Vitamin D-Dependent Rickets Type 3

Mendelian MONDO:0033640 Pathograph 4 Show in embeddings browser Metabolic Bone Disorders Inborn Error of Metabolism

Vitamin D-dependent rickets type 3 is caused by a de novo gain-of-function missense variant in CYP3A4 that converts a promiscuous drug-metabolizing enzyme into a highly efficient inactivator of vitamin D metabolites. Both 25-hydroxyvitamin D and calcitriol are low, but for the opposite reason to types 1A and 1B: synthesis is intact and catabolism is accelerated. This makes type 3 the only member of the series in which the lesion is in degradation rather than production or reception of the hormone, and it explains the characteristic resistance to both parent and activated vitamin D - supplied hormone is destroyed as fast as it is given.

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1
Inheritance
3
Pathophys.
2
Phenotypes
4
Pathograph
1
Genes
1
Medical Actions
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
The reported patients carry the same heterozygous de novo missense variant. The mechanism is a gain of enzymatic function, so a single allele suffices, unlike the recessive loss-of-function types 1A, 1B and 2A.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Neither patient had a mutation in any genes known to cause VDDR; however, using whole exome sequencing analysis, we identified a recurrent de novo missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that alters the conformation of substrate recognition site 4 (SRS-4)."
Documents the same heterozygous de novo variant in two unrelated patients.
⚙

Pathophysiology

3
Accelerated Catabolism of Vitamin D Metabolites
The variant enzyme oxidizes calcitriol far more efficiently than wild-type CYP3A4, and more efficiently than CYP24A1, the physiological inactivator. The active hormone and its precursor are cleared before they can act. Because the defect is in the degradation limb, giving more substrate does not help: the same enzyme destroys the supplement, which is the feature that separates this disorder from every other member of the series.
Vitamin D Catabolism GO:0042359 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Vitamin D Catabolism, annotated with vitamin D metabolic process (GO:0042359). GO:0042359 is a biological process from the Gene Ontology. ↑ INCREASED
CYP3A4 Vitamin D Metabolite Oxidation GO:0008395 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves CYP3A4 Vitamin D Metabolite Oxidation, annotated with steroid hydroxylase activity (GO:0008395), qualified as gain of function. GO:0008395 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Hormone Deficiency Despite Intact Synthesis Accelerated clearance depletes both metabolites without any defect in their production.
Show evidence (1 reference)
PMID:29461981 SUPPORT In Vitro
"In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1, the principal inactivator of vitamin D metabolites."
Quantifies the gain of catabolic function against both wild-type enzyme and the physiological inactivator.
Hormone Deficiency Despite Intact Synthesis
Serum 25-hydroxyvitamin D and calcitriol are both low, mimicking nutritional deficiency or a synthetic block, while the synthetic enzymes are normal. Vitamin D receptor signalling in the intestine falls and the calciopenic cascade follows. This is the disorder-specific instance of the module's calciopenic trigger arm, entered from the catabolic side.
Enterocyte CL:0000584 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Enterocyte (CL:0000584). CL:0000584 is a cell type from the Cell Ontology.
Vitamin D Receptor Signaling GO:0070561 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Vitamin D Receptor Signaling, annotated with vitamin D receptor signaling pathway (GO:0070561). GO:0070561 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Defective Skeletal Mineralization Reduced calcium and phosphate supply lowers the calcium-phosphate product at the mineralization front.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Records the low levels of both metabolites together with resistance to both parent and activated vitamin D.
Defective Skeletal Mineralization
Early-onset rickets that responds poorly to conventional vitamin D and calcitriol dosing.
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
Bone UBERON:0001474 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Bone, annotated with bone element (UBERON:0001474). UBERON:0001474 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Documents early-onset rickets as the presenting skeletal phenotype.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Vitamin D-Dependent Rickets Type 3 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

2
Musculoskeletal 1
Rickets HP:0002748 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rickets (HP:0002748). HP:0002748 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Names rickets as the presenting feature in both reported patients.
Other 1
Low circulating vitamin D metabolites Decreased circulating vitamin D concentration HP:0100512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating vitamin D concentration (HP:0100512). HP:0100512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Reports reduced levels of both vitamin D metabolites.
🧬

