Osteogenesis Imperfecta Type XIII

Mendelian MONDO:0013924 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XIII (OI type XIII) is a rare autosomal recessive brittle-bone disease caused by biallelic loss-of-function variants in BMP1, the gene encoding bone morphogenetic protein 1 and its longer alternatively spliced isoform mammalian Tolloid (mTLD). BMP1/mTLD is the procollagen C-proteinase: an astacin-family secreted metalloprotease that cleaves the C-terminal propeptide (PICP) from types I-III procollagen and also participates in processing of other extracellular-matrix substrates including the small leucine-rich proteoglycan decorin and activation of lysyl oxidase. Defective BMP1/mTLD proteolytic activity leads to delayed/abnormal cleavage of the type I procollagen C-propeptide and impaired assembly of mature heterotypic collagen fibrils, producing a defective bone collagen matrix with severe skeletal fragility, recurrent fractures from early childhood, short stature with limb deformity, and a characteristic and unusual feature among OI types: bone fragility paradoxically associated with INCREASED (high) bone mineral density and hypermineralization of the bone matrix, distinguishing it mechanistically from the chaperone (SERPINH1, FKBP10) and 3-hydroxylation-complex (CRTAP, P3H1/LEPRE1, PPIB) recessive OI types. The disorder was first defined in a consanguineous human kindred and its osteogenic role confirmed in a zebrafish bmp1a mutant.

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1
Inheritance
3
Pathophys.
9
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
6
References
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic (homozygous or compound heterozygous) loss-of-function BMP1 variants; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:22052668 SUPPORT Human Clinical
"Herein, we have studied a consanguineous Egyptian family with two children diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI)"
Establishes the autosomal recessive inheritance of BMP1-related OI in a consanguineous kindred.
⚙

Pathophysiology

3
BMP1/mTLD Loss Abolishes Procollagen C-Proteinase Activity
BMP1 encodes the secreted astacin metalloprotease bone morphogenetic protein 1 and its longer isoform mammalian Tolloid (mTLD), which together constitute the principal procollagen C-terminal-propeptide (PICP) endopeptidase for type I procollagen. Biallelic loss-of-function BMP1 variants (e.g., the protease-domain p.Phe249Leu missense and signal-peptide variants) destroy or attenuate this proteolytic activity, so excess mutant BMP1/mTLD fails to enhance cleavage of the C-terminal propeptide of proalpha1(I). This is a proteolytic (enzymatic) lesion, mechanistically distinct from the chaperone and prolyl-3-hydroxylation defects of other 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.
collagen biosynthetic process (procollagen C-propeptide proteolysis) GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen biosynthetic process (procollagen C-propeptide proteolysis), annotated with collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Procollagen Processing and Abnormal Collagen Fibril Assembly Without BMP1/mTLD C-proteinase activity, the type I procollagen C-propeptide is not cleaved normally, impairing maturation and assembly of collagen fibrils.
Show evidence (2 references)
PMID:22052668 SUPPORT In Vitro
"proalpha1(I) cleavage was not enhanced by an excess of the mutant protein, proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with deficient PICP proteolytic activity."
Demonstrates that the causative BMP1 variant abolishes the procollagen C-proteinase (PICP) activity of BMP1/mTLD, the proximal lesion of OI type XIII.
PMID:22482805 SUPPORT Human Clinical
"we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures."
Identifies a homozygous BMP1 mutation underlying bone fragility with increased bone mineral density, defining the disorder.
Defective Procollagen Processing and Abnormal Collagen Fibril Assembly
Deficient BMP1/mTLD activity causes delayed cleavage of the type I procollagen C-propeptide and also hampers processing of prodecorin, a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. The combined defect impairs assembly of mature heterotypic type I/V collagen fibrils in the extracellular matrix, yielding a structurally abnormal bone collagen scaffold.
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. 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.
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
Downstream
Abnormally Mineralized Bone Matrix and Skeletal Fragility The defective collagen scaffold yields an abnormally mineralized bone matrix that, despite high mineral content, is mechanically weak and fracture-prone.
