Osteogenesis Imperfecta Type XI

Mendelian MONDO:0012592 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XI (OI type XI) is an autosomal recessive, moderately severe to progressive-deforming brittle bone disease caused by biallelic loss-of-function variants in FKBP10, the gene encoding FKBP65, a 65 kDa endoplasmic-reticulum-resident peptidyl-prolyl cis-trans isomerase (immunophilin) and molecular chaperone that participates in type I procollagen folding and maturation. Unlike the prolyl 3-hydroxylation complex defects of OI types VII/VIII/IX, the principal molecular consequence of FKBP65 loss is not a generalized collagen-folding failure: helix folding, chain incorporation and melting temperature are largely preserved. Instead, FKBP65 is required for hydroxylation of the collagen telopeptide lysyl residues that form the intermolecular cross-links of bone collagen — acting through (or alongside) the lysyl hydroxylase LH2 (PLOD2) — so its absence produces diminished telopeptide lysyl hydroxylation, markedly reduced collagen cross-linking, and reduced deposition of collagen into a sparse, disorganized extracellular matrix. The resulting structurally inadequate bone matrix mineralizes abnormally, yielding low bone mass, recurrent fractures, bone deformity, progressive scoliosis and short stature. OI type XI sits on a phenotypic continuum with Bruck syndrome (OI with congenital joint contractures): FKBP10 mutations cause both contracture-free recessive OI and Bruck-syndrome-like OI with congenital contractures, and the FKBP10/PLOD2 telopeptide-cross-linking axis explains the mechanistic overlap between FKBP10-related OI and PLOD2-related Bruck syndrome type II. The disorder was first defined as a distinct recessive OI in consanguineous Turkish and Mexican-American kindreds (Alanay et al., 2010).

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1
Inheritance
3
Pathophys.
7
Phenotypes
3
Pathograph
1
Genes
3
Medical Actions
5
References
🏷

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic (homozygous or compound heterozygous) loss-of-function FKBP10 variants; heterozygous carriers are clinically unaffected.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20362275 SUPPORT Human Clinical
"We studied a cohort of five consanguineous Turkish families, originating from the Black Sea region of Turkey, with moderately severe recessively inherited OI and identified a novel locus for OI on chromosome 17. In these families, and in a Mexican-American family, homozygosity for mutations in..."
Establishes the autosomal recessive inheritance of OI type XI from biallelic (homozygous) FKBP10 (FKBP65) loss-of-function variants in consanguineous kindreds.
⚙

Pathophysiology

3
FKBP10 Loss Eliminates the ER Chaperone/Isomerase FKBP65
FKBP10 encodes FKBP65, a 65 kDa endoplasmic-reticulum-resident peptidyl-prolyl cis-trans isomerase and immunophilin that acts as a chaperone in type I procollagen folding and maturation. Biallelic loss-of-function FKBP10 variants (frameshifts and premature termination codons causing mRNA instability, or missense variants causing loss of most of the protein) eliminate FKBP65 from the ER. In contrast to the prolyl 3-hydroxylation complex (CRTAP/P3H1/CyPB, deficient in OI types VII/VIII/IX), loss of FKBP65 leaves general collagen helical folding, chain incorporation and thermal stability largely intact, pointing to a more specialized role in collagen post-translational modification rather than bulk folding.
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.
protein folding (procollagen chaperoning by FKBP65) GO:0006457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein folding (procollagen chaperoning by FKBP65), annotated with protein folding (GO:0006457). GO:0006457 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Diminished Telopeptide Lysyl Hydroxylation and Collagen Cross-Linking Without FKBP65, hydroxylation of the collagen telopeptide lysines required for intermolecular cross-link formation is diminished, reducing collagen cross-linking.
Show evidence (3 references)
PMID:22949511 SUPPORT Human Clinical
"We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI."
Identifies FKBP10/FKBP65 (a 65 kDa prolyl cis-trans isomerase) loss as the proximal lesion in a large recessive-OI cohort.
PMID:22718341 SUPPORT In Vitro
"a child with moderate type XI OI has a homozygous FKBP10 mutation (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and FKBP65 protein is absent from proband cells."
Demonstrates that the type XI OI FKBP10 variant abolishes FKBP65 protein in patient cells, the proximal molecular defect.
