function variants in
  CCDC134, the gene encoding a secreted, endoplasmic-reticulum-resident coiled-coil
  protein that regulates osteoblast differentiation and bone formation. CCDC134
  is widely expressed and was originally implicated in the regulation of the
  mitogen-activated protein kinase (MAPK)/ERK signaling pathway; more recent work
  places it as an ER luminal specificity factor that, together with the
  oligosaccharyltransferase OST-A, protects the ER chaperone HSP90B1 (GRP94)
  during folding, and whose disruption impairs WNT and IGF1R receptor signaling.
  The defining human allele is a recurrent homozygous translation-start-site
  variant (c.2T>C) that abolishes CCDC134 protein, first identified in
  consanguineous families of Moroccan origin and subsequently in unrelated
  ancestries. Loss of CCDC134 dysregulates osteoblast signaling (increased ERK1/2
  phosphorylation, reduced osteopontin and COL1A1 expression) and impairs bone
  matrix formation and mineralization, producing severe, progressively deforming
  OI with short stature, gracile long bones, recurrent fractures, and
  pseudarthroses (non-union), characteristically without dentinogenesis
  imperfecta, and with poor response to bisphosphonate therapy.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from a biallelic (homozygous) loss-of-function
    CCDC134 variant; the recurrent allele is the homozygous translation-start-site
    variant c.2T>C.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in
      CCDC134 gene in three patients from two unrelated families with severe bone
      fragility that did not respond to bisphosphonate treatment, short stature,
      and gracile long bones with pseudarthroses but no dentinogenesis
      imperfecta.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XXII from a
      biallelic (homozygous) CCDC134 loss-of-function variant in unrelated
      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: CCDC134 Loss Eliminates a Secreted ER Regulator of Osteoblast Signaling
  description: >-
    CCDC134 encodes a secreted, endoplasmic-reticulum-resident protein that is
    widely expressed and regulates osteoblast differentiation and bone formation.
    It was originally implicated in the regulation of the MAPK/ERK signaling
    pathway, and is now understood as an ER luminal specificity factor that, with
    the oligosaccharyltransferase OST-A, protects the ER chaperone HSP90B1 (GRP94)
    during folding. The recurrent OI type XXII allele is a homozygous
    translation-start-site variant (c.2T>C) that abolishes CCDC134 protein, as
    confirmed by the absence of CCDC134 in patient cells.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: MAPK cascade (ERK1/2 signaling)
    term:
      id: GO:0000165
      label: MAPK cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CCDC134 encodes a secreted protein widely expressed and implicated in the
      regulation of some mitogen-activated protein kinases (MAPK) signaling
      pathway.
    explanation: >-
      Defines CCDC134 as the secreted MAPK-regulating protein whose loss causes
      OI type XXII.
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blot and immunofluorescence analyses confirmed the absence of
      CCDC134 protein in patient cells compared with controls.
    explanation: >-
      Documents that the c.2T>C variant eliminates CCDC134 protein, the proximal
      lesion of the disorder.
  - reference: PMID:39509507
    reference_title: "Regulated N-glycosylation controls chaperone function and receptor trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Genetic analyses linked OST-A to HSP90B1, an ER chaperone for membrane
      receptors, and CCDC134, an ER luminal protein.
    explanation: >-
      Establishes CCDC134 as an ER luminal protein acting with OST-A and the ER
      chaperone HSP90B1, refining the ER-resident mechanism.
  downstream:
  - target: Dysregulated Osteoblast Signaling and Impaired Bone Matrix Formation
    description: >-
      Loss of CCDC134 dysregulates osteoblast MAPK/ERK and WNT/IGF1R signaling and
      reduces osteoblast matrix-protein expression and mineralization.
- name: Dysregulated Osteoblast Signaling and Impaired Bone Matrix Formation
  description: >-
    In CCDC134-deficient osteoblasts, ERK1/2 phosphorylation is increased while
    osteopontin (OPN) mRNA and COL1A1 expression and mineralization are reduced,
    indicating dysregulated osteoblast differentiation and bone-forming function.
    Independently, disruption of the CCDC134-HSP90B1-OST-A ER pathway impairs WNT
    and IGF1R receptor signaling, both osteogenic pathways, linking CCDC134 loss to
    the LRP5/6-WNT and MAPK/ERK axes that govern bone formation.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: regulation of canonical Wnt signaling pathway
    term:
      id: GO:0060828
      label: regulation of canonical Wnt signaling pathway
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we demonstrated that CCDC134 mutations are associated with increased Erk1/2
      phosphorylation, decreased OPN mRNA and COL1A1 expression and reduced
      mineralization in patient osteoblasts compared with controls.
    explanation: >-
      Documents the dysregulated osteoblast signaling (increased ERK1/2, reduced
      OPN/COL1A1, reduced mineralization) caused by CCDC134 loss.