Show evidence (2 references)
PMID:25656619 SUPPORT Human Clinical
"BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis."
Documents the dual procollagen C-propeptide and prodecorin processing defect that disrupts collagen fibrillogenesis in BMP1-related OI.
PMID:25656619 SUPPORT Human Clinical
"transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM."
Demonstrates impaired heterotypic collagen fibril assembly resulting from BMP1/mTLD deficiency.
Abnormally Mineralized Bone Matrix and Skeletal Fragility
The abnormal collagen matrix in BMP1/mTLD deficiency mineralizes aberrantly: histomorphometry shows hyperosteoidosis with delayed onset of mineralization, yet the mineralized matrix becomes hypermineralized (high calcium content). The net result is bone that is paradoxically dense (high areal bone mineral density) but mechanically brittle, producing recurrent fractures, deformity, and short stature. This high-bone-mass fragility distinguishes OI type XIII from the typically low-density 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.
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 abnormal ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:24091809 SUPPORT Human Clinical
"It thus appears that disturbed C-propeptide cleavage impairs mineralization in two ways: first, the onset of mineralization is delayed, leading to an increased amount of unmineralized osteoid, and second, once mineralization starts, too much mineral is incorporated into the bone matrix,..."
Documents the dual mineralization defect (hyperosteoidosis plus hypermineralization) of the bone matrix in BMP1-related OI.
PMID:22482805 SUPPORT Model Organism
"Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone."
Zebrafish bmp1a data establish that BMP1 is required downstream of osteoblast maturation for mature collagen generation in bone, underlying the matrix fragility.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Osteogenesis Imperfecta Type XIII 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

9
Eye 1
Blue Sclerae HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22052668 SUPPORT Human Clinical
"long eyelashes, faint blue sclera, long philtrum"
Documents faint blue sclerae in a molecularly confirmed BMP1-related OI patient.
PMID:22052668 SUPPORT Human Clinical
"have in common blue sclera, kyphoscoliosis, and presence of hernia"
Identifies blue sclerae as one of the connective-tissue features shared by BMP1/mTLD deficiency (alongside kyphoscoliosis and hernia).
Head and Neck 1
Wormian Bones HP:0002645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wormian bones (HP:0002645). HP:0002645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22052668 SUPPORT Human Clinical
"Skull X-ray showed wormian bones."
Documents wormian bones on skull radiography in a molecularly confirmed BMP1-related OI patient; the affected sibling likewise had wormian bones.
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:22052668 SUPPORT Human Clinical
"Lower limbs showed bowing of femora, severely angulated deformed leg bones"
Documents bowing and deformity of the long bones in a patient with BMP1-related OI.
Musculoskeletal 4
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:27576954 SUPPORT Human Clinical
"These individuals had recurrent fractures from early childhood"
Documents recurrent fractures from early childhood as the cardinal feature of BMP1-related OI.
Increased Bone Mineral Density HP:0011001 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased bone mineral density (HP:0011001). HP:0011001 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27576954 SUPPORT Human Clinical
"In the majority of patients, bone fragility was associated with increased bone mineral density (BMD)"
Documents the characteristic association of BMP1-related OI bone fragility with increased bone mineral density.
PMID:22482805 SUPPORT Human Clinical
"a consanguineous family affected by increased bone mineral density and multiple recurrent fractures."
Independent kindred showing increased bone mineral density with recurrent fractures in BMP1-related OI.
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 (2 references)
PMID:22052668 SUPPORT Human Clinical
"She also had kyphoscoliosis and pectus carinatum."
Documents kyphoscoliosis in a molecularly confirmed BMP1-related OI patient.
PMID:25656619 SUPPORT Human Clinical
"severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis"
Independent kindred documenting variable kyphoscoliosis as part of the severe, progressive BMP1-related OI phenotype.