PMID:22718341 SUPPORT In Vitro
"Normal chain incorporation, helix folding, and collagen T(m) support a minimal general collagen chaperone role for FKBP65."
Establishes that FKBP65 loss does not impair general collagen folding, distinguishing OI type XI mechanism from a generalized folding-chaperone defect.
Diminished Telopeptide Lysyl Hydroxylation and Collagen Cross-Linking
FKBP65 is required for hydroxylation of the telopeptide lysyl residues that form the intermolecular cross-links of bone collagen, acting through or alongside the lysyl hydroxylase LH2 (PLOD2) — possibly via its peptidyl-prolyl isomerase function granting LH2 access to the telopeptide lysines. In its absence, mass spectrometry shows near-absence of telopeptide lysine hydroxylation in secreted collagen, producing diminished intermolecular cross-linking. This shared telopeptide-cross-linking axis mechanistically links FKBP10-related OI to PLOD2-related Bruck syndrome type II.
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.
peptidyl-lysine hydroxylation (collagen telopeptide lysines) GO:0017185 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidyl-lysine hydroxylation (collagen telopeptide lysines), annotated with peptidyl-lysine hydroxylation (GO:0017185). GO:0017185 is a biological process from the Gene Ontology. ↓ DECREASED collagen biosynthetic process (post-translational maturation) GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen biosynthetic process (post-translational maturation), annotated with collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced Collagen Deposition, Defective Bone Matrix, and Fragility Undercrosslinked collagen is poorly deposited into the extracellular matrix, forming a sparse, disorganized, abnormally mineralized bone matrix that is mechanically fragile.
Show evidence (2 references)
PMID:22949511 SUPPORT Human Clinical
"there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues."
Documents diminished telopeptide lysyl hydroxylation and intermolecular cross-linking on FKBP65 loss, and the mechanistic overlap with PLOD2/LH2 Bruck syndrome type II.
PMID:22718341 SUPPORT In Vitro
"Mass spectrometry reveals absence of hydroxylation of the collagen telopeptide lysine involved in cross-linking, suggesting that FKBP65 is required for lysyl hydroxylase activity or access to type I collagen telopeptide lysines, perhaps through its function as a peptidylprolyl isomerase."
Provides direct mass-spectrometry evidence that FKBP65 loss abolishes telopeptide lysine hydroxylation, the cross-linking defect underlying the matrix abnormality.
Reduced Collagen Deposition, Defective Bone Matrix, and Fragility
The undercrosslinked collagen is deposited into the extracellular matrix in markedly reduced amounts despite near-normal secretion, producing sparse, disorganized collagen fibrils and a collagen-to-mineral matrix ratio far below normal. The structurally inadequate, abnormally mineralized bone matrix yields low bone mass and severe skeletal fragility, manifesting clinically as recurrent fractures, bone deformity, progressive scoliosis and short stature; in the Bruck-overlap arm of the spectrum, congenital joint contractures accompany the bone fragility.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ⚠ ABNORMAL 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
Show evidence (2 references)
PMID:22718341 SUPPORT In Vitro
"there is a dramatic decrease in collagen deposited in culture despite normal collagen secretion."
Documents the reduced extracellular-matrix collagen deposition that produces the defective bone matrix in OI type XI.
PMID:22718341 SUPPORT In Vitro
"Immunofluorescence shows sparse, disorganized collagen fibrils in proband matrix."
Demonstrates the sparse, disorganized collagen fibril architecture of the defective bone matrix underlying 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 XI 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

7
Eye 1
White Sclerae (Blue Sclerae Characteristically Absent) HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (1 reference)
PMID:22718341 SUPPORT Human Clinical
"white sclerae, and normal dentition"
The homozygous-FKBP10 (type XI) proband of this pedigree had white sclerae; blue sclerae, a hallmark of classical dominant OI, were absent. This case is the FKBP10-null branch, molecularly distinct from the PPIB (type IX) branch of the same pedigree.
Head and Neck 1
Normal Dentition (Dentinogenesis Imperfecta Characteristically Absent) HP:0000703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is absent Dentinogenesis imperfecta (HP:0000703). HP:0000703 is a phenotype from the Human Phenotype Ontology.
