Osteogenesis Imperfecta Type XVI

Mendelian MONDO:0014544 Pathograph 3 Show in embeddings browser Osteogenesis imperfecta

Osteogenesis imperfecta type XVI (OI type XVI) is a severe autosomal recessive brittle bone disease caused by biallelic loss-of-function variants in CREB3L1, the gene encoding OASIS (old astrocyte specifically induced substance). OASIS is an endoplasmic-reticulum-stress-induced bZIP (basic leucine zipper) transcription factor of the CREB/ATF family that carries a transmembrane domain and is activated by regulated intramembrane proteolysis (RIP) in response to ER stress, releasing a cytosolic/nuclear transcriptional fragment. OASIS is highly expressed in osteoblasts, where it directly activates transcription of the type I collagen gene COL1A1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter, and contributes to secretion of bone matrix proteins; its expression and proteolytic processing are induced by BMP2 signaling required for bone formation. Biallelic loss-of-function of CREB3L1 — first described as a homozygous 11p11.2 contiguous genomic deletion, and subsequently as nonsense (premature stop) and missense point variants — reduces COL1A1 transcriptional activation and type I collagen synthesis by osteoblasts, yielding a defective, collagen-poor bone matrix with low bone mass and extreme skeletal fragility. The phenotype spans perinatally lethal disease to severe OI surviving infancy, with recurrent prenatal and postnatal fractures, reduced bone mineral density, growth deficiency, and bone deformity; heterozygous carriers are mildly or unaffected. The disorder is recapitulated by the OASIS-deficient (Creb3l1/OASIS-/-) mouse, which exhibits severe osteopenia, decreased bone-matrix type I collagen, and spontaneous fractures.

Ask OpenScientist

Ask a research question about Osteogenesis Imperfecta Type XVI. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

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

Classifications

ISDS Skeletal Nosology
osteogenesis imperfecta and decreased bone density
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance from biallelic loss-of-function CREB3L1 (OASIS) variants; heterozygous carriers exhibit a mild or no phenotype.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:24079343 SUPPORT Human Clinical
"We detected a homozygous genomic deletion of CREB3L1 in a family with severe OI."
Establishes the autosomal recessive inheritance of OI type XVI from a biallelic (homozygous) CREB3L1 loss-of-function lesion.
PMID:29936144 SUPPORT Human Clinical
"A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes."
Confirms recessive inheritance with an unaffected heterozygous family background in a molecularly defined OI type XVI case.
⚙

