Osteogenesis Imperfecta Type X

Mendelian MONDO:0013459 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type X (OI type X) is a severe autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in SERPINH1, the gene encoding heat shock protein 47 (HSP47). HSP47 is an endoplasmic-reticulum-resident, collagen-specific molecular chaperone that binds collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen and is essential for correct folding of procollagen, accelerating and stabilizing triple-helix formation before pH-dependent dissociation at the ER/cis-Golgi boundary. Mechanistically HSP47 acts downstream of the CRTAP/P3H1/CyPB prolyl 3-hydroxylation complex (deficient in OI types VII/VIII/IX), monitoring the integrity of the type I procollagen triple helix as a late ER quality-control step. In OI type X the disease-causing missense variant (c.233T>C, p.Leu78Pro) destabilizes HSP47 and leads to its proteasomal degradation; loss of the chaperone allows type I procollagen to transit the ER too rapidly and to accumulate abnormally in the Golgi, with a fraction of secreted procollagen being protease-sensitive (helically compromised). The resulting defective, abnormally folded bone collagen matrix fails to mineralize normally, producing extreme skeletal fragility, recurrent congenital fractures, reduced bone mineral density, growth deficiency, and bone deformity. The disorder was first defined in a consanguineous human kindred (Christiansen et al., 2010) and is recapitulated by a naturally occurring recessive SERPINH1 missense mutation in Dachshunds.

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

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from a biallelic (homozygous) loss-of-function SERPINH1 missense variant; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20188343 SUPPORT Human Clinical
"We have identified an autosomal-recessive missense mutation (c.233T>C, p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe OI phenotype."
Establishes the autosomal recessive inheritance of OI type X from a biallelic SERPINH1 (HSP47) missense variant.
⚙

Pathophysiology

3
SERPINH1 Loss Eliminates the ER Collagen-Specific Chaperone HSP47
SERPINH1 encodes HSP47, an endoplasmic-reticulum-resident, collagen-specific molecular chaperone that binds collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen and is essential for its correct folding, accelerating and stabilizing triple-helix formation. The OI type X missense variant (p.Leu78Pro) destabilizes HSP47 and targets it for proteasomal degradation, so the chaperone is effectively absent from the ER. HSP47 acts downstream of the CRTAP/P3H1/CyPB prolyl 3-hydroxylation complex, functioning as a late ER folding chaperone and quality-control monitor rather than a collagen-modifying enzyme.
osteoblast CL:0000062 fibroblast CL:0000057
protein folding (procollagen chaperoning by HSP47) GO:0006457 ↓ DECREASED
Downstream
Impaired Procollagen Quality Control and Defective Secretion Without HSP47 to chaperone and monitor the triple helix, type I procollagen transits the ER too rapidly, misfolds, and accumulates abnormally in the Golgi.
Show evidence (3 references)
PMID:20188343 SUPPORT Human Clinical
"The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome."
Documents that the OI type X SERPINH1 variant eliminates ER HSP47 by proteasomal degradation, the proximal lesion of the disorder.
PMID:30541925 SUPPORT In Vitro
"Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident molecular chaperone essential for correct folding of procollagen in mammalian cells."
Defines HSP47 as the ER collagen-folding chaperone whose loss causes OI type X.
PMID:30541925 SUPPORT In Vitro
"Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen in the ER and can prevent its local unfolding or aggregate formation, resulting in accelerating triple-helix formation of procollagen."
Describes the molecular chaperone function of HSP47 in procollagen triple-helix folding that is lost in OI type X.