∅ ABSENT
Show evidence (1 reference)
PMID:22718341 SUPPORT Human Clinical
"white sclerae, and normal dentition"
The homozygous-FKBP10 (type XI) proband had normal dentition; dentinogenesis imperfecta was documented as absent.
Musculoskeletal 3
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:22949511 SUPPORT Human Clinical
"The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families."
Documents fractures as a core clinical effect of FKBP10 mutations in OI type XI.
Reduced Bone Mineral Density HP:0004349 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced bone mineral density (HP:0004349). HP:0004349 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22949511 SUPPORT Human Clinical
"These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result."
Documents abnormal bone mass and quality (reduced bone mineral density) resulting from FKBP10 deficiency.
Progressive Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive scoliosis, annotated with Scoliosis (HP:0002650), qualified as course progressive. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22949511 SUPPORT Human Clinical
"The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families."
Documents progressive scoliosis as a core clinical effect of FKBP10 mutations in OI type XI.
Growth 1
Growth Deficiency Growth delay HP:0001510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth delay (HP:0001510). HP:0001510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22949511 SUPPORT Human Clinical
"The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures"
Documents short stature (growth deficiency) as a clinical effect of FKBP10 mutations.
Other 1
Congenital Joint Contractures (Bruck-Syndrome Overlap) Congenital contracture HP:0002803 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital joint contractures, annotated with Congenital contracture (HP:0002803). HP:0002803 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20839288 SUPPORT Human Clinical
"Bruck syndrome is a recessive disorder featuring congenital contractures in addition to bone fragility"
Documents congenital contractures as the defining feature of the Bruck syndrome end of the FKBP10 phenotypic spectrum.
PMID:22949511 SUPPORT Human Clinical
"a high incidence of joint contractures at birth"
Documents the high incidence of congenital joint contractures in the FKBP10 cohort, the Bruck-overlap phenotype.
🧬

Genetic Associations

1
FKBP10 (FKBP65) Loss-of-Function Mutation (Causative)
Gene: FKBP10 (FKBP65, ER peptidyl-prolyl isomerase/chaperone) hgnc:18169 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FKBP10 (FKBP65, ER peptidyl-prolyl isomerase/chaperone), annotated with FKBP10 (hgnc:18169). hgnc:18169 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:20362275 SUPPORT Human Clinical
"homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified. Further, we determined that FKBP10 mutations affect type I procollagen secretion."
Identifies homozygous FKBP10 (FKBP65) mutations as the cause of recessive OI, defining the OI type XI gene.
PMID:20839288 SUPPORT Human Clinical
"Here we describe five families with OI-like bone fragility in association with congenital contractures who all had FKBP10 mutations. Therefore, we conclude that FKBP10 mutations are a cause of recessive osteogenesis imperfecta and Bruck syndrome"
Establishes FKBP10 mutations as a cause of both recessive OI and Bruck syndrome, documenting the contracture-associated end of the spectrum.
💊

Medical Actions

3
Bisphosphonate Therapy
Action: Bisphosphonate TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Bisphosphonate Therapy (NCIT:C198585). NCIT:C198585 is a clinical intervention from the NCI Thesaurus. NCIT:C198585
Intravenous bisphosphonates (e.g., pamidronate, zoledronic acid) are the pharmacological mainstay of severe OI, increasing bone mineral density and reducing fracture frequency. They are antiresorptive and do not correct the underlying collagen-cross-linking defect.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Bisphosphonates continue to be used most extensively in those with vertebral fractures, frequent long bone fractures, or more severe OI."
GeneReviews documents bisphosphonates as the mainstay pharmacotherapy for severe OI, the management category that applies to OI type XI.
Orthopedic Surgery and Intramedullary Rodding
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Intramedullary (telescoping) rod fixation and corrective osteotomy stabilize fracture-prone, deformed long bones; spinal surgery addresses progressive scoliosis. In FKBP10-related OI type XI, corrective orthopedic procedures and intramedullary rodding have been used to restore ambulation.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when indicated to provide anatomic positioning of limbs"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical and occupational therapy increase mobility and muscle strength, improve bone stability, and help prevent contractures and deformity — of particular relevance in the Bruck-overlap arm with congenital joint 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.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XI is suspected in an individual with moderately severe to progressive-deforming recessive OI (recurrent fractures, low bone mass, deformity, short stature, ± congenital joint contractures suggesting Bruck-syndrome overlap) when COL1A1/COL1A2 and the recessive 3-hydroxylation-complex genes (CRTAP, P3H1/LEPRE1, PPIB) are negative. Diagnosis is confirmed by identifying biallelic FKBP10 loss-of-function variants by gene-panel or exome sequencing. Supportive findings include absence of FKBP65 protein and biochemical demonstration of diminished collagen telopeptide lysyl hydroxylation and cross-linking.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20362275 SUPPORT Human Clinical
"homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that participates in type I procollagen folding, was identified."
