Osteogenesis Imperfecta Type XVII

Mendelian MONDO:0014672 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XVII (OI type XVII) is a severe autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in SPARC, the gene encoding osteonectin (also called secreted protein acidic and rich in cysteine, SPARC, or BM-40). Osteonectin is a collagen-binding matricellular glycoprotein — one of the most abundant noncollagenous proteins in bone — that binds collagen type I and other extracellular-matrix proteins and regulates collagen fibril assembly, matrix maturation, metalloproteinase expression, and bone mineralization. The disorder is mechanistically distinct from the intracellular collagen-folding/modification recessive OI types (CRTAP/P3H1/CyPB 3-hydroxylation complex, HSP47 chaperone): OI type XVII is a matricellular/extracellular-matrix-protein OI in which the primary lesion lies in a secreted matrix regulator rather than in an intracellular collagen biosynthetic enzyme or chaperone. The defining human variants (c.497G>A, p.Arg166His and c.787G>A, p.Glu263Lys) disrupt an intramolecular salt bridge essential for SPARC binding to collagen type I; SPARC secretion is reduced in some patients, and bone material is hypermineralized at the trabecular level despite the overall fragility. Loss of osteonectin function compromises osteoblast formation, maturation, and survival and, in osteonectin-null mice, produces decreased bone formation and profound osteopenia. Clinically OI type XVII presents as severe, progressive bone fragility with recurrent fractures, low bone mineral density, growth deficiency, and bone deformity.

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1
Inheritance
3
Pathophys.
8
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 biallelic (homozygous) loss-of-function SPARC variants; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26027498 SUPPORT Human Clinical
"we identified two homozygous variants in SPARC"
Establishes the autosomal recessive (biallelic homozygous) inheritance of OI type XVII from SPARC variants.
⚙

Pathophysiology

3
SPARC Loss-of-Function Disrupts Osteonectin Collagen Binding in the Bone ECM
SPARC encodes osteonectin, a secreted collagen-binding matricellular glycoprotein and one of the most abundant noncollagenous proteins in bone. Osteonectin binds collagen type I and other extracellular-matrix proteins and regulates collagen fibril assembly and matrix maturation. The defining OI type XVII missense variants (p.Arg166His, p.Glu263Lys) substitute residues that form an intramolecular salt bridge essential for SPARC binding to collagen type I, so the proximal lesion is loss of the collagen-binding matricellular function of secreted osteonectin in the bone ECM — distinct from the intracellular collagen-folding/modification recessive OI types.
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.
extracellular matrix organization (osteonectin collagen binding) GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (osteonectin collagen binding), annotated with extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Bone Matrix Maturation and Osteoblast Function Loss of osteonectin collagen binding impairs collagen fibril maturation and compromises osteoblast formation, maturation, and survival, degrading bone matrix quality.
Show evidence (2 references)
PMID:26027498 SUPPORT Human Clinical
"Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix."
Defines osteonectin/SPARC as a collagen type I-binding extracellular-matrix glycoprotein, the matricellular function lost in OI type XVII.
PMID:26027498 SUPPORT Human Clinical
"the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I."
Documents that the OI type XVII variants disrupt residues essential for SPARC binding to collagen type I, the molecular basis of the matricellular defect.
Impaired Bone Matrix Maturation and Osteoblast Function
Osteonectin supports bone remodeling and the maintenance of bone mass; its loss compromises osteoblast formation, maturation, and survival and impairs collagen fibril organization within the bone extracellular matrix. In OI type XVII patient fibroblasts, SPARC secretion is reduced and collagen type I secretion is mildly delayed with some overmodification, reflecting disturbed matrix maturation. Osteonectin-null mice show decreased bone formation and decreased osteoblast number and surface, the cellular basis of the matrix defect.
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.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ⚠ ABNORMAL ossification (bone formation) GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ossification (bone formation), annotated with ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Bone Matrix, Reduced Bone Mineral Density, and Skeletal Fragility Impaired collagen matrix maturation and osteoblast function yield a defective bone extracellular matrix with reduced bone mass and mechanical strength, producing severe skeletal fragility.