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 (2 references)
PMID:22052668 SUPPORT Human Clinical
"hyperextensibility of elbow, wrist, and interphalangeal (IP) joints"
Documents joint hyperextensibility in a molecularly confirmed BMP1-related OI patient; the affected sibling likewise had hyperextensible joints.
PMID:27576954 SUPPORT Human Clinical
"are hypermobile and have no evidence of dentinogenesis imperfecta"
Independent BMP1-OI cohort documenting joint hypermobility (and, notably, absence of dentinogenesis imperfecta).
Growth 1
Short Stature with Limb Deformity Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (short stature), annotated with Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25656619 SUPPORT Human Clinical
"severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis"
Documents short stature with rhizomelic shortening as part of the severe BMP1-related OI phenotype.
Other 1
Umbilical Hernia HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22052668 SUPPORT Human Clinical
"She had a large umbilical hernia, 5-cm wide and 7-cm long with abdominal content"
Documents a large umbilical hernia in a molecularly confirmed BMP1-related OI patient; the affected sibling likewise had a large umbilical hernia.
🧬

Genetic Associations

1
BMP1 Loss-of-Function Mutation (Causative)
Gene: BMP1 (procollagen C-proteinase / mammalian Tolloid) hgnc:1067 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BMP1 (procollagen C-proteinase / mammalian Tolloid), annotated with BMP1 (hgnc:1067). hgnc:1067 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:22052668 SUPPORT Human Clinical
"We conclude that BMP1 is an additional gene mutated in AR-OI."
Establishes BMP1 as the causative gene for this autosomal recessive form of OI.
PMID:27576954 SUPPORT Human Clinical
"To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming."
Documents the rarity and phenotypic range of BMP1-related OI.
💊

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 are widely used in severe OI to reduce fracture frequency. In BMP1-related OI, however, they must be used with caution because the bone material density is already very high; antiresorptive therapy has been reduced or discontinued in some patients over concerns about increasing bone stiffness and chalk-stick fractures.
Show evidence (1 reference)
PMID:27576954 SUPPORT Human Clinical
"Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures."
Documents the use and the BMP1-specific caution around bisphosphonate therapy in this high-bone-density form of OI.
Orthopedic Surgery
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 kyphoscoliosis.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when indicated to provide anatomic positioning of limbs"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity, applicable to OI type XIII.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical and occupational therapy improve mobility and muscle strength and prevent contractures; early physical therapy follows brief post-fracture immobilization.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Fractures are treated with as short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed"
GeneReviews documents early physical therapy and brief immobilization as part of standard OI fracture rehabilitation, applicable to OI type XIII.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XIII is suspected in a child with severe recessive OI (recurrent fractures, deformity) particularly when bone fragility is accompanied by high rather than low bone mineral density and COL1A1/COL1A2 testing is negative. Diagnosis is confirmed by identifying biallelic BMP1 loss-of-function variants by gene-panel or exome sequencing; supportive findings include deficient procollagen C-propeptide processing in cultured fibroblasts. Reported patients characteristically have no dentinogenesis imperfecta, and extraskeletal connective-tissue features (umbilical hernia, joint hyperextensibility, variable blue sclerae) can further support the diagnosis.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:22052668 SUPPORT Human Clinical
"Mutation analysis identified both patients with a Phe249Leu homozygous missense change within the BMP1 protease domain"
Molecular identification of biallelic BMP1 variants establishes the diagnosis of OI type XIII.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XIII
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 13
  term:
    id: MONDO:0013924
    label: osteogenesis imperfecta type 13
description: >-
  Osteogenesis imperfecta type XIII (OI type XIII) is a rare autosomal recessive
  brittle-bone disease caused by biallelic loss-of-function variants in BMP1, the
