Osteogenesis Imperfecta Type XV

Mendelian MONDO:0014086 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XV (OI type XV; WNT1-related OI) is an autosomal recessive brittle-bone disease caused by biallelic loss-of-function (or hypofunctional) variants in WNT1, the gene encoding the secreted signaling ligand WNT1. Unlike the classic dominant collagen-defect forms of OI (COL1A1/COL1A2) and the recessive collagen-processing forms, OI type XV is a signaling-pathway OI: WNT1 is a secreted WNT ligand that binds the Frizzled receptor and the LRP5/6 coreceptor to activate canonical WNT/beta-catenin signaling, a pathway essential for osteoblast differentiation, bone formation, and bone mass maintenance. Disease-causing WNT1 variants fail to activate canonical LRP5-mediated WNT/beta-catenin signaling, reduce expression of WNT target genes, and impair osteoblast differentiation and mineralization, producing a moderately severe and progressive phenotype with reduced bone mass, recurrent fractures, growth deficiency, and long-bone deformity that is not easily distinguished from dominant OI type III. A subset of patients with biallelic WNT1 variants also have central nervous system involvement (brain malformation such as cerebellar hypoplasia and neurodevelopmental impairment), reflecting the developmental role of WNT1 in the brain. The allelic context is informative: heterozygous WNT1 missense variants instead cause dominantly inherited early-onset osteoporosis, underscoring WNT1 dosage as a determinant of bone mass. The central role of the WNT axis in osteoanabolic bone formation underpins the therapeutic rationale for WNT-pathway-directed (e.g., anti-sclerostin) anabolic agents.

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1
Inheritance
3
Pathophys.
11
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
4
References
šŸ·

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
šŸ‘Ŗ

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic loss-of-function or hypofunctional WNT1 variants; heterozygous carriers are unaffected for OI, although a heterozygous WNT1 variant can instead cause dominant early-onset osteoporosis.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:23499309 SUPPORT Human Clinical
"We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures."
Establishes the autosomal recessive inheritance of OI type XV from hypofunctional/biallelic WNT1 variants.
PMID:23499310 SUPPORT Human Clinical
"Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type"
Independent confirmation that biallelic WNT1 loss-of-function causes recessive, moderately severe and progressive OI.
āš™