Show evidence (3 references)
PMID:12746322 SUPPORT Model Organism
"These data indicate that osteonectin is important for osteoblast formation, maturation, and survival."
Demonstrates that loss of osteonectin compromises osteoblast formation, maturation, and survival, the cellular basis of the OI type XVII matrix defect.
PMID:12746322 SUPPORT Model Organism
"Mutant cells exhibited decreased formation of mineralized nodules, as well as diminished expression of osteocalcin mRNA and response to PTH."
Documents impaired mineralized-nodule formation and osteoblast differentiation in osteonectin-null cells, linking SPARC loss to defective bone matrix maturation.
PMID:26027498 SUPPORT In Vitro
"Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals."
Documents delayed collagen type I secretion in OI type XVII patient fibroblasts, reflecting disturbed collagen matrix maturation downstream of the SPARC defect.
Defective Bone Matrix, Reduced Bone Mineral Density, and Skeletal Fragility
The disturbed osteonectin-dependent collagen matrix and impaired osteoblast function produce a defective bone extracellular matrix with abnormal mineralization. Although trabecular bone material can be hypermineralized at the material level, the overall result is reduced bone mass and mechanical strength with severe bone fragility. Osteonectin-null mice develop profound osteopenia from decreased bone formation, recapitulating the reduced bone mass of OI type XVII. Clinically this manifests as recurrent fractures, low bone mineral density, growth deficiency, vertebral compression, and bone deformity.
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.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ⚠ ABNORMAL ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:10749571 SUPPORT Model Organism
"We found that osteonectin-null mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, leading to decreased bone remodeling with a negative bone balance and causing profound osteopenia."
The osteonectin-null mouse recapitulates the decreased bone formation and profound osteopenia (reduced bone mass) of OI type XVII.
PMID:26027498 SUPPORT Human Clinical
"these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans."
Establishes that biallelic SPARC loss-of-function causes severe human bone fragility, the defining clinical feature of OI type XVII.
⬡

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 XVII 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

8
Limbs 1
Bone Deformity 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:20301472 SUPPORT Human Clinical
"individuals with severe skeletal deformities, mobility impairments"
GeneReviews documents severe skeletal deformities as a feature of OI, applicable to the bone deformity (long-bone bowing) of severe OI type XVII.
Musculoskeletal 5
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:26027498 SUPPORT Human Clinical
"two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV"
Documents severe bone fragility (recurrent fractures) as the cardinal clinical feature of SPARC-related OI type XVII.
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:10749571 SUPPORT Model Organism
"We found that osteonectin-null mice have decreased bone formation and decreased osteoblast and osteoclast surface and number, leading to decreased bone remodeling with a negative bone balance and causing profound osteopenia."
Osteonectin-null mice develop profound osteopenia (reduced bone mass), modeling the low bone mineral density of OI type XVII.
Scoliosis VERY_FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34462290 SUPPORT Human Clinical
"common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3)"
A phenotype-expansion review found scoliosis in 5/5 reported OI type XVII patients, supporting scoliosis as a very frequent distinguishing phenotype (derived-count justification for the frequency band).
Vertebral Compression Fractures VERY_FREQUENT HP:0002953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral compression fracture (HP:0002953). HP:0002953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34462290 SUPPORT Human Clinical
"common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3)"
Vertebral compression fractures were present in 5/5 reported OI type XVII patients, a very frequent distinguishing feature of the vertebral fragility in this OI type (derived-count justification for the frequency band).
Muscle Weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (neuromuscular weakness), annotated with Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34462290 SUPPORT Human Clinical
"both patients reported here presented with significant neuromuscular weakness prompting early workup"
Documents significant neuromuscular weakness as a presenting feature of OI type XVII, part of the myopathy-mimicking neuromuscular presentation that broadens the SPARC-OI phenotype.
Nervous System 1
Motor Delay VERY_FREQUENT HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34462290 SUPPORT Human Clinical
"common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3)"
Delayed motor development was reported in 3/3 assessed OI type XVII patients and is highlighted as a common phenotypic expression of this OI type (derived-count justification for the frequency band).
Growth 1
Growth Deficiency Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"short stature"
GeneReviews documents short stature (growth deficiency) as part of the OI phenotype, applicable to the severe presentation of OI type XVII.