Pathophysiology

3
CREB3L1 Loss Eliminates the ER-Stress Transducer OASIS in Osteoblasts
CREB3L1 encodes OASIS, a bZIP transcription factor of the CREB/ATF family that has a transmembrane domain and is processed by regulated intramembrane proteolysis (RIP) in response to ER stress; it is highly expressed in osteoblasts. Biallelic loss-of-function CREB3L1 variants (the original 11p11.2 contiguous deletion, premature stop codons, or missense variants in the bZIP domain) eliminate or inactivate OASIS. OASIS expression and its RIP processing are induced by BMP2 signaling, which is required for bone formation, linking ER-stress-induced OASIS signaling to osteoblast function.
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.
response to endoplasmic reticulum stress (OASIS RIP activation) GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal response to endoplasmic reticulum stress (OASIS RIP activation), annotated with response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ⚠ ABNORMAL osteoblast differentiation (OASIS-dependent) GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal osteoblast differentiation (OASIS-dependent), annotated with osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced Transcriptional Activation of COL1A1 and Type I Collagen Synthesis Loss of OASIS removes the transcriptional activator that drives osteoblast-specific COL1A1 expression, reducing type I collagen synthesis and bone-matrix protein secretion.
Show evidence (3 references)
PMID:24079343 SUPPORT Human Clinical
"CREB3L1 encodes OASIS, an endoplasmic reticulum-stress transducer that regulates type I procollagen expression during murine bone formation."
Defines OASIS as the ER-stress transducer encoded by CREB3L1 whose loss causes OI type XVI.
PMID:19767743 SUPPORT Model Organism
"OASIS is processed by regulated intramembrane proteolysis (RIP) in response to ER stress, and is highly expressed in osteoblasts."
Documents that OASIS is an osteoblast-enriched ER-stress transducer activated by regulated intramembrane proteolysis, the function lost in OI type XVI.
PMID:30657919 SUPPORT In Vitro
"the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development."
Establishes the role of OASIS in osteoblast differentiation during bone development, disrupted by CREB3L1 loss-of-function.
Reduced Transcriptional Activation of COL1A1 and Type I Collagen Synthesis
OASIS directly activates transcription of the type I collagen gene COL1A1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter and contributes to the secretion of bone matrix proteins. When OASIS is lost or its DNA-binding/bZIP activity is impaired, COL1A1 transcriptional activation falls and osteoblasts synthesize markedly less type I collagen. In OASIS-deficient human osteoblasts, CREB3L1 mRNA and collagen I are reduced and the rough ER is ultrastructurally abnormal; in mice, OASIS-/- osteoblasts show decreased type I collagen in the bone matrix and an abnormally expanded rough ER engorged with bone matrix proteins, reflecting impaired collagen production and secretion.
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.
regulation of COL1A1 transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of COL1A1 transcription by RNA polymerase II, annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↓ DECREASED collagen biosynthetic process (type I collagen) GO:0032964 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased collagen biosynthetic process (type I collagen), annotated with collagen biosynthetic process (GO:0032964). GO:0032964 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Collagen-Poor Bone Matrix, Low Bone Mass, and Skeletal Fragility Deficient osteoblast type I collagen synthesis produces a collagen-poor, defective bone extracellular matrix with low bone mass and reduced mechanical strength.
Show evidence (3 references)
PMID:19767743 SUPPORT Model Organism
"Here we identify the gene for type 1 collagen, Col1a1, as a target of OASIS, and demonstrate that OASIS activates the transcription of Col1a1 through an unfolded protein response element (UPRE)-like sequence in the osteoblast-specific Col1a1 promoter region."
Establishes that OASIS transcriptionally activates COL1A1, the function whose loss reduces type I collagen synthesis in OI type XVI.
PMID:30657919 SUPPORT In Vitro
"In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability."
Demonstrates that a pathogenic CREB3L1 bZIP-domain missense variant decreases OASIS-mediated type I collagen transcriptional activation.
PMID:29936144 SUPPORT In Vitro
"Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%) and FB (21%); however, collagen I levels were only reduced in hOBs (5-10%)."
Documents markedly reduced CREB3L1 expression and an osteoblast-specific reduction of type I collagen in OASIS-deficient human cells.
Collagen-Poor Bone Matrix, Low Bone Mass, and Skeletal Fragility
Reduced osteoblast type I collagen production yields a defective, collagen-deficient bone extracellular matrix with low trabecular thickness, reduced mineral apposition, and impaired mechanical strength, producing very low bone mass and severe skeletal fragility. Clinically this manifests as recurrent prenatal and postnatal fractures, reduced bone mineral density, growth deficiency, and bone deformity. The OASIS-deficient (OASIS-/-) mouse recapitulates the disorder with severe osteopenia, decreased bone-matrix type I collagen, dysfunctional osteoblasts, and spontaneous fractures.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology.
bone mineralization GO:0030282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased bone mineralization (GO:0030282). GO:0030282 is a biological process from the Gene Ontology. ↓ DECREASED ossification GO:0001503 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ossification (GO:0001503). GO:0001503 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:19767743 SUPPORT Model Organism
"OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins."
Demonstrates that OASIS loss produces a collagen-poor bone matrix and severe osteopenia, the matrix defect underlying OI type XVI fragility.
PMID:29936144 SUPPORT Human Clinical
"Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization."
Documents the abnormal human bone matrix (low trabecular thickness and mineral apposition) underlying the skeletal fragility of OI type XVI.
⬡