  gene encoding bone morphogenetic protein 1 and its longer alternatively spliced
  isoform mammalian Tolloid (mTLD). BMP1/mTLD is the procollagen C-proteinase: an
  astacin-family secreted metalloprotease that cleaves the C-terminal propeptide
  (PICP) from types I-III procollagen and also participates in processing of other
  extracellular-matrix substrates including the small leucine-rich proteoglycan
  decorin and activation of lysyl oxidase. Defective BMP1/mTLD proteolytic activity
  leads to delayed/abnormal cleavage of the type I procollagen C-propeptide and
  impaired assembly of mature heterotypic collagen fibrils, producing a defective
  bone collagen matrix with severe skeletal fragility, recurrent fractures from
  early childhood, short stature with limb deformity, and a characteristic and
  unusual feature among OI types: bone fragility paradoxically associated with
  INCREASED (high) bone mineral density and hypermineralization of the bone matrix,
  distinguishing it mechanistically from the chaperone (SERPINH1, FKBP10) and
  3-hydroxylation-complex (CRTAP, P3H1/LEPRE1, PPIB) recessive OI types. The
  disorder was first defined in a consanguineous human kindred and its osteogenic
  role confirmed in a zebrafish bmp1a mutant.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous or compound
    heterozygous) loss-of-function BMP1 variants; heterozygous carriers are
    clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we have studied a consanguineous Egyptian family with two children
      diagnosed with severe autosomal recessive osteogenesis imperfecta (AR-OI)
    explanation: >-
      Establishes the autosomal recessive inheritance of BMP1-related OI in a
      consanguineous kindred.
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: BMP1/mTLD Loss Abolishes Procollagen C-Proteinase Activity
  description: >-
    BMP1 encodes the secreted astacin metalloprotease bone morphogenetic protein 1
    and its longer isoform mammalian Tolloid (mTLD), which together constitute the
    principal procollagen C-terminal-propeptide (PICP) endopeptidase for type I
    procollagen. Biallelic loss-of-function BMP1 variants (e.g., the protease-domain
    p.Phe249Leu missense and signal-peptide variants) destroy or attenuate this
    proteolytic activity, so excess mutant BMP1/mTLD fails to enhance cleavage of
    the C-terminal propeptide of proalpha1(I). This is a proteolytic (enzymatic)
    lesion, mechanistically distinct from the chaperone and prolyl-3-hydroxylation
    defects of other 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: collagen biosynthetic process (procollagen C-propeptide proteolysis)
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      proalpha1(I) cleavage was not enhanced by an excess of the mutant protein,
      proving that the Phe249Leu mutation leads to a BMP1/mTLD protein with
      deficient PICP proteolytic activity.
    explanation: >-
      Demonstrates that the causative BMP1 variant abolishes the procollagen
      C-proteinase (PICP) activity of BMP1/mTLD, the proximal lesion of OI type XIII.
  - reference: PMID:22482805
    reference_title: "Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous
      family affected by increased bone mineral density and multiple recurrent
      fractures.
    explanation: >-
      Identifies a homozygous BMP1 mutation underlying bone fragility with increased
      bone mineral density, defining the disorder.
  downstream:
  - target: Defective Procollagen Processing and Abnormal Collagen Fibril Assembly
    description: >-
      Without BMP1/mTLD C-proteinase activity, the type I procollagen C-propeptide
      is not cleaved normally, impairing maturation and assembly of collagen fibrils.
- name: Defective Procollagen Processing and Abnormal Collagen Fibril Assembly
  description: >-
    Deficient BMP1/mTLD activity causes delayed cleavage of the type I procollagen
    C-propeptide and also hampers processing of prodecorin, a small leucine-rich
    proteoglycan that regulates collagen fibrillogenesis. The combined defect
    impairs assembly of mature heterotypic type I/V collagen fibrils in the
    extracellular matrix, yielding a structurally abnormal bone collagen scaffold.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25656619
    reference_title: "Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the
      type I procollagen C-propeptide but also hampers the processing of the small
      leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis.
    explanation: >-
      Documents the dual procollagen C-propeptide and prodecorin processing defect
      that disrupts collagen fibrillogenesis in BMP1-related OI.