🧬

Genetic Associations

1
SPARC (Osteonectin) Loss-of-Function Mutations (Causative)
Gene: SPARC (osteonectin, BM-40; collagen-binding matricellular glycoprotein) hgnc:11219 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPARC (osteonectin, BM-40; collagen-binding matricellular glycoprotein), annotated with SPARC (hgnc:11219). hgnc:11219 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:26027498 SUPPORT Human Clinical
"we identified two homozygous variants in SPARC (GenBank: NM_003118.3;"
Identifies the causative biallelic homozygous SPARC variants defining OI type XVII in humans (c.497G>A p.Arg166His and c.787G>A p.Glu263Lys).
PMID:26027498 SUPPORT Human Clinical
"The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2."
Documents reduced SPARC secretion in a patient fibroblast line, supporting loss of osteonectin function as the disease mechanism.
💊

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, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying matricellular collagen-binding 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 XVII.
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 long bones; spinal surgery addresses progressive scoliosis.
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 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 increase bone stability, improve mobility and muscle strength, and prevent contractures and deformity; 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.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XVII is suspected in a child with severe recessive OI (recurrent fractures, low bone mineral density, deformity) when COL1A1/COL1A2 and the intracellular collagen-folding/modification recessive OI genes (CRTAP, P3H1/LEPRE1, PPIB, SERPINH1) are negative. Diagnosis is confirmed by identifying biallelic SPARC (osteonectin) loss-of-function variants by gene-panel or exome sequencing. Supportive findings include reduced SPARC secretion and mildly delayed/overmodified collagen type I in patient fibroblasts.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26027498 SUPPORT Human Clinical
"Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC"
Molecular identification of biallelic SPARC variants by exome sequencing establishes the diagnosis of OI type XVII.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XVII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 17
  term:
    id: MONDO:0014672
    label: osteogenesis imperfecta type 17
description: >-
  Osteogenesis imperfecta type XVII (OI type XVII) is a severe autosomal
  recessive brittle bone disease caused by biallelic loss-of-function variants in
  SPARC, the gene encoding osteonectin (also called secreted protein acidic and
  rich in cysteine, SPARC, or BM-40). Osteonectin is a collagen-binding
  matricellular glycoprotein — one of the most abundant noncollagenous proteins
  in bone — that binds collagen type I and other extracellular-matrix proteins
  and regulates collagen fibril assembly, matrix maturation, metalloproteinase
  expression, and bone mineralization. The disorder is mechanistically distinct
  from the intracellular collagen-folding/modification recessive OI types
  (CRTAP/P3H1/CyPB 3-hydroxylation complex, HSP47 chaperone): OI type XVII is a
  matricellular/extracellular-matrix-protein OI in which the primary lesion lies
  in a secreted matrix regulator rather than in an intracellular collagen
  biosynthetic enzyme or chaperone. The defining human variants (c.497G>A,
  p.Arg166His and c.787G>A, p.Glu263Lys) disrupt an intramolecular salt bridge
  essential for SPARC binding to collagen type I; SPARC secretion is reduced in
  some patients, and bone material is hypermineralized at the trabecular level
  despite the overall fragility. Loss of osteonectin function compromises
  osteoblast formation, maturation, and survival and, in osteonectin-null mice,
  produces decreased bone formation and profound osteopenia. Clinically OI type
  XVII presents as severe, progressive bone fragility with recurrent fractures,
  low bone mineral density, growth deficiency, and bone deformity.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous) loss-of-function
    SPARC variants; heterozygous carriers are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two homozygous variants in SPARC
    explanation: >-
      Establishes the autosomal recessive (biallelic homozygous) inheritance of
      OI type XVII from SPARC variants.
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: SPARC Loss-of-Function Disrupts Osteonectin Collagen Binding in the Bone ECM
  description: >-
    SPARC encodes osteonectin, a secreted collagen-binding matricellular
    glycoprotein and one of the most abundant noncollagenous proteins in bone.