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 XVI 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
Eye 1
Blue Sclerae HP:0000592 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blue sclerae (HP:0000592). HP:0000592 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29936144 SUPPORT Human Clinical
"The proband, a boy with severe OI, had blue sclera and tooth agenesis."
Documents blue sclerae in a molecularly confirmed (homozygous CREB3L1 stop codon) OI type XVI patient, a classic OI extraskeletal feature.
Head and Neck 1
Tooth Agenesis HP:0009804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tooth agenesis (HP:0009804). HP:0009804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29936144 SUPPORT Human Clinical
"The proband, a boy with severe OI, had blue sclera and tooth agenesis."
Documents tooth agenesis in a molecularly confirmed OI type XVI patient, a dental anomaly in the CREB3L1 (OASIS)-related phenotype.
Limbs 1
Bone Deformity Bowing of the long bones HP:0006487 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bone deformity (bowing of the long bones), annotated with Bowing of the long bones (HP:0006487). HP:0006487 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20024590 SUPPORT Model Organism
"OASIS-/- mice exhibit severe osteopenia involving a decrease in type I collagen in the bone matrix and a dysfunction of osteoblasts, which show abnormal expansion of the rough ER. These phenotypic features of osteopenia are similar to those observed in OI type I."
Establishes the fragile, deformity-prone bone of the OASIS-deficient model that parallels human OI; long-bone deformity reflects this weak matrix.
Musculoskeletal 2
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:29936144 SUPPORT Human Clinical
"Clinical response to life-long bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures."
Documents repeated (recurrent) fractures as a cardinal feature of OI type XVI in a molecularly confirmed patient.
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 (2 references)
PMID:19767743 SUPPORT Model Organism
"OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type I collagen in the bone matrix and a decline in the activity of osteoblasts, which showed abnormally expanded rough ER, containing of a large amount of bone matrix proteins."
Model-organism evidence that OASIS deficiency produces severe osteopenia (reduced bone mineral density), the phenotype seen in OI type XVI.
PMID:29936144 SUPPORT Human Clinical
"Bone histomorphometry and qBEI were similar to collagen I OI, with low trabecular thickness and mineral apposition rate, and increased bone matrix mineralization."
Human bone analysis documents the low-bone-mass, abnormal-mineralization phenotype of OI type XVI.
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:24079343 SUPPORT Human Clinical
"Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous brittle bone disorder."
Anchors OI type XVI within the brittle bone disorder spectrum whose severe forms include growth deficiency; supplementary to the model-organism small body size.
🧬

Genetic Associations

1
CREB3L1 (OASIS) Loss-of-Function Mutations (Causative)
Gene: CREB3L1 (OASIS, ER-stress bZIP transcription factor) hgnc:18856 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CREB3L1 (OASIS, ER-stress bZIP transcription factor), annotated with CREB3L1 (hgnc:18856). hgnc:18856 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:24079343 SUPPORT Human Clinical
"We detected a homozygous genomic deletion of CREB3L1 in a family with severe OI."
Identifies the founding causative lesion of OI type XVI, a homozygous 11p11.2 CREB3L1 deletion.
PMID:29936144 SUPPORT Human Clinical
"A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes."
Documents a homozygous CREB3L1 premature stop codon (point variant) as a cause of OI type XVI, expanding the allelic spectrum beyond the deletion.
PMID:30657919 SUPPORT Human Clinical
"a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain."
Documents a homozygous CREB3L1 bZIP-domain missense allele causing lethal OI type XVI, broadening the mutational 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; in OI type XVI, life-long bisphosphonate treatment steadily increased bone mineral density although fractures persisted. They are antiresorptive and do not correct the underlying transcriptional collagen defect. The OASIS-deficient mouse responds to risedronate with increased trabecular bone, supporting bisphosphonate efficacy in this disorder.
Show evidence (2 references)
PMID:29936144 SUPPORT Human Clinical
"Clinical response to life-long bisphosphonate treatment was as expected in severe OI with steadily increasing bone mineral density, but despite this the boy suffered repeated childhood fractures."
Documents the clinical use and partial response of bisphosphonate therapy in a molecularly confirmed OI type XVI patient.
PMID:20024590 SUPPORT Model Organism
"Histological and histomorphometric analyses revealed that the trabecular bones increased dramatically in OASIS-/- mice treated with RIS, owing to the inhibition of bone resorption."
Model-organism evidence that bisphosphonate (risedronate) treatment improves bone mass in the OASIS-deficient model of OI type XVI.
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. Surgical management is standard in severe OI such as OI type XVI.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"intramedullary rodding when indicated to provide anatomic positioning of limbs"
GeneReviews documents intramedullary rodding as standard orthopedic management for OI long-bone fractures and deformity, applicable to OI type XVI.
Physical Therapy and Rehabilitation
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physical and occupational therapy increase bone stability, improve mobility and muscle strength, and prevent contractures and deformity; early physical therapy follows brief post-fracture immobilization.
Show evidence (1 reference)
PMID:20301472 SUPPORT Human Clinical
"Fractures are treated with as short a period of immobility as is practical, small and lightweight casts, and physical therapy as soon as casts are removed"
GeneReviews documents early physical therapy and brief immobilization as part of standard OI fracture rehabilitation.
🔬