Pathophysiology

3
WNT1 Loss-of-Function Abolishes Canonical WNT/Beta-Catenin Signaling
WNT1 is a secreted signaling protein that binds the Frizzled receptor (FZD) and the coreceptor LRP5/6 to activate canonical WNT/beta-catenin signaling. Biallelic loss-of-function or hypofunctional WNT1 variants (frameshift, nonsense, splice-site, missense) yield WNT1 protein that fails to activate canonical LRP5-mediated WNT-regulated beta-catenin signaling, so beta-catenin does not accumulate to induce WNT target genes. This places OI type XV mechanistically apart from the collagen-defect OI types: the proximal lesion is failure of an osteoanabolic signaling ligand rather than a defect in type I collagen.
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. osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology.
canonical Wnt signaling pathway GO:0060070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. ā†“ DECREASED Wnt signaling pathway GO:0016055 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Wnt signaling pathway (GO:0016055). GO:0016055 is a biological process from the Gene Ontology. ā†“ DECREASED
Downstream
Impaired Osteoblast Differentiation and Bone Formation Loss of canonical WNT/beta-catenin signaling impairs osteoblast differentiation and the osteoanabolic activity needed for bone formation and mineralization.
Show evidence (3 references)
PMID:23499310 SUPPORT Human Clinical
"WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5)."
Defines WNT1 as a secreted ligand acting through FZD and the LRP5 coreceptor, the signaling axis disrupted in OI type XV.
PMID:23499309 SUPPORT In Vitro
"Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated Ī²-catenin signaling."
Documents that disease-causing WNT1 proteins fail to activate canonical LRP5-mediated WNT/beta-catenin signaling, the proximal molecular defect.
PMID:23656646 SUPPORT In Vitro
"In contrast to wild type WNT1, WNT1C218G and WNT1S295* did not induce significant accumulation of non-phosphorylated or total Ī²-catenin in either cytosolic or nuclear fractions"
Shows mutant WNT1 fails to drive beta-catenin accumulation, confirming loss of canonical WNT signaling output.
Impaired Osteoblast Differentiation and Bone Formation
Canonical WNT/beta-catenin signaling drives osteoblast differentiation and bone formation; WNT1 expression rises as osteoblasts differentiate, indicating a role for WNT1 in osteoblast function and bone development. With WNT1 signaling lost, WNT target-gene induction and osteoblast-mediated mineralization are reduced, so the osteoanabolic bone-formation program cannot proceed normally.
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. osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 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. ā†“ DECREASED 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. ā†“ DECREASED
Downstream
Reduced Bone Mass and Skeletal Fragility Deficient osteoblast-mediated bone formation and mineralization yield low bone mass and a mechanically weak skeleton prone to fracture and deformity.
Show evidence (2 references)
PMID:23499309 SUPPORT In Vitro
"Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development."
Links WNT1 to osteoblast differentiation and bone development, the program impaired when WNT1 signaling is lost.
PMID:23656646 SUPPORT In Vitro
"These assays demonstrate the markedly diminished capacity of the abnormal proteins to induce canonical WNT signaling and associated osteoblast differentiation."
Functional assays confirm that mutant WNT1 impairs canonical WNT signaling and the associated osteoblast differentiation.
Reduced Bone Mass and Skeletal Fragility
The deficit in WNT-driven osteoblast bone formation and mineralization produces low bone mineral density and impaired bone quality, manifesting clinically as reduced bone mass, recurrent low-impact fractures, vertebral compression, growth deficiency, and progressive long-bone deformity. In affected children, radiographs show severe osteopenia with multiple fractures and sequelae including vertebral compression fractures, kyphoscoliosis, severe short stature, and long-bone deformities.
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. osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 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. ā†“ DECREASED
Show evidence (2 references)
PMID:23656646 SUPPORT Human Clinical
"Radiographs of both affected children showed severe osteopenia with multiple fractures and sequelae over time, including vertebral compression fractures, resultant kyphoscoliosis, severe short stature, and long bone deformities"
Documents the low-bone-mass, multiple-fracture, deformity phenotype that results from impaired WNT1-driven bone formation.
PMID:23656646 SUPPORT In Vitro
"In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce canonical WNT signaling, their target genes, and mineralization."
Connects loss of WNT1 signaling to impaired target-gene induction and mineralization, the cellular basis of the reduced bone mass.
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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 XV Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Eye 1
White Sclerae (Blue Sclerae Characteristically Absent) HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
āˆ… ABSENT
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"Their sclerae are white."
The characterized WNT1-related OI siblings had white sclerae; blue sclerae (a hallmark of classical dominant OI) were absent.
Head and Neck 1
Normal Dentition (Dentinogenesis Imperfecta Characteristically Absent) HP:0000703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Dentinogenesis imperfecta (HP:0000703). HP:0000703 is a phenotype from the Human Phenotype Ontology.
āˆ… ABSENT
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"Permanent dentition is relatively normal in both with few caries and no signs of dentinogenesis imperfecta."
The characterized WNT1-related OI siblings had normal permanent dentition; dentinogenesis imperfecta was documented as absent.
Limbs 1
Bowing of the Long Bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"her height is more than 2 SD below the mean (less than 3 feet) with severe long bone deformities"
Documents severe long-bone deformities (including bowing) in an OI type XV patient.
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:23499309 SUPPORT Human Clinical
"We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures."
Documents recurrent fractures as a defining feature of WNT1-related recessive 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:23499309 SUPPORT Human Clinical
"We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures."
Documents reduced bone mass (low bone mineral density) in OI type XV.
Vertebral Compression Fractures 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:23656646 SUPPORT Human Clinical
"vertebral compression fractures, resultant kyphoscoliosis"
Documents vertebral compression fractures in radiographically evaluated WNT1-related recessive OI patients.
Kyphoscoliosis HP:0002751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphoscoliosis (HP:0002751). HP:0002751 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"vertebral compression fractures, resultant kyphoscoliosis"
Documents kyphoscoliosis resulting from vertebral compression fractures in WNT1-related recessive OI.
Joint Hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"Their hands are markedly hyperextensible with marked laxity at the interphalangeal joints."
Documents marked joint hypermobility (hyperextensible hands, interphalangeal joint laxity) in WNT1-related recessive OI.
Nervous System 1
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"She has severe intellectual disability with absence of speech, and has been quadriplegic from toddlerhood."
Documents severe intellectual disability in a WNT1-related OI patient with CNS involvement; not all patients are affected, so this is a feature of the severe subset.
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:23656646 SUPPORT Human Clinical
"Radiographs of both affected children showed severe osteopenia with multiple fractures and sequelae over time, including vertebral compression fractures, resultant kyphoscoliosis, severe short stature, and long bone deformities"
Documents severe short stature (growth deficiency) in WNT1-related OI.
Other 1
Central Nervous System Involvement Aplasia/Hypoplasia involving the central nervous system HP:0002977 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the cerebellum (CNS hypoplasia), annotated with Aplasia/Hypoplasia involving the central nervous system (HP:0002977). HP:0002977 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"Her MRI revealed severe hypoplasia of the left cerebellar hemisphere with a short midbrain"
Documents cerebellar (CNS) hypoplasia in a severely affected WNT1-related OI patient, supporting CNS involvement in the disorder.
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Genetic Associations