Impaired Procollagen Quality Control and Defective Secretion
HSP47 normally monitors the integrity of the type I procollagen triple helix at the ER/cis-Golgi boundary; in its absence the rate of transit from the ER to the Golgi is increased and helical structure is compromised. Type I procollagen accumulates abnormally in the Golgi of patient fibroblasts, and a fraction of the secreted type I procollagen is protease-sensitive, reflecting an improperly folded triple helix. The net result is secretion of structurally defective collagen.
fibroblast CL:0000057 osteoblast CL:0000062
collagen biosynthetic process GO:0032964 ⚠ ABNORMAL
Downstream
Defective Bone Collagen Matrix, Undermineralization, and Fragility Structurally defective, helically compromised collagen assembles into an abnormal bone extracellular matrix that fails to mineralize normally, producing skeletal fragility.
Show evidence (2 references)
PMID:20188343 SUPPORT In Vitro
"Type I procollagen accumulates in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen is protease sensitive."
Documents abnormal Golgi accumulation and protease-sensitive (misfolded) secreted procollagen in HSP47-deficient patient fibroblasts.
PMID:20188343 SUPPORT In Vitro
"These findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised."
Establishes HSP47's role as a triple-helix quality-control monitor whose loss accelerates ER-to-Golgi transit and compromises helical structure.
Defective Bone Collagen Matrix, Undermineralization, and Fragility
The misfolded, abnormally processed type I collagen assembles into a defective bone extracellular matrix with abnormal collagen fibril formation and impaired mineralization, yielding very low bone mineral density and severe bone fragility. Clinically this manifests as recurrent congenital fractures, bone deformity, and growth deficiency. The pivotal chaperone role of HSP47 in collagen matrix formation is underscored by the embryonic lethality of HSP47 gene disruption in mice from impaired collagen fibril formation.
osteoblast CL:0000062 chondrocyte CL:0000138
bone mineralization GO:0030282 ↓ DECREASED collagen fibril organization GO:0030199 ⚠ ABNORMAL
Show evidence (2 references)
PMID:30541925 SUPPORT Model Organism
"disruption of the Hsp47 gene in mice causes embryonic lethality due to impaired basement membrane and collagen fibril formation."
Demonstrates that loss of HSP47 impairs collagen fibril formation, the matrix defect underlying OI type X bone fragility.
PMID:23508630 SUPPORT Human Clinical
"SERPINH1, which encodes the collagen chaperone HSP47"
Places SERPINH1/HSP47 deficiency within the recessive OI genes whose mishandled collagen assembly produces fragile, abnormally mineralized bone.
⬡

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 X Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Head and Neck 1
Dentinogenesis Imperfecta (Variable — Absent in the Compound-Heterozygous Patient) Dentinogenesis imperfecta HP:0000703
∅ ABSENT
Show evidence (1 reference)
PMID:29520608 SUPPORT Human Clinical
"The patient suffered from multiple fractures, low bone mass, and bone deformities in the femur, without dentinogenesis imperfecta or hearing loss."
Documents absence of dentinogenesis imperfecta (and hearing loss) in the second, compound-heterozygous SERPINH1 patient, establishing dental involvement as variable rather than obligate in OI type X.
Limbs 1
Bone Deformity Bowing of the long bones HP:0006487
Show evidence (1 reference)
PMID:20188343 SUPPORT Human Clinical
"Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span."
Documents bone deformity (manifesting as long-bone bowing) as part of the OI phenotype caused by the SERPINH1 mutation.
Musculoskeletal 3
Recurrent Fractures Recurrent fractures HP:0002757
Show evidence (2 references)
PMID:20188343 SUPPORT Human Clinical
"Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span."
Documents bone fragility and fractures as the cardinal feature of the OI phenotype caused by the SERPINH1 mutation.
PMID:29520608 SUPPORT Human Clinical
"We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X."
A second, independent human OI type X patient presented with recurrent fractures, confirming this as the cardinal feature of SERPINH1-related OI (patient-specific rather than a generic OI characterization).
Reduced Bone Mineral Density Reduced bone mineral density HP:0004349
Show evidence (1 reference)
PMID:23508630 SUPPORT Human Clinical
"All cause fragile bone in infancy, which can include overmineralization or undermineralization defects as well as abnormal collagen posttranslational modifications."