Diagnosis

1
Molecular Genetic Diagnosis
OI type XVI is suspected in an infant or fetus with severe recessive OI (recurrent prenatal/postnatal fractures, low bone mineral density, deformity) when COL1A1/COL1A2 and other recessive OI genes are negative. Diagnosis is confirmed by identifying a biallelic CREB3L1 (OASIS) loss-of-function lesion — the 11p11.2 contiguous deletion, a premature stop codon, or a bZIP-domain missense variant — by deletion analysis and gene-panel or exome sequencing. Supportive cellular findings include markedly reduced CREB3L1 mRNA and type I collagen in cultured osteoblasts with abnormal rough-ER ultrastructure.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:29936144 SUPPORT Human Clinical
"A homozygous CREB3L1 stop codon mutation was detected by sequencing, while several family members were heterozygotes."
Molecular sequencing identification of a biallelic CREB3L1 variant establishes the diagnosis of OI type XVI.
{ }

Source YAML

click to show 
name: Osteogenesis Imperfecta Type XVI
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Osteogenesis imperfecta type 16
  term:
    id: MONDO:0014544
    label: osteogenesis imperfecta type 16
description: >-
  Osteogenesis imperfecta type XVI (OI type XVI) is a severe autosomal recessive
  brittle bone disease caused by biallelic loss-of-function variants in CREB3L1,
  the gene encoding OASIS (old astrocyte specifically induced substance). OASIS
  is an endoplasmic-reticulum-stress-induced bZIP (basic leucine zipper)
  transcription factor of the CREB/ATF family that carries a transmembrane domain
  and is activated by regulated intramembrane proteolysis (RIP) in response to ER
  stress, releasing a cytosolic/nuclear transcriptional fragment. OASIS is highly
  expressed in osteoblasts, where it directly activates transcription of the type
  I collagen gene COL1A1 through an unfolded protein response element (UPRE)-like
  sequence in the osteoblast-specific Col1a1 promoter, and contributes to
  secretion of bone matrix proteins; its expression and proteolytic processing
  are induced by BMP2 signaling required for bone formation. Biallelic
  loss-of-function of CREB3L1 — first described as a homozygous 11p11.2 contiguous
  genomic deletion, and subsequently as nonsense (premature stop) and missense
  point variants — reduces COL1A1 transcriptional activation and type I collagen
  synthesis by osteoblasts, yielding a defective, collagen-poor bone matrix with
  low bone mass and extreme skeletal fragility. The phenotype spans perinatally
  lethal disease to severe OI surviving infancy, with recurrent prenatal and
  postnatal fractures, reduced bone mineral density, growth deficiency, and bone
  deformity; heterozygous carriers are mildly or unaffected. The disorder is
  recapitulated by the OASIS-deficient (Creb3l1/OASIS-/-) mouse, which exhibits
  severe osteopenia, decreased bone-matrix type I collagen, and spontaneous
  fractures.
parents:
- Osteogenesis imperfecta
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive inheritance from biallelic loss-of-function CREB3L1
    (OASIS) variants; heterozygous carriers exhibit a mild or no phenotype.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24079343
    reference_title: "Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected a homozygous genomic deletion of CREB3L1 in a family with
      severe OI.
    explanation: >-
      Establishes the autosomal recessive inheritance of OI type XVI from a
      biallelic (homozygous) CREB3L1 loss-of-function lesion.
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous CREB3L1 stop codon mutation was detected by sequencing, while
      several family members were heterozygotes.
    explanation: >-
      Confirms recessive inheritance with an unaffected heterozygous family
      background in a molecularly defined OI type XVI case.
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: CREB3L1 Loss Eliminates the ER-Stress Transducer OASIS in Osteoblasts
  description: >-
    CREB3L1 encodes OASIS, a bZIP transcription factor of the CREB/ATF family
    that has a transmembrane domain and is processed by regulated intramembrane
    proteolysis (RIP) in response to ER stress; it is highly expressed in
    osteoblasts. Biallelic loss-of-function CREB3L1 variants (the original
    11p11.2 contiguous deletion, premature stop codons, or missense variants in
    the bZIP domain) eliminate or inactivate OASIS. OASIS expression and its RIP
    processing are induced by BMP2 signaling, which is required for bone
    formation, linking ER-stress-induced OASIS signaling to osteoblast function.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress (OASIS RIP activation)