  - reference: PMID:25656619
    reference_title: "Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transmission electron microscopy of the dermis show impaired assembly of
      heterotypic type I/V collagen fibrils in the ECM.
    explanation: >-
      Demonstrates impaired heterotypic collagen fibril assembly resulting from
      BMP1/mTLD deficiency.
  downstream:
  - target: Abnormally Mineralized Bone Matrix and Skeletal Fragility
    description: >-
      The defective collagen scaffold yields an abnormally mineralized bone matrix
      that, despite high mineral content, is mechanically weak and fracture-prone.
- name: Abnormally Mineralized Bone Matrix and Skeletal Fragility
  description: >-
    The abnormal collagen matrix in BMP1/mTLD deficiency mineralizes aberrantly:
    histomorphometry shows hyperosteoidosis with delayed onset of mineralization,
    yet the mineralized matrix becomes hypermineralized (high calcium content). The
    net result is bone that is paradoxically dense (high areal bone mineral density)
    but mechanically brittle, producing recurrent fractures, deformity, and short
    stature. This high-bone-mass fragility distinguishes OI type XIII from the
    typically low-density recessive OI types.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: ABNORMAL
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24091809
    reference_title: "Hyperosteoidosis and hypermineralization in the same bone: bone tissue analyses in a boy with a homozygous BMP1 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It thus appears that disturbed C-propeptide cleavage impairs mineralization
      in two ways: first, the onset of mineralization is delayed, leading to an
      increased amount of unmineralized osteoid, and second, once mineralization
      starts, too much mineral is incorporated into the bone matrix, resulting in
      hypermineralization.
    explanation: >-
      Documents the dual mineralization defect (hyperosteoidosis plus
      hypermineralization) of the bone matrix in BMP1-related OI.
  - reference: PMID:22482805
    reference_title: "Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Bmp1a is critically required for mature-collagen generation, downstream of
      osteoblast maturation, in bone.
    explanation: >-
      Zebrafish bmp1a data establish that BMP1 is required downstream of osteoblast
      maturation for mature collagen generation in bone, underlying the matrix
      fragility.
genetic:
- name: BMP1 Loss-of-Function Mutation
  association: Causative
  gene_term:
    preferred_term: BMP1 (procollagen C-proteinase / mammalian Tolloid)
    term:
      id: hgnc:1067
      label: BMP1
  notes: >-
    OI type XIII is caused by biallelic (homozygous or compound heterozygous)
    loss-of-function variants in BMP1, encoding the procollagen C-proteinase BMP1
    and its longer isoform mTLD. Reported alleles include the protease-domain
    p.Phe249Leu missense, signal-peptide variants (e.g., c.34G>C, p.Gly12Arg), and
    nonsense/frameshift variants. Fewer than 20 affected individuals have been
    reported, with a phenotype ranging from mild to severe/progressively deforming.
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that BMP1 is an additional gene mutated in AR-OI.
    explanation: >-
      Establishes BMP1 as the causative gene for this autosomal recessive form of OI.
  - reference: PMID:27576954
    reference_title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, less than 20 individuals with OI have been identified with BMP1
      mutations, with skeletal phenotypes ranging from mild to severe and
      progressively deforming.
    explanation: >-
      Documents the rarity and phenotypic range of BMP1-related OI.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent fractures from early childhood, the
    cardinal feature of OI type XIII.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:27576954
    reference_title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These individuals had recurrent fractures from early childhood
    explanation: >-
      Documents recurrent fractures from early childhood as the cardinal feature of
      BMP1-related OI.
- name: Increased Bone Mineral Density
  description: >-
    A characteristic and unusual feature of BMP1-related OI: bone fragility is
    paradoxically associated in most patients with increased (high) bone mineral
    density and hypermineralized bone material, distinguishing it from the typically
    low-density recessive OI types.
  phenotype_term:
    preferred_term: Increased bone mineral density
    term:
      id: HP:0011001
      label: Increased bone mineral density
  evidence:
  - reference: PMID:27576954
    reference_title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the majority of patients, bone fragility was associated with increased
      bone mineral density (BMD)
    explanation: >-
      Documents the characteristic association of BMP1-related OI bone fragility
      with increased bone mineral density.