Molecular identification of biallelic FKBP10 variants establishes the diagnosis of OI type XI.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XI
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 11
  term:
    id: MONDO:0012592
    label: osteogenesis imperfecta type 11
description: >-
  Osteogenesis imperfecta type XI (OI type XI) is an autosomal recessive,
  moderately severe to progressive-deforming brittle bone disease caused by
  biallelic loss-of-function variants in FKBP10, the gene encoding FKBP65, a
  65 kDa endoplasmic-reticulum-resident peptidyl-prolyl cis-trans isomerase
  (immunophilin) and molecular chaperone that participates in type I procollagen
  folding and maturation. Unlike the prolyl 3-hydroxylation complex defects of
  OI types VII/VIII/IX, the principal molecular consequence of FKBP65 loss is not
  a generalized collagen-folding failure: helix folding, chain incorporation and
  melting temperature are largely preserved. Instead, FKBP65 is required for
  hydroxylation of the collagen telopeptide lysyl residues that form the
  intermolecular cross-links of bone collagen — acting through (or alongside) the
  lysyl hydroxylase LH2 (PLOD2) — so its absence produces diminished telopeptide
  lysyl hydroxylation, markedly reduced collagen cross-linking, and reduced
  deposition of collagen into a sparse, disorganized extracellular matrix. The
  resulting structurally inadequate bone matrix mineralizes abnormally, yielding
  low bone mass, recurrent fractures, bone deformity, progressive scoliosis and
  short stature. OI type XI sits on a phenotypic continuum with Bruck syndrome
  (OI with congenital joint contractures): FKBP10 mutations cause both
  contracture-free recessive OI and Bruck-syndrome-like OI with congenital
  contractures, and the FKBP10/PLOD2 telopeptide-cross-linking axis explains the
  mechanistic overlap between FKBP10-related OI and PLOD2-related Bruck syndrome
  type II. The disorder was first defined as a distinct recessive OI in
  consanguineous Turkish and Mexican-American kindreds (Alanay et al., 2010).
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic (homozygous or compound
    heterozygous) loss-of-function FKBP10 variants; heterozygous carriers are
    clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20362275
    reference_title: "Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied a cohort of five consanguineous Turkish families, originating
      from the Black Sea region of Turkey, with moderately severe recessively
      inherited OI and identified a novel locus for OI on chromosome 17. In these
      families, and in a Mexican-American family, homozygosity for mutations in
      FKBP10, which encodes FKBP65, a chaperone that participates in type I
      procollagen folding, was identified.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XI from biallelic
      (homozygous) FKBP10 (FKBP65) loss-of-function variants in consanguineous
      kindreds.
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: FKBP10 Loss Eliminates the ER Chaperone/Isomerase FKBP65
  description: >-
    FKBP10 encodes FKBP65, a 65 kDa endoplasmic-reticulum-resident peptidyl-prolyl
    cis-trans isomerase and immunophilin that acts as a chaperone in type I
    procollagen folding and maturation. Biallelic loss-of-function FKBP10 variants
    (frameshifts and premature termination codons causing mRNA instability, or
    missense variants causing loss of most of the protein) eliminate FKBP65 from
    the ER. In contrast to the prolyl 3-hydroxylation complex (CRTAP/P3H1/CyPB,
    deficient in OI types VII/VIII/IX), loss of FKBP65 leaves general collagen
    helical folding, chain incorporation and thermal stability largely intact,
    pointing to a more specialized role in collagen post-translational
    modification rather than bulk folding.