Documents the undermineralization/abnormal collagen matrix that underlies the reduced bone mineral density of SERPINH1-related recessive OI.
Vertebral Compression Fractures Vertebral compression fracture HP:0002953
Show evidence (1 reference)
PMID:29520608 SUPPORT Human Clinical
"Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone fracture risk and reshaping the compressed vertebral bodies of this patient."
Documents compressed vertebral bodies (vertebral compression fracture) in a human OI type X patient, later reshaped under bisphosphonate therapy.
Growth 1
Growth Deficiency Growth delay HP:0001510
Show evidence (2 references)
PMID:20188343 SUPPORT Human Clinical
"Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span."
Documents short stature (growth deficiency) as part of the OI phenotype caused by the SERPINH1 mutation.
PMID:29520608 SUPPORT Human Clinical
"We identified novel compound heterozygous mutations in SERPINH1 in a Chinese boy suffering from recurrent fractures, femoral deformities, and growth retardation, which resulted in extremely rare autosomal recessive OI type X."
Documents growth retardation in a second, independent human OI type X patient, corroborating growth deficiency as a SERPINH1-related feature.
🧬

Genetic Associations

1
SERPINH1 (HSP47) Loss-of-Function Mutation (Causative)
Gene: SERPINH1 (HSP47, collagen-specific ER chaperone) hgnc:1546
Show evidence (3 references)
PMID:20188343 SUPPORT Human Clinical
"We have identified an autosomal-recessive missense mutation (c.233T>C, p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe OI phenotype."
Identifies the causative homozygous SERPINH1 missense variant defining OI type X in humans.
PMID:29520608 SUPPORT Human Clinical
"Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G in exon 2 and c.1214G>A in exon 5."
Documents a second, independent human OI type X patient with compound heterozygous SERPINH1 variants, broadening the allelic spectrum beyond the founding homozygous p.Leu78Pro allele.
PMID:19629171 SUPPORT Model Organism
"A missense mutation (c.977C>T, p.L326P) located in an evolutionary conserved domain was perfectly associated with the OI phenotype."
Documents a naturally occurring recessive SERPINH1 missense mutation causing OI in Dachshunds, a model that establishes SERPINH1 as an OI gene.
💊

Medical Actions

3
Bisphosphonate Therapy
Action: Bisphosphonate Therapy NCIT:C198585
Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of severe OI, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying collagen-chaperone defect.
Show evidence (2 references)
PMID:20301472 SUPPORT Human Clinical
"Bisphosphonates continue to be used most extensively in those with vertebral fractures, frequent long bone fractures, or more severe OI."
GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for severe OI, the management category that applies to OI type X.
PMID:29520608 SUPPORT Human Clinical
"Long-term treatment of BPs was effective in increasing BMD Z-score, reducing fracture incidence and reshaping vertebrae compression."
Provides SERPINH1-specific longitudinal evidence that long-term bisphosphonate therapy raised BMD, reduced fractures, and reshaped compressed vertebrae in an OI type X patient.
Orthopedic Surgery and Intramedullary Rodding
Action: surgical procedure MAXO:0000004
Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed long bones; spinal surgery addresses progressive scoliosis.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when indicated to provide anatomic positioning of limbs"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity.