1
WNT1 Loss-of-Function / Hypofunctional Mutations (Causative)
Gene: WNT1 (Wnt family member 1; secreted WNT ligand) hgnc:12774 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is WNT1 (Wnt family member 1; secreted WNT ligand), annotated with WNT1 (hgnc:12774). hgnc:12774 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:23499310 SUPPORT Human Clinical
"Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1)."
Identifies WNT1 as the causative gene in recessive OI (type XV) across four families.
PMID:23656646 SUPPORT Human Clinical
"In a separate family with 2 siblings affected by recessive osteogenesis imperfecta, we identified a homozygous nonsense mutation, c.884Cā†’A, p.Ser295*."
Documents a homozygous WNT1 nonsense allele causing recessive OI, alongside the dominant osteoporosis allele in the same report.
PMID:23499309 SUPPORT Human Clinical
"In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation."
Catalogs the spectrum of recessive WNT1 mutations causing OI type XV.
šŸ’Š

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 WNT-signaling 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 XV.
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.
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Diagnosis

1
Molecular Genetic Diagnosis
OI type XV is suspected in an infant or child with recessive OI (reduced bone mass, recurrent fractures, progressive deformity), particularly when COL1A1/ COL1A2 collagen studies are normal and other recessive OI genes are negative; CNS involvement in a severely affected child is a clue. Diagnosis is confirmed by identifying biallelic WNT1 variants by gene-panel or exome sequencing, distinguishing it from dominant OI type III, which it clinically resembles.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:23656646 SUPPORT Human Clinical
"Given the family history with two affected siblings and the negative fibroblast collagen studies, whole exome sequencing was performed as described previously7 to identify a potential recessive OI gene."
Illustrates the diagnostic pathway: negative collagen studies followed by exome sequencing identifying the recessive WNT1 gene.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XV
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 15
  term:
    id: MONDO:0014086
    label: osteogenesis imperfecta type 15
description: >-
  Osteogenesis imperfecta type XV (OI type XV; WNT1-related OI) is an autosomal
  recessive brittle-bone disease caused by biallelic loss-of-function (or
  hypofunctional) variants in WNT1, the gene encoding the secreted signaling
  ligand WNT1. Unlike the classic dominant collagen-defect forms of OI
  (COL1A1/COL1A2) and the recessive collagen-processing forms, OI type XV is a
  signaling-pathway OI: WNT1 is a secreted WNT ligand that binds the Frizzled
  receptor and the LRP5/6 coreceptor to activate canonical WNT/beta-catenin
  signaling, a pathway essential for osteoblast differentiation, bone formation,
  and bone mass maintenance. Disease-causing WNT1 variants fail to activate
  canonical LRP5-mediated WNT/beta-catenin signaling, reduce expression of WNT
  target genes, and impair osteoblast differentiation and mineralization,
  producing a moderately severe and progressive phenotype with reduced bone mass,
  recurrent fractures, growth deficiency, and long-bone deformity that is not
  easily distinguished from dominant OI type III. A subset of patients with
  biallelic WNT1 variants also have central nervous system involvement (brain
  malformation such as cerebellar hypoplasia and neurodevelopmental impairment),
  reflecting the developmental role of WNT1 in the brain. The allelic context is
  informative: heterozygous WNT1 missense variants instead cause dominantly
  inherited early-onset osteoporosis, underscoring WNT1 dosage as a determinant of
  bone mass. The central role of the WNT axis in osteoanabolic bone formation
  underpins the therapeutic rationale for WNT-pathway-directed (e.g.,
  anti-sclerostin) anabolic agents.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic loss-of-function or
    hypofunctional WNT1 variants; heterozygous carriers are unaffected for OI,
    although a heterozygous WNT1 variant can instead cause dominant early-onset
    osteoporosis.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report that hypofunctional alleles of WNT1 cause autosomal-recessive
      osteogenesis imperfecta, a congenital disorder characterized by reduced bone
      mass and recurrent fractures.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XV from
      hypofunctional/biallelic WNT1 variants.
  - reference: PMID:23499310
    reference_title: "WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic loss-of-function mutations in WNT1 result in a recessive
      clinical picture that includes bone fragility with a moderately severe and
      progressive presentation that is not easily distinguished from dominant OI type
    explanation: >-
      Independent confirmation that biallelic WNT1 loss-of-function causes
      recessive, moderately severe and progressive OI.
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: WNT1 Loss-of-Function Abolishes Canonical WNT/Beta-Catenin Signaling
  description: >-