  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 FKBP65)
    term:
      id: GO:0006457
      label: protein folding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans
      isomerase, FKBP65, in 38 members of 21 families with OI.
    explanation: >-
      Identifies FKBP10/FKBP65 (a 65 kDa prolyl cis-trans isomerase) loss as the
      proximal lesion in a large recessive-OI cohort.
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a child with moderate type XI OI has a homozygous FKBP10 mutation
      (c.1271_1272delCCinsA). Proband FKBP10 transcripts are 4% of control and
      FKBP65 protein is absent from proband cells.
    explanation: >-
      Demonstrates that the type XI OI FKBP10 variant abolishes FKBP65 protein in
      patient cells, the proximal molecular defect.
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Normal chain incorporation, helix folding, and collagen T(m) support a
      minimal general collagen chaperone role for FKBP65.
    explanation: >-
      Establishes that FKBP65 loss does not impair general collagen folding,
      distinguishing OI type XI mechanism from a generalized folding-chaperone
      defect.
  downstream:
  - target: Diminished Telopeptide Lysyl Hydroxylation and Collagen Cross-Linking
    description: >-
      Without FKBP65, hydroxylation of the collagen telopeptide lysines required
      for intermolecular cross-link formation is diminished, reducing collagen
      cross-linking.
- name: Diminished Telopeptide Lysyl Hydroxylation and Collagen Cross-Linking
  description: >-
    FKBP65 is required for hydroxylation of the telopeptide lysyl residues that
    form the intermolecular cross-links of bone collagen, acting through or
    alongside the lysyl hydroxylase LH2 (PLOD2) — possibly via its peptidyl-prolyl
    isomerase function granting LH2 access to the telopeptide lysines. In its
    absence, mass spectrometry shows near-absence of telopeptide lysine
    hydroxylation in secreted collagen, producing diminished intermolecular
    cross-linking. This shared telopeptide-cross-linking axis mechanistically
    links FKBP10-related OI to PLOD2-related Bruck syndrome type II.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: peptidyl-lysine hydroxylation (collagen telopeptide lysines)
    term:
      id: GO:0017185
      label: peptidyl-lysine hydroxylation
    modifier: DECREASED
  - preferred_term: collagen biosynthetic process (post-translational maturation)
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is diminished hydroxylation of the telopeptide lysyl residues involved
      in intermolecular cross-link formation in bone. The phenotype overlaps with
      that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the
      enzyme that hydroxylates the telopeptide lysyl residues.
    explanation: >-
      Documents diminished telopeptide lysyl hydroxylation and intermolecular
      cross-linking on FKBP65 loss, and the mechanistic overlap with PLOD2/LH2
      Bruck syndrome type II.
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mass spectrometry reveals absence of hydroxylation of the collagen
      telopeptide lysine involved in cross-linking, suggesting that FKBP65 is
      required for lysyl hydroxylase activity or access to type I collagen
      telopeptide lysines, perhaps through its function as a peptidylprolyl
      isomerase.
    explanation: >-
      Provides direct mass-spectrometry evidence that FKBP65 loss abolishes
      telopeptide lysine hydroxylation, the cross-linking defect underlying the
      matrix abnormality.
  downstream:
  - target: Reduced Collagen Deposition, Defective Bone Matrix, and Fragility
    description: >-
      Undercrosslinked collagen is poorly deposited into the extracellular matrix,
      forming a sparse, disorganized, abnormally mineralized bone matrix that is
      mechanically fragile.
- name: Reduced Collagen Deposition, Defective Bone Matrix, and Fragility
  description: >-
    The undercrosslinked collagen is deposited into the extracellular matrix in
    markedly reduced amounts despite near-normal secretion, producing sparse,
    disorganized collagen fibrils and a collagen-to-mineral matrix ratio far below
    normal. The structurally inadequate, abnormally mineralized bone matrix
    yields low bone mass and severe skeletal fragility, manifesting clinically as
    recurrent fractures, bone deformity, progressive scoliosis and short stature;
    in the Bruck-overlap arm of the spectrum, congenital joint contractures
    accompany the bone fragility.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      there is a dramatic decrease in collagen deposited in culture despite normal
      collagen secretion.
    explanation: >-
      Documents the reduced extracellular-matrix collagen deposition that produces
      the defective bone matrix in OI type XI.