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: ABNORMAL
  - preferred_term: osteoblast differentiation (OASIS-dependent)
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24079343
    reference_title: "Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CREB3L1 encodes OASIS, an endoplasmic reticulum-stress transducer that
      regulates type I procollagen expression during murine bone formation.
    explanation: >-
      Defines OASIS as the ER-stress transducer encoded by CREB3L1 whose loss
      causes OI type XVI.
  - reference: PMID:19767743
    reference_title: "Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OASIS is processed by regulated intramembrane proteolysis (RIP) in
      response to ER stress, and is highly expressed in osteoblasts.
    explanation: >-
      Documents that OASIS is an osteoblast-enriched ER-stress transducer
      activated by regulated intramembrane proteolysis, the function lost in OI
      type XVI.
  - reference: PMID:30657919
    reference_title: "A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the endoplasmic reticulum stress transducer old astrocyte specifically
      induced substance (OASIS), which has an important role in osteoblast
      differentiation during bone development.
    explanation: >-
      Establishes the role of OASIS in osteoblast differentiation during bone
      development, disrupted by CREB3L1 loss-of-function.
  downstream:
  - target: Reduced Transcriptional Activation of COL1A1 and Type I Collagen Synthesis
    description: >-
      Loss of OASIS removes the transcriptional activator that drives
      osteoblast-specific COL1A1 expression, reducing type I collagen synthesis
      and bone-matrix protein secretion.
- name: Reduced Transcriptional Activation of COL1A1 and Type I Collagen Synthesis
  description: >-
    OASIS directly activates transcription of the type I collagen gene COL1A1
    through an unfolded protein response element (UPRE)-like sequence in the
    osteoblast-specific Col1a1 promoter and contributes to the secretion of bone
    matrix proteins. When OASIS is lost or its DNA-binding/bZIP activity is
    impaired, COL1A1 transcriptional activation falls and osteoblasts synthesize
    markedly less type I collagen. In OASIS-deficient human osteoblasts, CREB3L1
    mRNA and collagen I are reduced and the rough ER is ultrastructurally
    abnormal; in mice, OASIS-/- osteoblasts show decreased type I collagen in the
    bone matrix and an abnormally expanded rough ER engorged with bone matrix
    proteins, reflecting impaired collagen production and secretion.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: regulation of COL1A1 transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  - preferred_term: collagen biosynthetic process (type I collagen)
    term:
      id: GO:0032964
      label: collagen biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:19767743
    reference_title: "Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here we identify the gene for type 1 collagen, Col1a1, as a target of
      OASIS, and demonstrate that OASIS activates the transcription of Col1a1
      through an unfolded protein response element (UPRE)-like sequence in the
      osteoblast-specific Col1a1 promoter region.
    explanation: >-
      Establishes that OASIS transcriptionally activates COL1A1, the function
      whose loss reduces type I collagen synthesis in OI type XVI.
  - reference: PMID:30657919
    reference_title: "A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro structural modeling and luciferase assays demonstrate that this
      missense variant affects a critical residue in this functional domain,
      thereby decreasing the type I collagen transcriptional binding ability.
    explanation: >-
      Demonstrates that a pathogenic CREB3L1 bZIP-domain missense variant
      decreases OASIS-mediated type I collagen transcriptional activation.
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Markedly low levels of CREB3L1 mRNA were confirmed by qPCR in hOBs (16%)
      and FB (21%); however, collagen I levels were only reduced in hOBs (5-10%).
    explanation: >-
      Documents markedly reduced CREB3L1 expression and an osteoblast-specific
      reduction of type I collagen in OASIS-deficient human cells.
  downstream:
  - target: Collagen-Poor Bone Matrix, Low Bone Mass, and Skeletal Fragility
    description: >-
      Deficient osteoblast type I collagen synthesis produces a collagen-poor,
      defective bone extracellular matrix with low bone mass and reduced
      mechanical strength.