    Osteonectin binds collagen type I and other extracellular-matrix proteins
    and regulates collagen fibril assembly and matrix maturation. The defining OI
    type XVII missense variants (p.Arg166His, p.Glu263Lys) substitute residues
    that form an intramolecular salt bridge essential for SPARC binding to
    collagen type I, so the proximal lesion is loss of the collagen-binding
    matricellular function of secreted osteonectin in the bone ECM — distinct
    from the intracellular collagen-folding/modification recessive OI types.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: extracellular matrix organization (osteonectin collagen binding)
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that
      binds to collagen type I and other proteins in the extracellular matrix.
    explanation: >-
      Defines osteonectin/SPARC as a collagen type I-binding extracellular-matrix
      glycoprotein, the matricellular function lost in OI type XVII.
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the residues substituted by these mutations form an
      intramolecular salt bridge in SPARC and are essential for the binding of
      SPARC to collagen type I.
    explanation: >-
      Documents that the OI type XVII variants disrupt residues essential for
      SPARC binding to collagen type I, the molecular basis of the matricellular
      defect.
  downstream:
  - target: Impaired Bone Matrix Maturation and Osteoblast Function
    description: >-
      Loss of osteonectin collagen binding impairs collagen fibril maturation and
      compromises osteoblast formation, maturation, and survival, degrading bone
      matrix quality.
- name: Impaired Bone Matrix Maturation and Osteoblast Function
  description: >-
    Osteonectin supports bone remodeling and the maintenance of bone mass; its
    loss compromises osteoblast formation, maturation, and survival and impairs
    collagen fibril organization within the bone extracellular matrix. In OI type
    XVII patient fibroblasts, SPARC secretion is reduced and collagen type I
    secretion is mildly delayed with some overmodification, reflecting disturbed
    matrix maturation. Osteonectin-null mice show decreased bone formation and
    decreased osteoblast number and surface, the cellular basis of the matrix
    defect.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  - preferred_term: ossification (bone formation)
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:12746322
    reference_title: "Osteonectin-null mutation compromises osteoblast formation, maturation, and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data indicate that osteonectin is important for osteoblast
      formation, maturation, and survival.
    explanation: >-
      Demonstrates that loss of osteonectin compromises osteoblast formation,
      maturation, and survival, the cellular basis of the OI type XVII matrix
      defect.
  - reference: PMID:12746322
    reference_title: "Osteonectin-null mutation compromises osteoblast formation, maturation, and survival."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mutant cells exhibited decreased formation of mineralized nodules, as well
      as diminished expression of osteocalcin mRNA and response to PTH.
    explanation: >-
      Documents impaired mineralized-nodule formation and osteoblast
      differentiation in osteonectin-null cells, linking SPARC loss to defective
      bone matrix maturation.
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Pulse-chase experiments showed that collagen type I secretion was mildly
      delayed in skin fibroblasts from both individuals.
    explanation: >-
      Documents delayed collagen type I secretion in OI type XVII patient
      fibroblasts, reflecting disturbed collagen matrix maturation downstream of
      the SPARC defect.
  downstream:
  - target: Defective Bone Matrix, Reduced Bone Mineral Density, and Skeletal Fragility
    description: >-
      Impaired collagen matrix maturation and osteoblast function yield a
      defective bone extracellular matrix with reduced bone mass and mechanical
      strength, producing severe skeletal fragility.
- name: Defective Bone Matrix, Reduced Bone Mineral Density, and Skeletal Fragility
  description: >-
    The disturbed osteonectin-dependent collagen matrix and impaired osteoblast
    function produce a defective bone extracellular matrix with abnormal
    mineralization. Although trabecular bone material can be hypermineralized at
    the material level, the overall result is reduced bone mass and mechanical
    strength with severe bone fragility. Osteonectin-null mice develop profound
    osteopenia from decreased bone formation, recapitulating the reduced bone
    mass of OI type XVII. Clinically this manifests as recurrent fractures, low
    bone mineral density, growth deficiency, vertebral compression, and bone
    deformity.
  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: ABNORMAL
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:10749571
    reference_title: "Osteopenia and decreased bone formation in osteonectin-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that osteonectin-null mice have decreased bone formation and
      decreased osteoblast and osteoclast surface and number, leading to
      decreased bone remodeling with a negative bone balance and causing profound
      osteopenia.
    explanation: >-
      The osteonectin-null mouse recapitulates the decreased bone formation and
      profound osteopenia (reduced bone mass) of OI type XVII.