Physical Therapy and Rehabilitation
Action: physical therapy MAXO:0000011
Physical and occupational therapy increase bone stability, improve mobility and muscle strength, and prevent contractures and deformity; early physical therapy follows brief post-fracture immobilization.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Fractures are treated with as short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed"
GeneReviews documents early physical therapy and brief immobilization as part of standard OI fracture rehabilitation.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type X
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 10
  term:
    id: MONDO:0013459
    label: osteogenesis imperfecta type 10
description: >-
  Osteogenesis imperfecta type X (OI type X) is a severe autosomal recessive
  brittle bone disease caused by biallelic loss-of-function variants in SERPINH1,
  the gene encoding heat shock protein 47 (HSP47). HSP47 is an
  endoplasmic-reticulum-resident, collagen-specific molecular chaperone that
  binds collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen and
  is essential for correct folding of procollagen, accelerating and stabilizing
  triple-helix formation before pH-dependent dissociation at the ER/cis-Golgi
  boundary. Mechanistically HSP47 acts downstream of the CRTAP/P3H1/CyPB prolyl
  3-hydroxylation complex (deficient in OI types VII/VIII/IX), monitoring the
  integrity of the type I procollagen triple helix as a late ER quality-control
  step. In OI type X the disease-causing missense variant (c.233T>C, p.Leu78Pro)
  destabilizes HSP47 and leads to its proteasomal degradation; loss of the
  chaperone allows type I procollagen to transit the ER too rapidly and to
  accumulate abnormally in the Golgi, with a fraction of secreted procollagen
  being protease-sensitive (helically compromised). The resulting defective,
  abnormally folded bone collagen matrix fails to mineralize normally, producing
  extreme skeletal fragility, recurrent congenital fractures, reduced bone
  mineral density, growth deficiency, and bone deformity. The disorder was first
  defined in a consanguineous human kindred (Christiansen et al., 2010) and is
  recapitulated by a naturally occurring recessive SERPINH1 missense mutation in
  Dachshunds.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from a biallelic (homozygous) loss-of-function
    SERPINH1 missense variant; heterozygous carriers are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified an autosomal-recessive missense mutation (c.233T>C,
      p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein
      HSP47, that leads to a severe OI phenotype.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type X from a
      biallelic SERPINH1 (HSP47) missense variant.
pathophysiology:
- name: SERPINH1 Loss Eliminates the ER Collagen-Specific Chaperone HSP47
  description: >-
    SERPINH1 encodes HSP47, an endoplasmic-reticulum-resident, collagen-specific
    molecular chaperone that binds collagenous (Gly-Xaa-Arg) repeats within
    triple-helical procollagen and is essential for its correct folding,
    accelerating and stabilizing triple-helix formation. The OI type X missense
    variant (p.Leu78Pro) destabilizes HSP47 and targets it for proteasomal
    degradation, so the chaperone is effectively absent from the ER. HSP47 acts
    downstream of the CRTAP/P3H1/CyPB prolyl 3-hydroxylation complex, functioning
    as a late ER folding chaperone and quality-control monitor rather than a
    collagen-modifying enzyme.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: protein folding (procollagen chaperoning by HSP47)
    term:
      id: GO:0006457
      label: protein folding
    modifier: DECREASED
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mutation results in degradation of the endoplasmic reticulum resident
      HSP47 via the proteasome.
    explanation: >-
      Documents that the OI type X SERPINH1 variant eliminates ER HSP47 by
      proteasomal degradation, the proximal lesion of the disorder.
  - reference: PMID:30541925
    reference_title: "Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident
      molecular chaperone essential for correct folding of procollagen in
      mammalian cells.
    explanation: >-
      Defines HSP47 as the ER collagen-folding chaperone whose loss causes OI
      type X.
  - reference: PMID:30541925
    reference_title: "Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical
      procollagen in the ER and can prevent its local unfolding or aggregate
      formation, resulting in accelerating triple-helix formation of procollagen.
    explanation: >-
      Describes the molecular chaperone function of HSP47 in procollagen
      triple-helix folding that is lost in OI type X.
  downstream:
  - target: Impaired Procollagen Quality Control and Defective Secretion
    description: >-
      Without HSP47 to chaperone and monitor the triple helix, type I procollagen
      transits the ER too rapidly, misfolds, and accumulates abnormally in the
      Golgi.
- name: Impaired Procollagen Quality Control and Defective Secretion
  description: >-
    HSP47 normally monitors the integrity of the type I procollagen triple helix
    at the ER/cis-Golgi boundary; in its absence the rate of transit from the ER
    to the Golgi is increased and helical structure is compromised. Type I
    procollagen accumulates abnormally in the Golgi of patient fibroblasts, and a
    fraction of the secreted type I procollagen is protease-sensitive, reflecting
    an improperly folded triple helix. The net result is secretion of structurally
    defective collagen.