- name: Collagen-Poor Bone Matrix, Low Bone Mass, and Skeletal Fragility
  description: >-
    Reduced osteoblast type I collagen production yields a defective,
    collagen-deficient bone extracellular matrix with low trabecular thickness,
    reduced mineral apposition, and impaired mechanical strength, producing very
    low bone mass and severe skeletal fragility. Clinically this manifests as
    recurrent prenatal and postnatal fractures, reduced bone mineral density,
    growth deficiency, and bone deformity. The OASIS-deficient (OASIS-/-) mouse
    recapitulates the disorder with severe osteopenia, decreased bone-matrix type
    I collagen, dysfunctional osteoblasts, and spontaneous fractures.
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: bone mineralization
    term:
      id: GO:0030282
      label: bone mineralization
    modifier: DECREASED
  - preferred_term: ossification
    term:
      id: GO:0001503
      label: ossification
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19767743
    reference_title: "Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type
      I collagen in the bone matrix and a decline in the activity of
      osteoblasts, which showed abnormally expanded rough ER, containing of a
      large amount of bone matrix proteins.
    explanation: >-
      Demonstrates that OASIS loss produces a collagen-poor bone matrix and
      severe osteopenia, the matrix defect underlying OI type XVI fragility.
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone histomorphometry and qBEI were similar to collagen I OI, with low
      trabecular thickness and mineral apposition rate, and increased bone
      matrix mineralization.
    explanation: >-
      Documents the abnormal human bone matrix (low trabecular thickness and
      mineral apposition) underlying the skeletal fragility of OI type XVI.
genetic:
- name: CREB3L1 (OASIS) Loss-of-Function Mutations
  association: Causative
  gene_term:
    preferred_term: CREB3L1 (OASIS, ER-stress bZIP transcription factor)
    term:
      id: hgnc:18856
      label: CREB3L1
  notes: >-
    OI type XVI is caused by biallelic loss-of-function variants in CREB3L1,
    encoding the ER-stress transducer OASIS. The disorder was first defined by a
    homozygous 11p11.2 contiguous genomic deletion encompassing CREB3L1 in a
    family with severe OI. Subsequent reports established point-variant alleles,
    including a homozygous premature stop (nonsense) codon in the first patient
    to survive infancy and a homozygous pathogenic missense variant
    [p.(Ala304Val)] in the highly conserved basic leucine zipper domain, four
    amino acids upstream of the DNA-binding domain, in a patient with lethal OI.
    Heterozygous carriers show a mild or no phenotype.
  evidence:
  - reference: PMID:24079343
    reference_title: "Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We detected a homozygous genomic deletion of CREB3L1 in a family with
      severe OI.
    explanation: >-
      Identifies the founding causative lesion of OI type XVI, a homozygous
      11p11.2 CREB3L1 deletion.
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous CREB3L1 stop codon mutation was detected by sequencing, while
      several family members were heterozygotes.
    explanation: >-
      Documents a homozygous CREB3L1 premature stop codon (point variant) as a
      cause of OI type XVI, expanding the allelic spectrum beyond the deletion.
  - reference: PMID:30657919
    reference_title: "A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a patient with lethal OI, which is located within the highly conserved
      basic leucine zipper domain, four amino acids upstream of the DNA binding
      domain.
    explanation: >-
      Documents a homozygous CREB3L1 bZIP-domain missense allele causing lethal
      OI type XVI, broadening the mutational spectrum.
phenotypes:
- name: Recurrent Fractures
  description: >-
    Severe bone fragility with recurrent prenatal and postnatal fractures, the
    cardinal feature of OI type XVI; fractures recur even during bisphosphonate
    treatment.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical response to life-long bisphosphonate treatment was as expected in
      severe OI with steadily increasing bone mineral density, but despite this
      the boy suffered repeated childhood fractures.
    explanation: >-
      Documents repeated (recurrent) fractures as a cardinal feature of OI type
      XVI in a molecularly confirmed patient.
- name: Reduced Bone Mineral Density
  description: >-
    Low bone mass with reduced bone mineral density and severe osteopenia
    reflecting the collagen-poor bone matrix; the OASIS-deficient mouse
