Osteogenesis Imperfecta Type XIX

Mendelian MONDO:0049223 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XIX (OI type XIX) is the only X-linked recessive form of osteogenesis imperfecta, a collagen-related brittle bone dysplasia. It is caused by hemizygous hypomorphic missense variants in MBTPS2 (on Xp22), which encodes site-2 metalloprotease (S2P), an integral Golgi membrane protease that, together with site-1 protease (S1P), performs regulated intramembrane proteolysis (RIP) of membrane-bound transcription factors transported from the ER under ER-stress or sterol-restriction conditions. S2P substrates include OASIS/CREB3L1 (a bZIP transcription factor expressed in osteoblasts that activates type I collagen transcription and complexes with SMAD4 to drive matrix-gene expression), ATF6 (unfolded protein response) and SREBP (sterol metabolism). OI-causing MBTPS2 substitutions occur at highly conserved S2P residues near the carboxyl end of the protein (e.g., p.N459S at the first residue of the metal-ion-coordinating NPDG motif, and p.L505F); the mutant protein is stable but functionally impaired, so RIP cleavage/activation of OASIS, ATF6 and SREBP is reduced. The downstream bone defect combines reduced type I collagen secretion by mutant cells, a broad defect in osteoblast differentiation, and reduced hydroxylation of the helical collagen lysine (K87) critical for crosslinking — the latter associated with reduced lysyl hydroxylase 1 (PLOD1/LH1) in proband osteoblasts and elevated urinary lysyl-/hydroxylysyl-pyridinoline ratio. The net result is mechanically weak bone with low bone mineral density and skeletal fragility. Affected males present with prenatal and childhood fractures, short stature, long-bone bowing, generalized osteopenia, scoliosis/vertebral wedging and pectal deformity, in the moderate-to-severe range; obligate-carrier mothers are clinically unaffected. OI type XIX is mechanistically continuous with CREB3L1-related OI type XVI: MBTPS2 defects impair RIP processing of the same OASIS transcription factor whose loss causes the recessive autosomal form, but the affected individuals lack the dermatological features (IFAP/KFSD/Olmsted) of other allelic MBTPS2 disorders.

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🏷

Classifications

ISDS Skeletal Nosology

👪

Inheritance

X-linked Recessive HP:0001419

X-linked recessive inheritance from hemizygous hypomorphic MBTPS2 missense variants at Xp22; affected males are the sons of obligate carrier mothers, who are clinically unaffected. This is the only non-autosomal form of OI.

X-linked recessive inheritance

Show evidence (2 references)

PMID:27380894 SUPPORT Human Clinical

"We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P)."

Establishes that OI type XIX follows X-linked recessive inheritance, caused by MBTPS2 (S2P) defects — the only non-autosomal form of OI.

PMID:27380894 SUPPORT Human Clinical

"The gene defects co-segregate with the phenotype in each pedigree and all affected individuals are the sons of obligate carriers."

Documents the X-linked recessive segregation pattern: affected males are sons of unaffected obligate-carrier mothers.

⚙

Pathophysiology

Hypomorphic MBTPS2 Impairs Site-2 Protease (S2P) Regulated Intramembrane Proteolysis

MBTPS2 encodes site-2 metalloprotease (S2P), an integral Golgi membrane protein that, with site-1 protease (S1P), sequentially cleaves membrane-spanning regulatory transcription factors (OASIS/CREB3L1, ATF6, SREBP) transported from the ER during ER stress or sterol restriction, releasing mature N-terminal fragments that enter the nucleus to activate transcription (regulated intramembrane proteolysis, RIP). OI-causing hemizygous missense substitutions at highly conserved S2P residues (p.N459S at the first residue of the metal-ion-coordinating NPDG motif; p.L505F) leave the protein stable and normally expressed but functionally impaired, so RIP cleavage/activation of OASIS, ATF6 and SREBP is reduced.

osteoblast CL:0000062 fibroblast CL:0000057

regulated intramembrane proteolysis of OASIS/ATF6/SREBP (S2P-dependent) GO:0034976 ⚠ ABNORMAL

Downstream

Defective OASIS-Driven Osteoblast Transcription and Reduced Type I Collagen Impaired S2P processing of OASIS/CREB3L1 reduces OASIS-dependent transcriptional output in osteoblasts, lowering type I collagen secretion and disrupting osteoblast differentiation.