    WNT1 is a secreted signaling protein that binds the Frizzled receptor (FZD)
    and the coreceptor LRP5/6 to activate canonical WNT/beta-catenin signaling.
    Biallelic loss-of-function or hypofunctional WNT1 variants (frameshift,
    nonsense, splice-site, missense) yield WNT1 protein that fails to activate
    canonical LRP5-mediated WNT-regulated beta-catenin signaling, so
    beta-catenin does not accumulate to induce WNT target genes. This places OI
    type XV mechanistically apart from the collagen-defect OI types: the proximal
    lesion is failure of an osteoanabolic signaling ligand rather than a defect in
    type I collagen.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: canonical Wnt signaling pathway
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
    modifier: DECREASED
  - preferred_term: Wnt signaling pathway
    term:
      id: GO:0016055
      label: Wnt signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23499310
    reference_title: "WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD)
      and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5).
    explanation: >-
      Defines WNT1 as a secreted ligand acting through FZD and the LRP5 coreceptor,
      the signaling axis disrupted in OI type XV.
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Initial functional
      analysis revealed that altered WNT1 proteins fail to activate canonical
      LRP5-mediated WNT-regulated Ī²-catenin signaling.
    explanation: >-
      Documents that disease-causing WNT1 proteins fail to activate canonical
      LRP5-mediated WNT/beta-catenin signaling, the proximal molecular defect.
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to wild type WNT1, WNT1C218G and WNT1S295* did not induce significant accumulation of non-phosphorylated or total Ī²-catenin in either cytosolic or nuclear fractions
    explanation: >-
      Shows mutant WNT1 fails to drive beta-catenin accumulation, confirming loss
      of canonical WNT signaling output.
  downstream:
  - target: Impaired Osteoblast Differentiation and Bone Formation
    description: >-
      Loss of canonical WNT/beta-catenin signaling impairs osteoblast
      differentiation and the osteoanabolic activity needed for bone formation
      and mineralization.
- name: Impaired Osteoblast Differentiation and Bone Formation
  description: >-
    Canonical WNT/beta-catenin signaling drives osteoblast differentiation and
    bone formation; WNT1 expression rises as osteoblasts differentiate,
    indicating a role for WNT1 in osteoblast function and bone development. With
    WNT1 signaling lost, WNT target-gene induction and osteoblast-mediated
    mineralization are reduced, so the osteoanabolic bone-formation program
    cannot proceed normally.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: DECREASED
  evidence:
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, osteoblasts
      cultured in vitro showed enhanced Wnt1 expression with advancing
      differentiation, indicating a role of WNT1 in osteoblast function and bone
      development.
    explanation: >-
      Links WNT1 to osteoblast differentiation and bone development, the program
      impaired when WNT1 signaling is lost.
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These assays demonstrate the markedly diminished capacity of the abnormal proteins to induce canonical WNT signaling and associated osteoblast differentiation.
    explanation: >-
      Functional assays confirm that mutant WNT1 impairs canonical WNT signaling
      and the associated osteoblast differentiation.
  downstream:
  - target: Reduced Bone Mass and Skeletal Fragility
    description: >-
      Deficient osteoblast-mediated bone formation and mineralization yield low
      bone mass and a mechanically weak skeleton prone to fracture and deformity.
- name: Reduced Bone Mass and Skeletal Fragility
  description: >-
    The deficit in WNT-driven osteoblast bone formation and mineralization
    produces low bone mineral density and impaired bone quality, manifesting
    clinically as reduced bone mass, recurrent low-impact fractures, vertebral
    compression, growth deficiency, and progressive long-bone deformity. In
    affected children, radiographs show severe osteopenia with multiple fractures
    and sequelae including vertebral compression fractures, kyphoscoliosis, severe
    short stature, and long-bone deformities.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographs of both affected children showed severe osteopenia with multiple fractures and sequelae over time, including vertebral compression fractures, resultant kyphoscoliosis, severe short stature, and long bone deformities
    explanation: >-
      Documents the low-bone-mass, multiple-fracture, deformity phenotype that
      results from impaired WNT1-driven bone formation.
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, aberrant forms of the WNT1 protein showed impaired capacity to induce
      canonical WNT signaling, their target genes, and mineralization.
    explanation: >-
      Connects loss of WNT1 signaling to impaired target-gene induction and
      mineralization, the cellular basis of the reduced bone mass.
genetic:
- name: WNT1 Loss-of-Function / Hypofunctional Mutations