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these observations show that homozygous mutations in SPARC
      can give rise to severe bone fragility in humans.
    explanation: >-
      Establishes that biallelic SPARC loss-of-function causes severe human bone
      fragility, the defining clinical feature of OI type XVII.
genetic:
- name: SPARC (Osteonectin) Loss-of-Function Mutations
  association: Causative
  gene_term:
    preferred_term: SPARC (osteonectin, BM-40; collagen-binding matricellular glycoprotein)
    term:
      id: hgnc:11219
      label: SPARC
  notes: >-
    Biallelic loss-of-function variants in SPARC, the gene encoding osteonectin,
    cause OI type XVII (MONDO:0014672; OMIM:616507). The defining human alleles
    are two homozygous missense variants (c.497G>A, p.Arg166His and c.787G>A,
    p.Glu263Lys) that disrupt an intramolecular salt bridge essential for SPARC
    binding to collagen type I. SPARC secretion is reduced in some patients.
  evidence:
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified two homozygous variants in SPARC (GenBank: NM_003118.3;
    explanation: >-
      Identifies the causative biallelic homozygous SPARC variants defining OI
      type XVII in humans (c.497G>A p.Arg166His and c.787G>A p.Glu263Lys).
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The amount of SPARC secreted by skin fibroblasts was reduced in individual
      1 but appeared normal in individual 2.
    explanation: >-
      Documents reduced SPARC secretion in a patient fibroblast line, supporting
      loss of osteonectin function as the disease mechanism.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent fractures, the cardinal feature of OI
    type XVII.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two unrelated girls with severe bone fragility and a clinical diagnosis of
      osteogenesis imperfecta type IV
    explanation: >-
      Documents severe bone fragility (recurrent fractures) as the cardinal
      clinical feature of SPARC-related OI type XVII.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mass with reduced bone mineral density reflecting the defective
    osteonectin-dependent bone matrix and decreased bone formation.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:10749571
    reference_title: "Osteopenia and decreased bone formation in osteonectin-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found that osteonectin-null mice have decreased bone formation and
      decreased osteoblast and osteoclast surface and number, leading to
      decreased bone remodeling with a negative bone balance and causing profound
      osteopenia.
    explanation: >-
      Osteonectin-null mice develop profound osteopenia (reduced bone mass),
      modeling the low bone mineral density of OI type XVII.
- name: Growth Deficiency
  description: >-
    Growth deficiency with short stature, part of the severe OI phenotype caused
    by SPARC deficiency.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature
    explanation: >-
      GeneReviews documents short stature (growth deficiency) as part of the OI
      phenotype, applicable to the severe presentation of OI type XVII.
- name: Bone Deformity
  description: >-
    Bone deformity, including bowing of the long bones, accompanies the fragility
    and recurrent fractures in OI type XVII, reflecting the structurally
    defective, mechanically weak bone.
  phenotype_term:
    preferred_term: Bone deformity (bowing of the long bones)
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with severe skeletal deformities, mobility impairments
    explanation: >-
      GeneReviews documents severe skeletal deformities as a feature of OI,
      applicable to the bone deformity (long-bone bowing) of severe OI type XVII.
- name: Scoliosis
  description: >-
    Scoliosis is a near-universal distinguishing feature of SPARC-related OI type
    XVII, reported in all known patients across the published cohort. It reflects
    the vertebral fragility and neuromuscular weakness characteristic of this OI
    type.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34462290
    reference_title: "Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      common clinical features in individuals with OI type XVII caused by SPARC
      variants include scoliosis (5/5), vertebral compression fractures (5/5),
      multiple long bone fractures (5/5) and delayed motor development (3/3)
    explanation: >-
      A phenotype-expansion review found scoliosis in 5/5 reported OI type XVII
      patients, supporting scoliosis as a very frequent distinguishing phenotype
      (derived-count justification for the frequency band).