Show evidence (2 references)

PMID:27380894 SUPPORT In Vitro

"Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen."

Establishes that hypomorphic MBTPS2 produces a stable but functionally impaired S2P that cannot perform RIP of its transcription-factor substrates, the proximal lesion of OI type XIX.

PMID:27380894 SUPPORT In Vitro

"mature intracellular OASIS cleavage fragment (50 kDa, S1P/S2P cleaved) was decreased, while the 55-kDa cleavage product (S1P cleaved) was increased, in fibroblasts with each mutation and in S2P p.L505F osteoblasts, indicating S2P cleavage impairment in OI probands"

Demonstrates at the molecular level that mutant S2P fails to complete the S2P-dependent cleavage step of OASIS in OI proband cells.

Defective OASIS-Driven Osteoblast Transcription and Reduced Type I Collagen

Fully processed OASIS/CREB3L1 normally activates Col1a1 transcription and complexes with SMAD4 to upregulate matrix genes. When S2P-mediated OASIS processing is impaired, OASIS (CREB3L1) and SMAD4 expression fall across osteoblast differentiation, alkaline phosphatase expression is reduced, and proband osteoblasts show a broad differentiation defect. Mutant cells secrete significantly less type I collagen (20-73% of control in fibroblasts). In parallel, hydroxylation of the collagen helical lysine K87 critical for crosslinking is reduced — associated with substantially decreased lysyl hydroxylase 1 (PLOD1/LH1) in proband osteoblasts — yielding collagen with fewer mature crosslinks.

osteoblast CL:0000062

OASIS-dependent regulation of COL1A1 transcription GO:0006357 ↓ DECREASED type I collagen biosynthesis and secretion GO:0032964 ↓ DECREASED osteoblast differentiation (S2P/OASIS-dependent) GO:0001649 ↓ DECREASED

Downstream

Mechanically Weak Bone Matrix, Low Bone Mass, and Skeletal Fragility Reduced collagen secretion plus impaired collagen crosslinking and defective osteoblast maturation yield a mechanically inferior bone matrix with low bone mass and fracture susceptibility.

Show evidence (3 references)

PMID:27380894 SUPPORT In Vitro

"Fibroblasts from OI probands secreted a significantly reduced amount of type I collagen"

Documents reduced type I collagen secretion by OI type XIX proband cells, a direct consequence of defective S2P/OASIS RIP signaling.

PMID:27380894 SUPPORT In Vitro

"Osteoblasts differentiated in culture revealed impaired expression of transcripts related to osteoblast maturation and RIP pathways"

Demonstrates the broad osteoblast differentiation defect produced by impaired RIP signaling in OI type XIX.

PMID:27380894 SUPPORT Human Clinical

"hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts."

Documents the collagen crosslinking defect (reduced K87 hydroxylation via decreased LH1) that compounds the reduced collagen secretion in OI type XIX.

Mechanically Weak Bone Matrix, Low Bone Mass, and Skeletal Fragility

The combination of reduced type I collagen secretion into bone matrix, impaired collagen crosslinking (reduced K87 hydroxylation, presumptively undermining bone strength), and defective osteoblast differentiation produces a mechanically weak, collagen-related bone defect with generalized osteopenia and low bone mineral density. Clinically this manifests in affected males as prenatal and childhood fractures, short stature, bowing of the long bones, scoliosis with anterior vertebral wedging, and pectal deformity in the moderate-to-severe OI range.

osteoblast CL:0000062

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

Show evidence (2 references)

PMID:27380894 SUPPORT Human Clinical

"Reduced collagen crosslinks presumptively undermine bone strength."

Links the molecular collagen-crosslinking defect to the mechanically weak bone underlying skeletal fragility in OI type XIX.

PMID:27380894 SUPPORT Human Clinical

"Affected adult males had fractures beginning during gestation, short stature, white sclerae, variable scoliosis and pectal deformity, striking tibial anterior angulation and generalized osteopenia"

Documents the clinical skeletal-fragility phenotype (fractures, short stature, deformity, generalized osteopenia) of OI type XIX.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Eye 1

Blue Sclerae (Age-Dependent / Variable) HP:0000592

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"his physical exam was notable for moderate short stature, blue sclerae, pectus carinatum and bowing of lower extremity long bones"

Documents blue sclerae in the young (2-year-old) MBTPS2-related OI proband; the description notes that adult males instead had white sclerae, so this phenotype is age-dependent.