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Immunofluorescence shows sparse, disorganized collagen fibrils in proband
      matrix.
    explanation: >-
      Demonstrates the sparse, disorganized collagen fibril architecture of the
      defective bone matrix underlying fragility.
genetic:
- name: FKBP10 (FKBP65) Loss-of-Function Mutation
  association: Causative
  gene_term:
    preferred_term: FKBP10 (FKBP65, ER peptidyl-prolyl isomerase/chaperone)
    term:
      id: hgnc:18169
      label: FKBP10
  notes: >-
    OI type XI is caused by biallelic loss-of-function variants in FKBP10, which
    encodes the 65 kDa ER peptidyl-prolyl cis-trans isomerase/chaperone FKBP65.
    Most reported alleles introduce premature termination codons or frameshifts
    (e.g., the recurrent c.831_832insC) leading to mRNA instability, or are
    missense variants that cause loss of most of the protein. The same gene
    underlies both contracture-free recessive OI and Bruck-syndrome-like OI with
    congenital contractures (FKBP10-related Bruck syndrome, often designated
    Bruck syndrome type 1), reflecting a phenotypic continuum.
  evidence:
  - reference: PMID:20362275
    reference_title: "Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that
      participates in type I procollagen folding, was identified. Further, we
      determined that FKBP10 mutations affect type I procollagen secretion.
    explanation: >-
      Identifies homozygous FKBP10 (FKBP65) mutations as the cause of recessive
      OI, defining the OI type XI gene.
  - reference: PMID:20839288
    reference_title: "Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe five families with OI-like bone fragility in association
      with congenital contractures who all had FKBP10 mutations. Therefore, we
      conclude that FKBP10 mutations are a cause of recessive osteogenesis
      imperfecta and Bruck syndrome
    explanation: >-
      Establishes FKBP10 mutations as a cause of both recessive OI and
      Bruck syndrome, documenting the contracture-associated end of the spectrum.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Bone fragility with recurrent fractures, frequently beginning at or near
    birth, the cardinal feature of OI type XI.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical effects of these mutations are short stature, a high incidence
      of joint contractures at birth and progressive scoliosis and fractures, but
      there is remarkable variability in phenotype even within families.
    explanation: >-
      Documents fractures as a core clinical effect of FKBP10 mutations in OI
      type XI.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mass / reduced bone mineral density reflecting the undercrosslinked,
    sparsely deposited, abnormally mineralized collagen matrix.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act
      during procollagen maturation to contribute to molecular stability and
      post-translational modification of type I procollagen, without which bone
      mass and quality are abnormal and fractures and contractures result.
    explanation: >-
      Documents abnormal bone mass and quality (reduced bone mineral density)
      resulting from FKBP10 deficiency.
- name: Growth Deficiency
  description: >-
    Short stature / growth deficiency, a consistent clinical feature of
    FKBP10-related OI type XI.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical effects of these mutations are short stature, a high incidence
      of joint contractures at birth and progressive scoliosis and fractures
    explanation: >-
      Documents short stature (growth deficiency) as a clinical effect of FKBP10
      mutations.
- name: Progressive Scoliosis
  description: >-
    Progressive scoliosis is a characteristic and consistent skeletal feature of
    FKBP10-related OI type XI, reflecting the mechanically inadequate,
    undercrosslinked bone matrix of the vertebral column; it is a distinguishing
    clinical effect reported across the FKBP10 cohorts alongside short stature,
    fractures and (in the Bruck-overlap arm) congenital contractures.
  phenotype_term:
    preferred_term: Progressive scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical effects of these mutations are short stature, a high incidence
      of joint contractures at birth and progressive scoliosis and fractures, but
      there is remarkable variability in phenotype even within families.
    explanation: >-
      Documents progressive scoliosis as a core clinical effect of FKBP10
      mutations in OI type XI.
- name: Congenital Joint Contractures (Bruck-Syndrome Overlap)
  description: >-
    Congenital joint contractures occur at high incidence in the Bruck-syndrome
    end of the FKBP10 phenotypic spectrum, distinguishing FKBP10-related Bruck
    syndrome from contracture-free recessive OI caused by the same gene. The
    contractures and bone fragility share the diminished-telopeptide-cross-linking
    mechanism that FKBP10-related disease holds in common with PLOD2-related
    Bruck syndrome type II.
  phenotype_term:
    preferred_term: Congenital joint contractures
    term:
      id: HP:0002803
      label: Congenital contracture
  evidence:
  - reference: PMID:20839288
    reference_title: "Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bruck syndrome is a recessive disorder featuring congenital contractures in
      addition to bone fragility
    explanation: >-
      Documents congenital contractures as the defining feature of the Bruck
      syndrome end of the FKBP10 phenotypic spectrum.