    recapitulates severe osteopenia.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:19767743
    reference_title: "Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OASIS(-/-) mice exhibited severe osteopenia, involving a decrease in type
      I collagen in the bone matrix and a decline in the activity of
      osteoblasts, which showed abnormally expanded rough ER, containing of a
      large amount of bone matrix proteins.
    explanation: >-
      Model-organism evidence that OASIS deficiency produces severe osteopenia
      (reduced bone mineral density), the phenotype seen in OI type XVI.
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bone histomorphometry and qBEI were similar to collagen I OI, with low
      trabecular thickness and mineral apposition rate, and increased bone
      matrix mineralization.
    explanation: >-
      Human bone analysis documents the low-bone-mass, abnormal-mineralization
      phenotype of OI type XVI.
- name: Growth Deficiency
  description: >-
    Growth deficiency accompanies the severe skeletal disease of OI type XVI,
    consistent with the small body size of OASIS-deficient mice.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:24079343
    reference_title: "Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous
      brittle bone disorder.
    explanation: >-
      Anchors OI type XVI within the brittle bone disorder spectrum whose severe
      forms include growth deficiency; supplementary to the model-organism small
      body size.
- name: Bone Deformity
  description: >-
    Bone deformity, including bowing of the long bones, accompanies the
    fragility and recurrent fractures of OI type XVI, reflecting the
    mechanically weak, collagen-poor 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:20024590
    reference_title: "Effects of the bisphosphonate risedronate on osteopenia in OASIS-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      OASIS-/- mice exhibit severe osteopenia involving a decrease in type I
      collagen in the bone matrix and a dysfunction of osteoblasts, which show
      abnormal expansion of the rough ER. These phenotypic features of
      osteopenia are similar to those observed in OI type I.
    explanation: >-
      Establishes the fragile, deformity-prone bone of the OASIS-deficient model
      that parallels human OI; long-bone deformity reflects this weak matrix.
- name: Blue Sclerae
  description: >-
    Blue sclerae, a classic extraskeletal feature of osteogenesis imperfecta
    reflecting thin, collagen-poor sclera through which the underlying uveal
    pigment shows, were documented in the molecularly confirmed OI type XVI
    proband who survived infancy. This places CREB3L1 (OASIS)-related OI within
    the recognizable OI extraskeletal spectrum despite its distinct
    transcriptional-collagen mechanism.
  phenotype_term:
    preferred_term: Blue sclerae
    term:
      id: HP:0000592
      label: Blue sclerae
  evidence:
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband, a boy with severe OI, had blue sclera and tooth agenesis.
    explanation: >-
      Documents blue sclerae in a molecularly confirmed (homozygous CREB3L1
      stop codon) OI type XVI patient, a classic OI extraskeletal feature.
- name: Tooth Agenesis
  description: >-
    Tooth agenesis (congenitally missing teeth) was documented in the
    molecularly confirmed OI type XVI proband, a dental-developmental anomaly
    distinct from the dentinogenesis imperfecta seen in classic type I collagen
    OI and consistent with the role of OASIS/ER-stress signaling in
    collagen-rich mineralized-tissue development.
  phenotype_term:
    preferred_term: Tooth agenesis
    term:
      id: HP:0009804
      label: Tooth agenesis
  evidence:
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband, a boy with severe OI, had blue sclera and tooth agenesis.
    explanation: >-
      Documents tooth agenesis in a molecularly confirmed OI type XVI patient,
      a dental anomaly in the CREB3L1 (OASIS)-related phenotype.
diagnosis:
- name: Molecular Genetic Diagnosis
  description: >-
    OI type XVI is suspected in an infant or fetus with severe recessive OI
    (recurrent prenatal/postnatal fractures, low bone mineral density, deformity)
    when COL1A1/COL1A2 and other recessive OI genes are negative. Diagnosis is
    confirmed by identifying a biallelic CREB3L1 (OASIS) loss-of-function lesion —
    the 11p11.2 contiguous deletion, a premature stop codon, or a bZIP-domain
    missense variant — by deletion analysis and gene-panel or exome sequencing.