- name: Vertebral Compression Fractures
  description: >-
    Vertebral compression fractures are a consistent feature of OI type XVII,
    reported in all known patients, reflecting the reduced bone mass and
    vertebral fragility of SPARC (osteonectin) deficiency.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34462290
    reference_title: "Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      common clinical features in individuals with OI type XVII caused by SPARC
      variants include scoliosis (5/5), vertebral compression fractures (5/5),
      multiple long bone fractures (5/5) and delayed motor development (3/3)
    explanation: >-
      Vertebral compression fractures were present in 5/5 reported OI type XVII
      patients, a very frequent distinguishing feature of the vertebral fragility
      in this OI type (derived-count justification for the frequency band).
- name: Motor Delay
  description: >-
    Delayed motor development is a common feature of OI type XVII and part of a
    distinctive neuromuscular presentation that can mimic a primary myopathy,
    distinguishing this OI type from the classic collagen-structural forms.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34462290
    reference_title: "Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      common clinical features in individuals with OI type XVII caused by SPARC
      variants include scoliosis (5/5), vertebral compression fractures (5/5),
      multiple long bone fractures (5/5) and delayed motor development (3/3)
    explanation: >-
      Delayed motor development was reported in 3/3 assessed OI type XVII patients
      and is highlighted as a common phenotypic expression of this OI type
      (derived-count justification for the frequency band).
- name: Muscle Weakness
  description: >-
    Significant neuromuscular weakness is an emerging distinguishing feature of
    OI type XVII: reported patients have presented with a neuromuscular phenotype
    that can prompt an initial presumed diagnosis of a primary myopathy. The
    mechanism connecting SPARC (osteonectin) loss to skeletal-muscle weakness is
    not yet established.
  phenotype_term:
    preferred_term: Muscle weakness (neuromuscular weakness)
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:34462290
    reference_title: "Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      both patients reported here presented with significant neuromuscular
      weakness prompting early workup
    explanation: >-
      Documents significant neuromuscular weakness as a presenting feature of OI
      type XVII, part of the myopathy-mimicking neuromuscular presentation that
      broadens the SPARC-OI phenotype.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XVII is suspected in a child with severe recessive OI (recurrent
    fractures, low bone mineral density, deformity) when COL1A1/COL1A2 and the
    intracellular collagen-folding/modification recessive OI genes (CRTAP,
    P3H1/LEPRE1, PPIB, SERPINH1) are negative. Diagnosis is confirmed by
    identifying biallelic SPARC (osteonectin) loss-of-function variants by
    gene-panel or exome sequencing. Supportive findings include reduced SPARC
    secretion and mildly delayed/overmodified collagen type I in patient
    fibroblasts.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:26027498
    reference_title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using whole-exome sequencing to identify the molecular defect in two
      unrelated girls with severe bone fragility and a clinical diagnosis of
      osteogenesis imperfecta type IV, we identified two homozygous variants in
      SPARC
    explanation: >-
      Molecular identification of biallelic SPARC variants by exome sequencing
      establishes the diagnosis of OI type XVII.
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 matricellular collagen-binding 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 XVII.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery addresses progressive
    scoliosis.
  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 increase bone stability, improve mobility
    and muscle strength, and prevent contractures and deformity; 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.
datasets: []
references:
- reference: PMID:26027498
  title: "Recessive osteogenesis imperfecta caused by missense mutations in SPARC."
- reference: PMID:12746322
  title: "Osteonectin-null mutation compromises osteoblast formation, maturation, and survival."
- reference: PMID:10749571
  title: "Osteopenia and decreased bone formation in osteonectin-deficient mice."
- reference: PMID:34462290
  title: "Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

5
PMID:26027498
Recessive osteogenesis imperfecta caused by missense mutations in SPARC.
No top-level findings curated for this source.
PMID:12746322
Osteonectin-null mutation compromises osteoblast formation, maturation, and survival.
No top-level findings curated for this source.
PMID:10749571
Osteopenia and decreased bone formation in osteonectin-deficient mice.
No top-level findings curated for this source.
PMID:34462290
Expanding the phenotype of SPARC-related osteogenesis imperfecta: clinical findings in two patients with pathogenic variants in SPARC and literature review.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.