  - reference: PMID:22482805
    reference_title: "Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a consanguineous family affected by increased bone mineral density and
      multiple recurrent fractures.
    explanation: >-
      Independent kindred showing increased bone mineral density with recurrent
      fractures in BMP1-related OI.
- name: Short Stature with Limb Deformity
  description: >-
    Severe, progressive disease with short stature (often with rhizomelic
    shortening) and deformity of the limbs.
  phenotype_term:
    preferred_term: Growth delay (short stature)
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:25656619
    reference_title: "Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe, progressive OI characterized by numerous fractures, short stature
      with rhizomelic shortening, and deformity of the limbs and variable
      kyphoscoliosis
    explanation: >-
      Documents short stature with rhizomelic shortening as part of the severe
      BMP1-related OI phenotype.
- name: Bowing of the Long Bones
  description: >-
    Long-bone bowing and deformity accompany the recurrent fractures and skeletal
    fragility, reflecting the mechanically weak bone.
  phenotype_term:
    preferred_term: Bowing of the long bones
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower limbs showed bowing of femora, severely angulated deformed leg bones
    explanation: >-
      Documents bowing and deformity of the long bones in a patient with
      BMP1-related OI.
- name: Umbilical Hernia
  description: >-
    A large umbilical hernia with abdominal contents is a recurrent and
    distinctive extraskeletal feature of BMP1-related OI, present in both
    affected siblings of the founding kindred and mirrored by the consistent
    gut herniation reported in Bmp1-null mice. It is attributed to reduced
    tensile strength of the ventral body wall secondary to defective collagen
    fibril formation (and possibly impaired BMP1 processing of dorsoventral
    patterning factors such as chordin), and is among the features that help
    distinguish BMP1-OI from most other OI types.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had a large umbilical hernia, 5-cm wide and 7-cm long with abdominal content
    explanation: >-
      Documents a large umbilical hernia in a molecularly confirmed BMP1-related
      OI patient; the affected sibling likewise had a large umbilical hernia.
- name: Kyphoscoliosis
  description: >-
    Progressive kyphoscoliosis of the thoracolumbar spine is a recurrent
    feature of the severe, progressively deforming BMP1-related OI phenotype,
    documented across independent kindreds.
  phenotype_term:
    preferred_term: Kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She also had kyphoscoliosis and pectus carinatum.
    explanation: >-
      Documents kyphoscoliosis in a molecularly confirmed BMP1-related OI patient.
  - reference: PMID:25656619
    reference_title: "Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      severe, progressive OI characterized by numerous fractures, short stature
      with rhizomelic shortening, and deformity of the limbs and variable
      kyphoscoliosis
    explanation: >-
      Independent kindred documenting variable kyphoscoliosis as part of the
      severe, progressive BMP1-related OI phenotype.
- name: Wormian Bones
  description: >-
    Wormian (intrasutural) bones of the skull, a classic radiographic marker of
    osteogenesis imperfecta, are documented on skull radiographs in BMP1-related
    OI.
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Skull X-ray showed wormian bones.
    explanation: >-
      Documents wormian bones on skull radiography in a molecularly confirmed
      BMP1-related OI patient; the affected sibling likewise had wormian bones.
- name: Joint Hypermobility
  description: >-
    Generalized joint hypermobility / ligamentous hyperextensibility is a
    recurrent connective-tissue feature of BMP1-related OI, consistent with the
    broad role of BMP1/mTLD in processing type III and V procollagens.
  phenotype_term:
    preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperextensibility of elbow, wrist, and interphalangeal (IP) joints
    explanation: >-
      Documents joint hyperextensibility in a molecularly confirmed BMP1-related
      OI patient; the affected sibling likewise had hyperextensible joints.
  - reference: PMID:27576954
    reference_title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      are hypermobile and have no evidence of dentinogenesis imperfecta
    explanation: >-
      Independent BMP1-OI cohort documenting joint hypermobility (and, notably,
      absence of dentinogenesis imperfecta).