  association: Causative
  gene_term:
    preferred_term: WNT1 (Wnt family member 1; secreted WNT ligand)
    term:
      id: hgnc:12774
      label: WNT1
  notes: >-
    OI type XV is caused by biallelic loss-of-function or hypofunctional variants
    in WNT1. Reported recessive alleles include homozygous missense, nonsense,
    frameshift, splice-site, and small-deletion variants; some nonsense/frameshift
    alleles are predicted to trigger nonsense-mediated decay and the absence of
    WNT1. By contrast, a heterozygous WNT1 missense variant (e.g., c.652T>G,
    p.Cys218Gly) causes dominantly inherited early-onset osteoporosis,
    illustrating WNT1 dosage sensitivity.
  evidence:
  - reference: PMID:23499310
    reference_title: "WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe four recessive-OI-affected families in
      which we identified causative mutations in wingless-type MMTV integration site
      family 1 (WNT1).
    explanation: >-
      Identifies WNT1 as the causative gene in recessive OI (type XV) across four
      families.
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a separate family with 2 siblings affected by recessive osteogenesis
      imperfecta, we identified a homozygous nonsense mutation, c.884Cā†’A, p.Ser295*.
    explanation: >-
      Documents a homozygous WNT1 nonsense allele causing recessive OI, alongside
      the dominant osteoporosis allele in the same report.
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In consanguineous families, we identified five
      homozygous mutations in WNT1: one frameshift mutation, two missense mutations,
      one splice-site mutation, and one nonsense mutation.
    explanation: >-
      Catalogs the spectrum of recessive WNT1 mutations causing OI type XV.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Recurrent low-trauma fractures beginning in infancy are the cardinal feature
    of OI type XV, often presenting as multiple fractures with progressive
    sequelae.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report that hypofunctional alleles of WNT1 cause autosomal-recessive
      osteogenesis imperfecta, a congenital disorder characterized by reduced bone
      mass and recurrent fractures.
    explanation: >-
      Documents recurrent fractures as a defining feature of WNT1-related
      recessive OI.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mass with reduced bone mineral density and severe osteopenia,
    reflecting deficient WNT-driven osteoblastic bone formation.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:23499309
    reference_title: "Mutations in WNT1 cause different forms of bone fragility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report that hypofunctional alleles of WNT1 cause autosomal-recessive
      osteogenesis imperfecta, a congenital disorder characterized by reduced bone
      mass and recurrent fractures.
    explanation: >-
      Documents reduced bone mass (low bone mineral density) in OI type XV.
- name: Growth Deficiency
  description: >-
    Severe short stature and growth deficiency develop in OI type XV as a
    consequence of repeated fractures and long-bone deformity.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Radiographs of both affected children showed severe osteopenia with multiple fractures and sequelae over time, including vertebral compression fractures, resultant kyphoscoliosis, severe short stature, and long bone deformities
    explanation: >-
      Documents severe short stature (growth deficiency) in WNT1-related OI.
- name: Bowing of the Long Bones
  description: >-
    Progressive long-bone deformity, including bowing, accompanies the recurrent
    fractures and low bone mass of OI type XV.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      her height is more than 2 SD below the mean (less than 3 feet) with severe long bone deformities
    explanation: >-
      Documents severe long-bone deformities (including bowing) in an OI type XV
      patient.
- name: Central Nervous System Involvement
  description: >-
    A subset of patients with biallelic WNT1 variants have central nervous system
    involvement reflecting the developmental role of WNT1 in the brain. One
    severely affected child had cerebellar hypoplasia with a short midbrain on
    MRI, supporting CNS hypoplasia as a feature in the severe end of the OI type
    XV spectrum.
  phenotype_term:
    preferred_term: Hypoplasia of the cerebellum (CNS hypoplasia)
    term:
      id: HP:0002977
      label: Aplasia/Hypoplasia involving the central nervous system
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her MRI revealed severe hypoplasia of the left cerebellar hemisphere with a short midbrain
    explanation: >-
      Documents cerebellar (CNS) hypoplasia in a severely affected WNT1-related OI
      patient, supporting CNS involvement in the disorder.
- name: Intellectual Disability
  description: >-
    Severe neurodevelopmental impairment, including intellectual disability and
    absence of speech, occurs in the severe CNS-involved end of the OI type XV
    spectrum, distinguishing it from the collagen-defect OI types.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has severe intellectual disability with absence of speech, and has been quadriplegic from toddlerhood.