Head and Neck 1

Dentinogenesis Imperfecta (Characteristically Absent) HP:0000703

∅ ABSENT

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"There are no signs of dentinogenesis imperfecta and the sclerae are white."

Documents that dentinogenesis imperfecta was absent (normal teeth) in MBTPS2-related OI, an explicitly negative discriminating feature.

Limbs 1

Bone Deformity Bowing of the long bones HP:0006487

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"As a newborn, the proband was noted to have bowing of humeri, radii and tibiae, and fractures of femora, ribs and clavicles, as well as generalized osteopenia"

Documents long-bone bowing (bone deformity) in an OI type XIX proband.

Musculoskeletal 3

Recurrent Fractures HP:0002757

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"Both patients had numerous fractures of upper and lower extremity long bones during childhood, but fractures declined post puberty."

Documents recurrent childhood fractures in molecularly confirmed OI type XIX patients.

Reduced Bone Mineral Density HP:0004349

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"His L2–L4 bone mineral density z-score=−4.7"

Documents markedly reduced bone mineral density in the OI type XIX index case.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"Both have white sclerae, kyphoscoliosis with anterior vertebral wedging and short stature"

Documents scoliosis (kyphoscoliosis with vertebral wedging) in OI type XIX.

Growth 1

Short Stature HP:0004322

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"Both patients had numerous fractures of upper and lower extremity long bones during childhood, but fractures declined post puberty. Both have white sclerae, kyphoscoliosis with anterior vertebral wedging and short stature"

Documents short stature as a feature of OI type XIX in affected males.

Other 1

Pectus Deformity Abnormal sternum morphology HP:0000766

Show evidence (2 references)

PMID:27380894 SUPPORT Human Clinical

"his physical exam was notable for moderate short stature, blue sclerae, pectus carinatum and bowing of lower extremity long bones"

Documents pectus carinatum in the MBTPS2-related OI proband.

PMID:27380894 SUPPORT Human Clinical

"He has a severe connatal pectus excavatum."

Documents severe pectus excavatum in an adult MBTPS2-related OI patient, showing the pectus deformity spans both carinatum and excavatum forms.

🧬

Genetic Associations

MBTPS2 (S2P) Hypomorphic Missense Mutations (Causative)

Gene: MBTPS2 (site-2 protease, S2P; RIP intramembrane metalloprotease) hgnc:15455

Show evidence (2 references)

PMID:27380894 SUPPORT Human Clinical

"MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues."

Identifies the causative MBTPS2 (S2P) missense variants in two independent OI kindreds, defining OI type XIX.

PMID:27380894 SUPPORT Human Clinical

"Mutations previously reported to cause substitutions in S2P (Supplementary Fig. 8) underlie a spectrum of dermatological conditions: IFAP syndrome, characterized by a triad of ichthyosis follicularis, atrichia and photophobia"

Documents the allelic MBTPS2 dermatological disorders distinct from the OI phenotype, supporting the genotype note.

💊

Medical Actions

Bisphosphonate Therapy

Action: Bisphosphonate Therapy NCIT:C198585

Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of moderate-to-severe OI, increasing bone mineral density and reducing fracture frequency in patients with vertebral fractures, frequent long-bone fractures, or more severe disease. They are antiresorptive and do not correct the underlying RIP/collagen defect of OI type XIX.

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 standard pharmacological treatment for severe OI, applicable to OI type XIX.

Orthopedic Surgery and Intramedullary Rodding

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

Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed long bones; spinal surgery may address progressive scoliosis. Surgical management is standard in moderate-to-severe OI such as OI type XIX.

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 XIX.

Physical Therapy and Rehabilitation

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

Physical and occupational therapy improve mobility and muscle strength and prevent contractures and deformity; early physical therapy follows brief post-fracture immobilization.