  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 biosynthetic process
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Type I procollagen accumulates in the Golgi of fibroblasts from the
      affected individual and a population of the secreted type I procollagen is
      protease sensitive.
    explanation: >-
      Documents abnormal Golgi accumulation and protease-sensitive (misfolded)
      secreted procollagen in HSP47-deficient patient fibroblasts.
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings suggest that HSP47 monitors the integrity of the triple
      helix of type I procollagen at the ER/cis-Golgi boundary and, when absent,
      the rate of transit from the ER to the Golgi is increased and helical
      structure is compromised.
    explanation: >-
      Establishes HSP47's role as a triple-helix quality-control monitor whose
      loss accelerates ER-to-Golgi transit and compromises helical structure.
  downstream:
  - target: Defective Bone Collagen Matrix, Undermineralization, and Fragility
    description: >-
      Structurally defective, helically compromised collagen assembles into an
      abnormal bone extracellular matrix that fails to mineralize normally,
      producing skeletal fragility.
- name: Defective Bone Collagen Matrix, Undermineralization, and Fragility
  description: >-
    The misfolded, abnormally processed type I collagen assembles into a defective
    bone extracellular matrix with abnormal collagen fibril formation and impaired
    mineralization, yielding very low bone mineral density and severe bone
    fragility. Clinically this manifests as recurrent congenital fractures, bone
    deformity, and growth deficiency. The pivotal chaperone role of HSP47 in
    collagen matrix formation is underscored by the embryonic lethality of HSP47
    gene disruption in mice from impaired collagen fibril formation.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30541925
    reference_title: "Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      disruption of the Hsp47 gene in mice causes embryonic lethality due to
      impaired basement membrane and collagen fibril formation.
    explanation: >-
      Demonstrates that loss of HSP47 impairs collagen fibril formation, the
      matrix defect underlying OI type X bone fragility.
  - reference: PMID:23508630
    reference_title: "Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SERPINH1, which encodes the collagen chaperone HSP47
    explanation: >-
      Places SERPINH1/HSP47 deficiency within the recessive OI genes whose
      mishandled collagen assembly produces fragile, abnormally mineralized bone.
genetic:
- name: SERPINH1 (HSP47) Loss-of-Function Mutation
  association: Causative
  gene_term:
    preferred_term: SERPINH1 (HSP47, collagen-specific ER chaperone)
    term:
      id: hgnc:1546
      label: SERPINH1
  notes: >-
    OI type X is caused by a biallelic loss-of-function variant in SERPINH1, the
    gene encoding the collagen-specific ER chaperone HSP47. The defining human
    allele is a homozygous missense variant (c.233T>C, p.Leu78Pro) that
    destabilizes HSP47 and leads to its proteasomal degradation. The allelic
    spectrum is broader than this founding homozygous allele: a second,
    non-consanguineous patient carried compound heterozygous SERPINH1 variants
    (c.149T>G in exon 2 and c.1214G>A in exon 5), expanding the genotype of this
    extremely rare disorder beyond a single founder allele. A naturally
    occurring recessive SERPINH1 missense mutation (c.977C>T, p.L326P) causes an
    analogous OI in Dachshunds, establishing SERPINH1 as a conserved OI gene.
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified an autosomal-recessive missense mutation (c.233T>C,
      p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein
      HSP47, that leads to a severe OI phenotype.
    explanation: >-
      Identifies the causative homozygous SERPINH1 missense variant defining OI
      type X in humans.
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound heterozygous variants were found in SERPINH1 as follows: c.149 T>G
      in exon 2 and c.1214G>A in exon 5.
    explanation: >-
      Documents a second, independent human OI type X patient with compound
      heterozygous SERPINH1 variants, broadening the allelic spectrum beyond the
      founding homozygous p.Leu78Pro allele.