- name: Blue Sclerae
  description: >-
    Sclerae in BMP1-related OI are variable; faint blue sclerae are documented
    in the founding kindred and blue sclerae are noted among the connective-tissue
    features BMP1-OI shares with the collagen III/V-related Ehlers-Danlos
    phenotypes, whereas other reported BMP1-OI patients have white/normal sclerae.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      long eyelashes, faint blue sclera, long philtrum
    explanation: >-
      Documents faint blue sclerae in a molecularly confirmed BMP1-related OI
      patient.
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      have in common blue sclera, kyphoscoliosis, and presence of hernia
    explanation: >-
      Identifies blue sclerae as one of the connective-tissue features shared by
      BMP1/mTLD deficiency (alongside kyphoscoliosis and hernia).
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XIII is suspected in a child with severe recessive OI (recurrent
    fractures, deformity) particularly when bone fragility is accompanied by high
    rather than low bone mineral density and COL1A1/COL1A2 testing is negative.
    Diagnosis is confirmed by identifying biallelic BMP1 loss-of-function variants
    by gene-panel or exome sequencing; supportive findings include deficient
    procollagen C-propeptide processing in cultured fibroblasts. Reported patients
    characteristically have no dentinogenesis imperfecta, and extraskeletal
    connective-tissue features (umbilical hernia, joint hyperextensibility,
    variable blue sclerae) can further support the diagnosis.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:22052668
    reference_title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis identified both patients with a Phe249Leu homozygous
      missense change within the BMP1 protease domain
    explanation: >-
      Molecular identification of biallelic BMP1 variants establishes the diagnosis
      of OI type XIII.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates are widely used in severe OI to reduce fracture
    frequency. In BMP1-related OI, however, they must be used with caution because
    the bone material density is already very high; antiresorptive therapy has been
    reduced or discontinued in some patients over concerns about increasing bone
    stiffness and chalk-stick fractures.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:27576954
    reference_title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intravenous bisphosphonate therapy was started in all patients, but
      discontinued in two patients and reduced in another due to concerns about
      increasing bone stiffness leading to chalk-stick fractures.
    explanation: >-
      Documents the use and the BMP1-specific caution around bisphosphonate therapy
      in this high-bone-density form of OI.
- name: Orthopedic Surgery
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery addresses progressive
    kyphoscoliosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity, applicable to OI type XIII.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy improve mobility and muscle strength and
    prevent contractures; early physical therapy follows brief post-fracture
    immobilization.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fractures are treated with as
      short a period of immobility as is practical, small and lightweight casts, and
      physical therapy as soon as casts are removed
    explanation: >-
      GeneReviews documents early physical therapy and brief immobilization as part
      of standard OI fracture rehabilitation, applicable to OI type XIII.
datasets: []
references:
- reference: PMID:22052668
  title: "Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta."
- reference: PMID:22482805
  title: "Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish."
- reference: PMID:25656619
  title: "Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta."
- reference: PMID:24091809
  title: "Hyperosteoidosis and hypermineralization in the same bone: bone tissue analyses in a boy with a homozygous BMP1 mutation."
- reference: PMID:27576954
  title: "Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

6
PMID:22052668
Identification of a mutation causing deficient BMP1/mTLD proteolytic activity in autosomal recessive osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:22482805
Attenuated BMP1 function compromises osteogenesis, leading to bone fragility in humans and zebrafish.
No top-level findings curated for this source.
PMID:25656619
Defective Proteolytic Processing of Fibrillar Procollagens and Prodecorin Due to Biallelic BMP1 Mutations Results in a Severe, Progressive Form of Osteogenesis Imperfecta.
No top-level findings curated for this source.
PMID:24091809
Hyperosteoidosis and hypermineralization in the same bone: bone tissue analyses in a boy with a homozygous BMP1 mutation.
No top-level findings curated for this source.
PMID:27576954
Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.