Show evidence (1 reference)

PMID:20301472 SUPPORT Human Clinical

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

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

🔬

Diagnosis

Molecular Genetic Diagnosis

OI type XIX is suspected in a male with moderate-to-severe collagen-related OI (prenatal/childhood fractures, low bone mineral density, long-bone bowing, scoliosis) showing an X-linked recessive pattern (affected males, carrier mothers) when COL1A1/COL1A2 and the autosomal recessive OI genes are negative. Diagnosis is confirmed by identifying a hemizygous pathogenic MBTPS2 (S2P) missense variant by X-chromosome linkage and next-generation (gene-panel/exome) sequencing. An elevated urinary lysyl- to hydroxylysyl-pyridinoline (LP/HP) ratio is a supportive collagen-crosslinking marker.

molecular genetic testing NCIT:C19770

Show evidence (1 reference)

PMID:27380894 SUPPORT Human Clinical

"Linkage analysis and next-generation sequencing (NGS) identified a novel MBTPS2 missense mutation in each pedigree."

Documents the molecular-genetic diagnostic route (linkage plus NGS) that establishes OI type XIX.

{ }

Source YAML

click to show

name: Osteogenesis Imperfecta Type XIX
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 19
  term:
    id: MONDO:0049223
    label: osteogenesis imperfecta, type 19
description: >-
  Osteogenesis imperfecta type XIX (OI type XIX) is the only X-linked recessive
  form of osteogenesis imperfecta, a collagen-related brittle bone dysplasia. It
  is caused by hemizygous hypomorphic missense variants in MBTPS2 (on Xp22),
  which encodes site-2 metalloprotease (S2P), an integral Golgi membrane protease
  that, together with site-1 protease (S1P), performs regulated intramembrane
  proteolysis (RIP) of membrane-bound transcription factors transported from the
  ER under ER-stress or sterol-restriction conditions. S2P substrates include
  OASIS/CREB3L1 (a bZIP transcription factor expressed in osteoblasts that
  activates type I collagen transcription and complexes with SMAD4 to drive
  matrix-gene expression), ATF6 (unfolded protein response) and SREBP (sterol
  metabolism). OI-causing MBTPS2 substitutions occur at highly conserved S2P
  residues near the carboxyl end of the protein (e.g., p.N459S at the first
  residue of the metal-ion-coordinating NPDG motif, and p.L505F); the mutant
  protein is stable but functionally impaired, so RIP cleavage/activation of
  OASIS, ATF6 and SREBP is reduced. The downstream bone defect combines reduced
  type I collagen secretion by mutant cells, a broad defect in osteoblast
  differentiation, and reduced hydroxylation of the helical collagen lysine (K87)
  critical for crosslinking — the latter associated with reduced lysyl
  hydroxylase 1 (PLOD1/LH1) in proband osteoblasts and elevated urinary
  lysyl-/hydroxylysyl-pyridinoline ratio. The net result is mechanically weak
  bone with low bone mineral density and skeletal fragility. Affected males
  present with prenatal and childhood fractures, short stature, long-bone bowing,
  generalized osteopenia, scoliosis/vertebral wedging and pectal deformity, in
  the moderate-to-severe range; obligate-carrier mothers are clinically
  unaffected. OI type XIX is mechanistically continuous with CREB3L1-related OI
  type XVI: MBTPS2 defects impair RIP processing of the same OASIS transcription
  factor whose loss causes the recessive autosomal form, but the affected
  individuals lack the dermatological features (IFAP/KFSD/Olmsted) of other
  allelic MBTPS2 disorders.
parents:
- Osteogenesis imperfecta
inheritance:
- name: X-linked Recessive
  description: >-
    X-linked recessive inheritance from hemizygous hypomorphic MBTPS2 missense
    variants at Xp22; affected males are the sons of obligate carrier mothers,
    who are clinically unaffected. This is the only non-autosomal form of OI.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified an X-linked recessive form of OI caused by defects in MBTPS2,
      which encodes site-2 metalloprotease (S2P).
    explanation: >-
      Establishes that OI type XIX follows X-linked recessive inheritance,
      caused by MBTPS2 (S2P) defects — the only non-autosomal form of OI.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene defects co-segregate with the phenotype in each pedigree and all
      affected individuals are the sons of obligate carriers.
    explanation: >-
      Documents the X-linked recessive segregation pattern: affected males are
      sons of unaffected obligate-carrier mothers.
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: Hypomorphic MBTPS2 Impairs Site-2 Protease (S2P) Regulated Intramembrane Proteolysis
  description: >-
    MBTPS2 encodes site-2 metalloprotease (S2P), an integral Golgi membrane
    protein that, with site-1 protease (S1P), sequentially cleaves
    membrane-spanning regulatory transcription factors (OASIS/CREB3L1, ATF6,
    SREBP) transported from the ER during ER stress or sterol restriction,