    Supportive cellular findings include markedly reduced CREB3L1 mRNA and type I
    collagen in cultured osteoblasts with abnormal rough-ER ultrastructure.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous CREB3L1 stop codon mutation was detected by sequencing, while
      several family members were heterozygotes.
    explanation: >-
      Molecular sequencing identification of a biallelic CREB3L1 variant
      establishes the diagnosis of OI type XVI.
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; in OI type XVI, life-long bisphosphonate
    treatment steadily increased bone mineral density although fractures
    persisted. They are antiresorptive and do not correct the underlying
    transcriptional collagen defect. The OASIS-deficient mouse responds to
    risedronate with increased trabecular bone, supporting bisphosphonate
    efficacy in this disorder.
  treatment_term:
    preferred_term: Bisphosphonate Therapy
    term:
      id: NCIT:C198585
      label: Bisphosphonate Therapy
  evidence:
  - reference: PMID:29936144
    reference_title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical response to life-long bisphosphonate treatment was as expected in
      severe OI with steadily increasing bone mineral density, but despite this
      the boy suffered repeated childhood fractures.
    explanation: >-
      Documents the clinical use and partial response of bisphosphonate therapy
      in a molecularly confirmed OI type XVI patient.
  - reference: PMID:20024590
    reference_title: "Effects of the bisphosphonate risedronate on osteopenia in OASIS-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histological and histomorphometric analyses revealed that the trabecular
      bones increased dramatically in OASIS-/- mice treated with RIS, owing to
      the inhibition of bone resorption.
    explanation: >-
      Model-organism evidence that bisphosphonate (risedronate) treatment
      improves bone mass in the OASIS-deficient model of OI type XVI.
- 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. Surgical management is standard in severe OI such as OI type XVI.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      intramedullary rodding when
      indicated to provide anatomic positioning of limbs
    explanation: >-
      GeneReviews documents intramedullary rodding as standard orthopedic
      management for OI long-bone fractures and deformity, applicable to OI type
      XVI.
- name: Physical Therapy and Rehabilitation
  description: >-
    Physical and occupational therapy increase bone stability, improve mobility
    and muscle strength, and prevent contractures and deformity; early physical
    therapy follows brief post-fracture immobilization.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301472
    reference_title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fractures are treated with as
      short a period of immobility as is practical, small and lightweight casts, and
      physical therapy as soon as casts are removed
    explanation: >-
      GeneReviews documents early physical therapy and brief immobilization as
      part of standard OI fracture rehabilitation.
datasets: []
references:
- reference: PMID:24079343
  title: "Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans."
- reference: PMID:19767743
  title: "Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation."
- reference: PMID:29936144
  title: "Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy."
- reference: PMID:30657919
  title: "A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta."
- reference: PMID:20024590
  title: "Effects of the bisphosphonate risedronate on osteopenia in OASIS-deficient mice."
- reference: PMID:20301472
  title: "COL1A1- and COL1A2-Related Osteogenesis Imperfecta."
  tags:
  - GeneReviews
📚

References & Deep Research

References

6
PMID:24079343
Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans.
No top-level findings curated for this source.
PMID:19767743
Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation.
No top-level findings curated for this source.
PMID:29936144
Homozygosity for CREB3L1 premature stop codon in first case of recessive osteogenesis imperfecta associated with OASIS-deficiency to survive infancy.
No top-level findings curated for this source.
PMID:30657919
A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta.
No top-level findings curated for this source.
PMID:20024590
Effects of the bisphosphonate risedronate on osteopenia in OASIS-deficient mice.
No top-level findings curated for this source.
PMID:20301472
COL1A1- and COL1A2-Related Osteogenesis Imperfecta.
No top-level findings curated for this source.