  - reference: PMID:39509507
    reference_title: "Regulated N-glycosylation controls chaperone function and receptor trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disruption of this pathway impairs WNT and IGF1R signaling and causes the
      bone developmental disorder osteogenesis imperfecta.
    explanation: >-
      Links CCDC134-pathway disruption to impaired WNT and IGF1R osteogenic
      signaling and to osteogenesis imperfecta, supporting the WNT/MAPK axis
      mechanism.
  downstream:
  - target: Defective Bone Matrix, Reduced Mineralization, and Skeletal Fragility
    description: >-
      Reduced collagen/matrix-protein expression and impaired mineralization yield
      a defective bone matrix with low bone mass and mechanical fragility.
- name: Defective Bone Matrix, Reduced Mineralization, and Skeletal Fragility
  description: >-
    Impaired osteoblast bone-matrix synthesis (reduced COL1A1 and osteopontin) and
    reduced mineralization produce a defective bone extracellular matrix with low
    bone mass and mechanical fragility. Clinically this manifests as severe,
    progressively deforming OI with recurrent fractures, gracile long bones,
    pseudarthroses (non-union fractures), bone deformity, and growth deficiency.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  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:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support that CCDC134 is a new gene involved in severe
      progressive deforming recessive osteogenesis imperfecta (type III).
    explanation: >-
      Establishes that CCDC134 loss causes severe, progressively deforming
      recessive OI with the fragile, deforming skeleton of this disorder.
  - 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: >-
      pro-α1(I) expression was very low in fibroblasts which had knockdown of
      IFITM5, SP7, BMP1, WNT1, CREB3L1, MBTPS2, and CCDC134.
    explanation: >-
      Cellular OI models show very low type I procollagen expression on CCDC134
      knockdown, consistent with reduced collagen matrix output underlying the
      bone fragility.
genetic:
- name: CCDC134 Loss-of-Function Mutation
  association: Causative
  gene_term:
    preferred_term: CCDC134 (secreted ER regulator of osteoblast signaling)
    term:
      id: hgnc:26185
      label: CCDC134
  notes: >-
    OI type XXII is caused by a biallelic loss-of-function variant in CCDC134.
    The defining and recurrent human allele is a homozygous translation-start-site
    variant (c.2T>C) that abolishes CCDC134 protein, first reported in
    consanguineous Moroccan families and subsequently identified in an individual
    of non-Moroccan (Brazilian) ancestry.
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in
      CCDC134 gene in three patients from two unrelated families with severe bone
      fragility that did not respond to bisphosphonate treatment, short stature,
      and gracile long bones with pseudarthroses but no dentinogenesis
      imperfecta.
    explanation: >-
      Identifies the causative homozygous CCDC134 translation-start-site variant
      (c.2T>C) defining OI type XXII.
  - reference: PMID:35019224
    reference_title: "The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a 9-year-old Brazilian boy, harboring the same homozygous
      variant in CCDC134, also presenting severe bone involvement.
    explanation: >-
      Confirms the recurrent homozygous CCDC134 variant in an unrelated ancestry,
      reinforcing CCDC134 as the causative OI type XXII gene.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent fractures, including a high prevalence of
    non-union (pseudarthrosis) fractures, the cardinal feature of OI type XXII.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in
      CCDC134 gene in three patients from two unrelated families with severe bone
      fragility that did not respond to bisphosphonate treatment, short stature,
      and gracile long bones with pseudarthroses but no dentinogenesis
      imperfecta.
    explanation: >-
      Documents severe bone fragility with gracile long bones and pseudarthroses
      (non-union fractures) in CCDC134-related OI.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mass with reduced mineralization, reflecting the defective collagen
    matrix and impaired osteoblast mineralization in CCDC134-deficient bone.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:35019224
    reference_title: "The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is a rare low-bone mass skeletal Mendelian
      disorder characterized by bone fragility leading to bone fractures, with
      deformities and stunted growth in the more severe phenotypes.
    explanation: >-
      Documents low bone mass as a defining feature of the severe OI phenotype
      caused by CCDC134, consistent with reduced bone mineral density.
- name: Short Stature
  description: >-
    Growth deficiency with short stature, part of the severe deforming OI
    phenotype caused by CCDC134 deficiency.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in
      CCDC134 gene in three patients from two unrelated families with severe bone
      fragility that did not respond to bisphosphonate treatment, short stature,
      and gracile long bones with pseudarthroses but no dentinogenesis
      imperfecta.
    explanation: >-
      Documents short stature as part of the CCDC134-related OI phenotype.