    releasing mature N-terminal fragments that enter the nucleus to activate
    transcription (regulated intramembrane proteolysis, RIP). OI-causing
    hemizygous missense substitutions at highly conserved S2P residues (p.N459S
    at the first residue of the metal-ion-coordinating NPDG motif; p.L505F) leave
    the protein stable and normally expressed but functionally impaired, so RIP
    cleavage/activation of OASIS, ATF6 and SREBP is reduced.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: regulated intramembrane proteolysis of OASIS/ATF6/SREBP (S2P-dependent)
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mutant S2P has normal stability, but impaired functioning in regulated
      intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription
      factors, consistent with decreased proband secretion of type I collagen.
    explanation: >-
      Establishes that hypomorphic MBTPS2 produces a stable but functionally
      impaired S2P that cannot perform RIP of its transcription-factor
      substrates, the proximal lesion of OI type XIX.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      mature intracellular OASIS cleavage fragment (50 kDa, S1P/S2P cleaved) was
      decreased, while the 55-kDa cleavage product (S1P cleaved) was increased,
      in fibroblasts with each mutation and in S2P p.L505F osteoblasts,
      indicating S2P cleavage impairment in OI probands
    explanation: >-
      Demonstrates at the molecular level that mutant S2P fails to complete the
      S2P-dependent cleavage step of OASIS in OI proband cells.
  downstream:
  - target: Defective OASIS-Driven Osteoblast Transcription and Reduced Type I Collagen
    description: >-
      Impaired S2P processing of OASIS/CREB3L1 reduces OASIS-dependent
      transcriptional output in osteoblasts, lowering type I collagen secretion
      and disrupting osteoblast differentiation.
- name: Defective OASIS-Driven Osteoblast Transcription and Reduced Type I Collagen
  description: >-
    Fully processed OASIS/CREB3L1 normally activates Col1a1 transcription and
    complexes with SMAD4 to upregulate matrix genes. When S2P-mediated OASIS
    processing is impaired, OASIS (CREB3L1) and SMAD4 expression fall across
    osteoblast differentiation, alkaline phosphatase expression is reduced, and
    proband osteoblasts show a broad differentiation defect. Mutant cells secrete
    significantly less type I collagen (20-73% of control in fibroblasts). In
    parallel, hydroxylation of the collagen helical lysine K87 critical for
    crosslinking is reduced — associated with substantially decreased lysyl
    hydroxylase 1 (PLOD1/LH1) in proband osteoblasts — yielding collagen with
    fewer mature crosslinks.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: OASIS-dependent regulation of COL1A1 transcription
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: type I collagen biosynthesis and secretion
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  - preferred_term: osteoblast differentiation (S2P/OASIS-dependent)
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Fibroblasts from OI probands secreted a significantly reduced amount of
      type I collagen
    explanation: >-
      Documents reduced type I collagen secretion by OI type XIX proband cells,
      a direct consequence of defective S2P/OASIS RIP signaling.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Osteoblasts differentiated in culture revealed impaired expression of
      transcripts related to osteoblast maturation and RIP pathways
    explanation: >-
      Demonstrates the broad osteoblast differentiation defect produced by
      impaired RIP signaling in OI type XIX.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hydroxylation of the collagen lysine residue (K87) critical for
      crosslinking is reduced in proband bone tissue, consistent with decreased
      lysyl hydroxylase 1 in proband osteoblasts.
    explanation: >-
      Documents the collagen crosslinking defect (reduced K87 hydroxylation via
      decreased LH1) that compounds the reduced collagen secretion in OI type XIX.
  downstream:
  - target: Mechanically Weak Bone Matrix, Low Bone Mass, and Skeletal Fragility
    description: >-
      Reduced collagen secretion plus impaired collagen crosslinking and
      defective osteoblast maturation yield a mechanically inferior bone matrix
      with low bone mass and fracture susceptibility.
- name: Mechanically Weak Bone Matrix, Low Bone Mass, and Skeletal Fragility
  description: >-
    The combination of reduced type I collagen secretion into bone matrix,
    impaired collagen crosslinking (reduced K87 hydroxylation, presumptively
    undermining bone strength), and defective osteoblast differentiation produces
    a mechanically weak, collagen-related bone defect with generalized osteopenia
    and low bone mineral density. Clinically this manifests in affected males as
    prenatal and childhood fractures, short stature, bowing of the long bones,