  - reference: PMID:22949511
    reference_title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a high incidence of joint contractures at birth
    explanation: >-
      Documents the high incidence of congenital joint contractures in the FKBP10
      cohort, the Bruck-overlap phenotype.
- name: White Sclerae (Blue Sclerae Characteristically Absent)
  description: >-
    Scleral hue in FKBP10 type XI OI is white-to-gray rather than the persistent
    blue sclerae typical of classical collagen-defect dominant OI. The molecularly
    confirmed FKBP10-null (type XI) proband had white sclerae. Recorded here as an
    explicitly absent phenotype: blue sclerae — a hallmark of collagen-defect OI —
    were not present, a feature that helps distinguish this chaperone/cross-linking
    OI from the classic dominant forms.
  phenotype_term:
    preferred_term: Blue sclerae
    modifier: ABSENT
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      white sclerae, and normal dentition
    explanation: >-
      The homozygous-FKBP10 (type XI) proband of this pedigree had white sclerae;
      blue sclerae, a hallmark of classical dominant OI, were absent. This case is
      the FKBP10-null branch, molecularly distinct from the PPIB (type IX) branch
      of the same pedigree.
- name: Normal Dentition (Dentinogenesis Imperfecta Characteristically Absent)
  description: >-
    The molecularly confirmed FKBP10-null (type XI) proband had normal dentition
    without dentinogenesis imperfecta. Recorded here as an explicitly absent
    phenotype: dentinogenesis imperfecta, a common feature of collagen-defect OI,
    was documented as absent in the primary human report.
  phenotype_term:
    preferred_term: Dentinogenesis imperfecta
    modifier: ABSENT
    term:
      id: HP:0000703
      label: Dentinogenesis imperfecta
  evidence:
  - reference: PMID:22718341
    reference_title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      white sclerae, and normal dentition
    explanation: >-
      The homozygous-FKBP10 (type XI) proband had normal dentition; dentinogenesis
      imperfecta was documented as absent.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XI is suspected in an individual with moderately severe to
    progressive-deforming recessive OI (recurrent fractures, low bone mass,
    deformity, short stature, ± congenital joint contractures suggesting
    Bruck-syndrome overlap) when COL1A1/COL1A2 and the recessive
    3-hydroxylation-complex genes (CRTAP, P3H1/LEPRE1, PPIB) are negative.
    Diagnosis is confirmed by identifying biallelic FKBP10 loss-of-function
    variants by gene-panel or exome sequencing. Supportive findings include
    absence of FKBP65 protein and biochemical demonstration of diminished
    collagen telopeptide lysyl hydroxylation and cross-linking.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20362275
    reference_title: "Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      homozygosity for mutations in FKBP10, which encodes FKBP65, a chaperone that
      participates in type I procollagen folding, was identified.
    explanation: >-
      Molecular identification of biallelic FKBP10 variants establishes the
      diagnosis of OI type XI.
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-cross-linking 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 XI.
- 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. In FKBP10-related OI type XI, corrective orthopedic procedures and
    intramedullary rodding have been used to restore ambulation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy increase mobility and muscle strength,
    improve bone stability, and help prevent contractures and deformity — of
    particular relevance in the Bruck-overlap arm with congenital joint
    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.
datasets: []
references:
- reference: PMID:20362275
  title: "Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta."
- reference: PMID:20839288
  title: "Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome."
- reference: PMID:22718341
  title: "Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix."
- reference: PMID:22949511
  title: "Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

5
PMID:20362275
Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:20839288
Mutations in FKBP10 cause recessive osteogenesis imperfecta and Bruck syndrome.
No top-level findings curated for this source.
PMID:22718341
Absence of FKBP10 in recessive type XI osteogenesis imperfecta leads to diminished collagen cross-linking and reduced collagen deposition in extracellular matrix.
No top-level findings curated for this source.
PMID:22949511
Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.