  - reference: PMID:19629171
    reference_title: "A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A missense mutation (c.977C>T, p.L326P) located in an evolutionary
      conserved domain was perfectly associated with the OI phenotype.
    explanation: >-
      Documents a naturally occurring recessive SERPINH1 missense mutation
      causing OI in Dachshunds, a model that establishes SERPINH1 as an OI gene.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent fractures, frequently congenital, the
    cardinal feature of OI type X.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is characterized by bone fragility and
      fractures that may be accompanied by bone deformity, dentinogenesis
      imperfecta, short stature, and shortened life span.
    explanation: >-
      Documents bone fragility and fractures as the cardinal feature of the OI
      phenotype caused by the SERPINH1 mutation.
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified novel compound heterozygous mutations in SERPINH1 in a
      Chinese boy suffering from recurrent fractures, femoral deformities, and
      growth retardation, which resulted in extremely rare autosomal recessive OI
      type X.
    explanation: >-
      A second, independent human OI type X patient presented with recurrent
      fractures, confirming this as the cardinal feature of SERPINH1-related OI
      (patient-specific rather than a generic OI characterization).
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mineral density and skeletal undermineralization reflecting the
    defective collagen matrix and impaired mineralization.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:23508630
    reference_title: "Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All cause fragile bone in infancy, which can include overmineralization or
      undermineralization defects as well as abnormal collagen posttranslational
      modifications.
    explanation: >-
      Documents the undermineralization/abnormal collagen matrix that underlies
      the reduced bone mineral density of SERPINH1-related recessive OI.
- name: Growth Deficiency
  description: >-
    Growth deficiency with short stature, part of the severe OI phenotype caused
    by SERPINH1 deficiency.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is characterized by bone fragility and
      fractures that may be accompanied by bone deformity, dentinogenesis
      imperfecta, short stature, and shortened life span.
    explanation: >-
      Documents short stature (growth deficiency) as part of the OI phenotype
      caused by the SERPINH1 mutation.
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified novel compound heterozygous mutations in SERPINH1 in a
      Chinese boy suffering from recurrent fractures, femoral deformities, and
      growth retardation, which resulted in extremely rare autosomal recessive OI
      type X.
    explanation: >-
      Documents growth retardation in a second, independent human OI type X
      patient, corroborating growth deficiency as a SERPINH1-related feature.
- name: Bone Deformity
  description: >-
    Bone deformity, including bowing of the long bones, accompanies the fragility
    and recurrent fractures in OI type X, reflecting the structurally defective,
    mechanically weak bone.
  phenotype_term:
    preferred_term: Bone deformity (bowing of the long bones)
    term:
      id: HP:0006487
      label: Bowing of the long bones
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is characterized by bone fragility and
      fractures that may be accompanied by bone deformity, dentinogenesis
      imperfecta, short stature, and shortened life span.
    explanation: >-
      Documents bone deformity (manifesting as long-bone bowing) as part of the
      OI phenotype caused by the SERPINH1 mutation.
- name: Vertebral Compression Fractures
  description: >-
    Vertebral compression is part of the severe skeletal fragility of OI type X.
    A second, independent SERPINH1 patient had compressed vertebral bodies that
    were reshaped by long-term bisphosphonate therapy, documenting vertebral
    compression fracture as a feature of the disorder.
  phenotype_term:
    preferred_term: Vertebral compression fracture
    term:
      id: HP:0002953
      label: Vertebral compression fracture
  evidence:
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bisphosphonates could be helpful in increasing BMD Z-score, reducing bone
      fracture risk and reshaping the compressed vertebral bodies of this
      patient.
    explanation: >-
      Documents compressed vertebral bodies (vertebral compression fracture) in
      a human OI type X patient, later reshaped under bisphosphonate therapy.
- name: Dentinogenesis Imperfecta (Variable — Absent in the Compound-Heterozygous Patient)
  description: >-
    Dental involvement is variable in OI type X rather than an obligate feature.