    scoliosis with anterior vertebral wedging, and pectal deformity in the
    moderate-to-severe OI range.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Reduced collagen crosslinks presumptively undermine bone strength.
    explanation: >-
      Links the molecular collagen-crosslinking defect to the mechanically weak
      bone underlying skeletal fragility in OI type XIX.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected adult males had fractures beginning during gestation, short
      stature, white sclerae, variable scoliosis and pectal deformity, striking
      tibial anterior angulation and generalized osteopenia
    explanation: >-
      Documents the clinical skeletal-fragility phenotype (fractures, short
      stature, deformity, generalized osteopenia) of OI type XIX.
genetic:
- name: MBTPS2 (S2P) Hypomorphic Missense Mutations
  association: Causative
  gene_term:
    preferred_term: MBTPS2 (site-2 protease, S2P; RIP intramembrane metalloprotease)
    term:
      id: hgnc:15455
      label: MBTPS2
  notes: >-
    OI type XIX is caused by hemizygous hypomorphic missense variants in MBTPS2
    at Xp22.12, encoding site-2 metalloprotease (S2P). The two founding alleles
    (p.N459S, at the first residue of the metal-ion-coordinating NPDG motif, and
    p.L505F) are highly conserved S2P substitutions that leave the protein stable
    but impair RIP of OASIS/ATF6/SREBP. MBTPS2 is also the cause of allelic
    X-linked dermatological disorders — IFAP/BRESHECK syndrome, keratosis
    follicularis spinulosa decalvans (KFSD), and Olmsted syndrome — but OI type
    XIX patients lack those skin/hair/eye features; this entry concerns the OI
    (bone-fragility) phenotype. Affected males are sons of unaffected obligate
    carriers.
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MBTPS2 missense mutations in two independent kindreds with moderate/severe
      OI cause substitutions at highly conserved S2P residues.
    explanation: >-
      Identifies the causative MBTPS2 (S2P) missense variants in two independent
      OI kindreds, defining OI type XIX.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations previously reported to cause substitutions in S2P (Supplementary
      Fig. 8) underlie a spectrum of dermatological conditions: IFAP syndrome,
      characterized by a triad of ichthyosis follicularis, atrichia and
      photophobia
    explanation: >-
      Documents the allelic MBTPS2 dermatological disorders distinct from the OI
      phenotype, supporting the genotype note.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XIX is suspected in a male with moderate-to-severe collagen-related
    OI (prenatal/childhood fractures, low bone mineral density, long-bone bowing,
    scoliosis) showing an X-linked recessive pattern (affected males, carrier
    mothers) when COL1A1/COL1A2 and the autosomal recessive OI genes are
    negative. Diagnosis is confirmed by identifying a hemizygous pathogenic
    MBTPS2 (S2P) missense variant by X-chromosome linkage and next-generation
    (gene-panel/exome) sequencing. An elevated urinary lysyl- to
    hydroxylysyl-pyridinoline (LP/HP) ratio is a supportive collagen-crosslinking
    marker.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Linkage analysis and next-generation sequencing (NGS) identified a novel
      MBTPS2 missense mutation in each pedigree.
    explanation: >-
      Documents the molecular-genetic diagnostic route (linkage plus NGS) that
      establishes OI type XIX.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of moderate-to-severe OI, increasing bone mineral
    density and reducing fracture frequency in patients with vertebral fractures,
    frequent long-bone fractures, or more severe disease. They are antiresorptive
    and do not correct the underlying RIP/collagen defect of OI type XIX.
  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 standard pharmacological
      treatment for severe OI, applicable to OI type XIX.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery may address progressive
    scoliosis. Surgical management is standard in moderate-to-severe OI such as
    OI type XIX.
  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 XIX.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy 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.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with fractures beginning during gestation and numerous
    fractures of upper and lower extremity long bones during childhood; the
    cardinal feature of OI type XIX.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had numerous fractures of upper and lower extremity long
      bones during childhood, but fractures declined post puberty.
    explanation: >-
      Documents recurrent childhood fractures in molecularly confirmed OI type
      XIX patients.
- name: Reduced Bone Mineral Density
  description: >-
    Generalized osteopenia with markedly reduced bone mineral density (e.g.,