    explanation: >-
      Documents severe intellectual disability in a WNT1-related OI patient with
      CNS involvement; not all patients are affected, so this is a feature of the
      severe subset.
- name: Vertebral Compression Fractures
  description: >-
    Vertebral compression fractures are part of the axial skeletal fragility of
    OI type XV, documented radiographically in severely affected children and
    contributing to progressive spinal deformity.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      vertebral compression fractures, resultant kyphoscoliosis
    explanation: >-
      Documents vertebral compression fractures in radiographically evaluated
      WNT1-related recessive OI patients.
- name: Kyphoscoliosis
  description: >-
    Progressive kyphoscoliosis develops as a sequela of vertebral compression
    fractures and low bone mass in OI type XV, a component of the axial deformity
    seen in the severe end of the spectrum.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      vertebral compression fractures, resultant kyphoscoliosis
    explanation: >-
      Documents kyphoscoliosis resulting from vertebral compression fractures in
      WNT1-related recessive OI.
- name: Joint Hypermobility
  description: >-
    Marked joint hypermobility with laxity is a feature of WNT1-related OI; the
    characterized siblings had markedly hyperextensible hands with laxity at the
    interphalangeal joints, overlapping the connective-tissue laxity seen across
    OI subtypes.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their hands are markedly hyperextensible with marked laxity at the interphalangeal joints.
    explanation: >-
      Documents marked joint hypermobility (hyperextensible hands, interphalangeal
      joint laxity) in WNT1-related recessive OI.
- name: White Sclerae (Blue Sclerae Characteristically Absent)
  description: >-
    Unlike the blue sclerae typical of classical dominant OI, the characterized
    WNT1-related OI siblings had white sclerae. Recorded here as an explicitly
    absent phenotype: blue sclerae ā€” a hallmark of collagen-defect OI ā€” were not
    present, a feature that helps distinguish this signaling-pathway OI from the
    classic dominant forms it otherwise clinically resembles.
  phenotype_term:
    preferred_term: Blue sclerae
    modifier: ABSENT
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Their sclerae are white.
    explanation: >-
      The characterized WNT1-related OI siblings had white sclerae; blue sclerae
      (a hallmark of classical dominant OI) were absent.
- name: Normal Dentition (Dentinogenesis Imperfecta Characteristically Absent)
  description: >-
    The characterized WNT1-related OI siblings had relatively normal permanent
    dentition without dentinogenesis imperfecta. Recorded here as an explicitly
    absent phenotype: dentinogenesis imperfecta, a common feature of collagen-defect
    OI, was documented as absent in the primary human report.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    modifier: ABSENT
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Permanent dentition is relatively normal in both with few caries and no signs of dentinogenesis imperfecta.
    explanation: >-
      The characterized WNT1-related OI siblings had normal permanent dentition;
      dentinogenesis imperfecta was documented as absent.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XV is suspected in an infant or child with recessive OI (reduced bone
    mass, recurrent fractures, progressive deformity), particularly when COL1A1/
    COL1A2 collagen studies are normal and other recessive OI genes are negative;
    CNS involvement in a severely affected child is a clue. Diagnosis is confirmed
    by identifying biallelic WNT1 variants by gene-panel or exome sequencing,
    distinguishing it from dominant OI type III, which it clinically resembles.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:23656646
    reference_title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given the family history with two affected siblings and the negative fibroblast collagen studies, whole exome sequencing was performed as described previously7 to identify a potential recessive OI gene.
    explanation: >-
      Illustrates the diagnostic pathway: negative collagen studies followed by
      exome sequencing identifying the recessive WNT1 gene.
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 WNT-signaling 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 XV.
- 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:23499309
  title: "Mutations in WNT1 cause different forms of bone fragility."
- reference: PMID:23499310
  title: "WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta."
- reference: PMID:23656646
  title: "WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
šŸ“š

References & Deep Research

References

4
PMID:23499309
Mutations in WNT1 cause different forms of bone fragility.
No top-level findings curated for this source.
PMID:23499310
WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:23656646
WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.