    Dentinogenesis imperfecta is a general OI hallmark and is described in the
    founding SERPINH1 kindred, but the second, independent human patient was
    explicitly reported to lack dentinogenesis imperfecta (and hearing loss).
    Recorded here as an explicitly documented-absent instance to flag the
    inconsistent reporting of dental involvement across the two characterized
    human cases; it is deliberately not asserted as a disease-level absent
    phenotype given the variability.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    modifier: ABSENT
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient suffered from multiple fractures, low bone mass, and bone
      deformities in the femur, without dentinogenesis imperfecta or hearing
      loss.
    explanation: >-
      Documents absence of dentinogenesis imperfecta (and hearing loss) in the
      second, compound-heterozygous SERPINH1 patient, establishing dental
      involvement as variable rather than obligate in OI type X.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type X is suspected in an infant with severe recessive OI (recurrent
    congenital fractures, low bone mineral density, deformity) when COL1A1/COL1A2
    and the recessive 3-hydroxylation-complex genes (CRTAP, P3H1/LEPRE1, PPIB)
    are negative. Diagnosis is confirmed by identifying a biallelic SERPINH1
    (HSP47) loss-of-function variant by gene-panel or exome sequencing.
    Supportive cellular findings include proteasomal loss of HSP47 with abnormal
    Golgi accumulation of type I procollagen.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:20188343
    reference_title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified an autosomal-recessive missense mutation (c.233T>C,
      p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein
      HSP47, that leads to a severe OI phenotype.
    explanation: >-
      Molecular identification of a biallelic SERPINH1 variant establishes the
      diagnosis of OI type X.
treatments:
- name: Bisphosphonate Therapy
  description: >-
    Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the
    pharmacological mainstay of severe OI, increasing bone mineral density and
    reducing fracture frequency. They are antiresorptive and do not correct the
    underlying collagen-chaperone defect.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bisphosphonates continue to be used most extensively in those with
      vertebral fractures, frequent long bone fractures, or more severe OI.
    explanation: >-
      GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for
      severe OI, the management category that applies to OI type X.
  - reference: PMID:29520608
    reference_title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Long-term treatment of BPs was effective in increasing BMD Z-score,
      reducing fracture incidence and reshaping vertebrae compression.
    explanation: >-
      Provides SERPINH1-specific longitudinal evidence that long-term
      bisphosphonate therapy raised BMD, reduced fractures, and reshaped
      compressed vertebrae in an OI type X patient.
- name: Orthopedic Surgery and Intramedullary Rodding
  description: >-
    Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize
    fracture-prone, deformed long bones; spinal surgery addresses progressive
    scoliosis.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      label: surgical procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy increase bone stability, improve mobility
    and muscle strength, and prevent contractures and deformity; early physical
    therapy follows brief post-fracture immobilization.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fractures are treated with as
      short a period of immobility as is practical, small and lightweight casts, and
      physical therapy as soon as casts are removed
    explanation: >-
      GeneReviews documents early physical therapy and brief immobilization as
      part of standard OI fracture rehabilitation.
datasets: []
references:
- reference: PMID:20188343
  title: "Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta."
- reference: PMID:19629171
  title: "A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta."
- reference: PMID:29520608
  title: "Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X."
- reference: PMID:30541925
  title: "Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease."
- reference: PMID:23508630
  title: "Bone collagen: new clues to its mineralization mechanism from recessive osteogenesis imperfecta."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

6
PMID:20188343
Homozygosity for a missense mutation in SERPINH1, which encodes the collagen chaperone protein HSP47, results in severe recessive osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:19629171
A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:29520608
Novel compound heterozygous mutations in SERPINH1 cause rare autosomal recessive osteogenesis imperfecta type X.
No top-level findings curated for this source.
PMID:30541925
Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease.
No top-level findings curated for this source.
PMID:23508630
Bone collagen: new clues to its mineralization mechanism from recessive 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.