    L2-L4 BMD z-score -4.7 in the index case), reflecting the collagen-related
    bone matrix defect.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His L2–L4 bone mineral density z-score=−4.7
    explanation: >-
      Documents markedly reduced bone mineral density in the OI type XIX index
      case.
- name: Short Stature
  description: >-
    Affected males have short stature, with severely affected adults reaching a
    final height comparable to a 5-6-year-old male.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both patients had numerous fractures of upper and lower extremity long
      bones during childhood, but fractures declined post puberty. Both have
      white sclerae, kyphoscoliosis with anterior vertebral wedging and short
      stature
    explanation: >-
      Documents short stature as a feature of OI type XIX in affected males.
- name: Bone Deformity
  description: >-
    Long-bone bowing (humeri, radii, tibiae) and striking tibial anterior
    angulation accompany the fragility of OI type XIX, 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:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a newborn, the proband was noted to have bowing of humeri, radii and
      tibiae, and fractures of femora, ribs and clavicles, as well as
      generalized osteopenia
    explanation: >-
      Documents long-bone bowing (bone deformity) in an OI type XIX proband.
- name: Scoliosis
  description: >-
    Scoliosis, including kyphoscoliosis with anterior vertebral wedging, is a
    recurrent spinal feature of OI type XIX.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both have white sclerae, kyphoscoliosis with anterior vertebral wedging
      and short stature
    explanation: >-
      Documents scoliosis (kyphoscoliosis with vertebral wedging) in OI type XIX.
- name: Blue Sclerae (Age-Dependent / Variable)
  description: >-
    Scleral hue is variable and age-dependent in OI type XIX: the young Thai
    proband had blue sclerae at age 2 years, whereas affected adult males in the
    same and the German pedigree had white sclerae. This age-dependent shift from
    blue to white sclerae contrasts with the persistently blue sclerae typical of
    classic dominant collagen-defect OI and is a useful clinical discriminator.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      his physical exam was notable for moderate short stature, blue sclerae,
      pectus carinatum and bowing of lower extremity long bones
    explanation: >-
      Documents blue sclerae in the young (2-year-old) MBTPS2-related OI proband;
      the description notes that adult males instead had white sclerae, so this
      phenotype is age-dependent.
- name: Dentinogenesis Imperfecta (Characteristically Absent)
  description: >-
    The characterized MBTPS2-related OI patients had normal teeth without
    dentinogenesis imperfecta. Recorded here as an explicitly absent phenotype:
    dentinogenesis imperfecta, a common feature of collagen-defect OI, was
    documented as absent, helping distinguish this signaling/proteolysis-pathway
    OI from the classic dominant forms it otherwise resembles.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    modifier: ABSENT
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There are no signs of dentinogenesis imperfecta and the sclerae are white.
    explanation: >-
      Documents that dentinogenesis imperfecta was absent (normal teeth) in
      MBTPS2-related OI, an explicitly negative discriminating feature.
- name: Pectus Deformity
  description: >-
    Anterior chest-wall (pectus) deformity is a recurrent feature of OI type XIX,
    presenting as pectus carinatum in the Thai proband and severe pectus excavatum
    in the German maternal uncle, reflecting thoracic-cage involvement in the
    generalized bone dysplasia.
  phenotype_term:
    preferred_term: Pectus deformity (pectus carinatum and pectus excavatum)
    term:
      id: HP:0000766
      label: Abnormal sternum morphology
  evidence:
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      his physical exam was notable for moderate short stature, blue sclerae,
      pectus carinatum and bowing of lower extremity long bones
    explanation: >-
      Documents pectus carinatum in the MBTPS2-related OI proband.
  - reference: PMID:27380894
    reference_title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He has a severe connatal pectus excavatum.
    explanation: >-
      Documents severe pectus excavatum in an adult MBTPS2-related OI patient,
      showing the pectus deformity spans both carinatum and excavatum forms.
datasets: []
references:
- reference: PMID:27380894
  title: "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews

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References & Deep Research

References

PMID:27380894

MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked 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.

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