- name: Bowing of the Long Bones
  description: >-
    Bone deformity, including bowing of the gracile long bones, accompanies the
    fragility and recurrent fractures in OI type XXII, reflecting the structurally
    weak bone in this progressively deforming disorder.
  phenotype_term:
    preferred_term: Bone deformity (bowing of the long bones)
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support that CCDC134 is a new gene involved in severe
      progressive deforming recessive osteogenesis imperfecta (type III).
    explanation: >-
      Documents the severe progressively deforming skeletal phenotype, which
      includes long-bone deformity such as bowing, in CCDC134-related OI.
- name: Pseudarthrosis (Fracture Non-Union)
  description: >-
    Pseudarthrosis (non-union of fractures forming a "false joint") is the
    distinctive hallmark of OI type XXII: the recurrent fractures of the gracile
    long bones characteristically fail to unite. This feature, together with the
    poor bisphosphonate response and the absence of dentinogenesis imperfecta,
    distinguishes CCDC134-related OI from most other severe recessive OI subtypes.
  phenotype_term:
    preferred_term: Pseudarthrosis (fracture non-union)
    term:
      id: HP:0005864
      label: Pseudoarthrosis
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature, and gracile long bones with pseudarthroses but no
      dentinogenesis imperfecta
    explanation: >-
      Documents pseudarthroses (fracture non-union) of the gracile long bones as a
      defining feature of CCDC134-related OI type XXII in the original cohort.
- name: Slender (Gracile) Long Bones
  description: >-
    The long bones in OI type XXII are gracile (slender, with narrow diaphyses),
    a structural feature of the poorly mineralized, matrix-deficient bone that
    contributes to their fragility, bowing, and predisposition to pseudarthrosis.
  phenotype_term:
    preferred_term: Slender (gracile) long bones
    term:
      id: HP:0003100
      label: Slender long bone
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature, and gracile long bones with pseudarthroses but no
      dentinogenesis imperfecta
    explanation: >-
      Documents the gracile (slender) long bones of CCDC134-related OI type XXII
      in the original cohort.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XXII is suspected in a child with severe, progressively deforming
    recessive OI (recurrent fractures, gracile long bones, pseudarthroses, short
    stature, poor bisphosphonate response, typically without dentinogenesis
    imperfecta) when COL1A1/COL1A2 and other recessive OI genes are negative.
    Diagnosis is confirmed by identifying a biallelic CCDC134 loss-of-function
    variant (typically the recurrent c.2T>C translation-start-site allele) by
    gene-panel or exome sequencing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:32181939
    reference_title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By whole-exome sequencing, we identified a homozygous variant (c.2T>C) in
      CCDC134 gene in three patients from two unrelated families with severe bone
      fragility that did not respond to bisphosphonate treatment, short stature,
      and gracile long bones with pseudarthroses but no dentinogenesis
      imperfecta.
    explanation: >-
      Molecular identification of a biallelic CCDC134 variant by exome sequencing
      establishes the diagnosis of OI type XXII.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of severe OI, but CCDC134-related OI type XXII is
    characteristically poorly responsive to bisphosphonate treatment, and
    pathway-targeted (e.g., RAS/MAPK-directed) therapies have been proposed as
    alternatives.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:35019224
    reference_title: "The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A poor response to bisphosphonate therapy was observed in these
      individuals.
    explanation: >-
      Documents that bisphosphonate therapy, the standard OI pharmacotherapy, is
      poorly effective in CCDC134-related OI type XXII.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed gracile long bones; surgical management also addresses
    pseudarthroses (non-union fractures) common in this disorder.
  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, applicable to OI type
      XXII.
- 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: >-
      Fractures are treated with as
      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, applicable to OI type XXII.
datasets: []
references:
- reference: PMID:32181939
  title: "Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta."
- reference: PMID:35019224
  title: "The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry."
- reference: PMID:38014644
  title: "Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta."
- reference: PMID:39509507
  title: "Regulated N-glycosylation controls chaperone function and receptor trafficking."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

5
PMID:32181939
Homozygous Loss-of-Function Mutations in CCDC134 Are Responsible for a Severe Form of Osteogenesis Imperfecta.
No top-level findings curated for this source.
PMID:35019224
The recurrent homozygous translation start site variant in CCDC134 in an individual with severe osteogenesis imperfecta of non-Morrocan ancestry.
No top-level findings curated for this source.
PMID:38014644
Assessing type I collagen expression and quality in cellular models of osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:39509507
Regulated N-glycosylation controls chaperone function and receptor trafficking.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.