Genetic Associations

1
De novo CYP3A4 gain-of-function variant (Causative)
Gene: CYP3A4 hgnc:2637 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CYP3A4 (hgnc:2637). hgnc:2637 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"As CYP3A4 mutations have not previously been linked to rickets, these findings provide insight into vitamin D metabolism and demonstrate that accelerated inactivation of vitamin D metabolites represents a mechanism for vitamin D deficiency."
Establishes CYP3A4 as a novel rickets gene acting through accelerated metabolite inactivation.
💊

Medical Actions

1
Vitamin D and Calcitriol Replacement (Resistant)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: calcitriol CHEBI:17823 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses calcitriol (CHEBI:17823). CHEBI:17823 is a therapeutic agent from Chemical Entities of Biological Interest. cholecalciferol CHEBI:28940 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cholecalciferol, annotated with calciol (CHEBI:28940). CHEBI:28940 is a therapeutic agent from Chemical Entities of Biological Interest.
Recorded as a treatment whose defining feature is that it FAILS. Because the lesion is in the degradation limb, the variant enzyme destroys supplied hormone as fast as it is given, so both parent vitamin D and activated calcitriol meet deficient responsiveness. This is what singles type 3 out within the series: in types 1A and 1B the hormone that is missing can simply be supplied, whereas here supplying it is defeated by the lesion itself. No effective regimen is asserted - the two reported patients are the entire clinical evidence base, and inventing a dosing recommendation from them would exceed what the source supports.
Mechanism Target:
MODULATES Accelerated Catabolism of Vitamin D Metabolites — Supplying parent or activated vitamin D raises substrate flux into the same accelerated catabolic pathway rather than correcting it, which is why the response is deficient rather than absent.
Show evidence (1 reference)
PMID:29461981 SUPPORT Human Clinical
"Here we describe two unrelated patients with early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to parent and activated forms of vitamin D."
Reports deficient responsiveness to both parent and activated vitamin D, the therapeutic consequence of the catabolic gain of function.
{ }

Source YAML

click to show 
name: Vitamin D-Dependent Rickets Type 3
synonyms:
- VDDR3
- CYP3A4-related vitamin D-dependent rickets
- Vitamin D hypercatabolism rickets
creation_date: "2026-08-19T00:00:00Z"
category: Mendelian
description: >-
  Vitamin D-dependent rickets type 3 is caused by a de novo gain-of-function
  missense variant in CYP3A4 that converts a promiscuous drug-metabolizing enzyme
  into a highly efficient inactivator of vitamin D metabolites. Both
  25-hydroxyvitamin D and calcitriol are low, but for the opposite reason to
  types 1A and 1B: synthesis is intact and catabolism is accelerated. This makes
  type 3 the only member of the series in which the lesion is in degradation
  rather than production or reception of the hormone, and it explains the
  characteristic resistance to both parent and activated vitamin D - supplied
  hormone is destroyed as fast as it is given.
disease_term:
  preferred_term: vitamin D-dependent rickets, type 3
  term:
    id: MONDO:0033640
    label: vitamin D-dependent rickets, type 3
parents:
- Metabolic Bone Disorders
- Inborn Error of Metabolism
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The reported patients carry the same heterozygous de novo missense variant.
    The mechanism is a gain of enzymatic function, so a single allele suffices,
    unlike the recessive loss-of-function types 1A, 1B and 2A.
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither patient had a mutation in any genes known to cause VDDR; however,
      using whole exome sequencing analysis, we identified a recurrent de novo
      missense mutation, c.902T>C (p.I301T), in CYP3A4 in both subjects that
      alters the conformation of substrate recognition site 4 (SRS-4).
    explanation: >-
      Documents the same heterozygous de novo variant in two unrelated patients.
genetic:
- name: De novo CYP3A4 gain-of-function variant
  gene_term:
    preferred_term: CYP3A4
    term:
      id: hgnc:2637
      label: CYP3A4
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    The recurrent c.902T>C (p.Ile301Thr) variant remodels substrate recognition
    site 4, which is what redirects the enzyme's activity toward vitamin D
    metabolites.
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As CYP3A4 mutations have not previously been linked to rickets, these
      findings provide insight into vitamin D metabolism and demonstrate that
      accelerated inactivation of vitamin D metabolites represents a mechanism for
      vitamin D deficiency.
    explanation: >-
      Establishes CYP3A4 as a novel rickets gene acting through accelerated
      metabolite inactivation.
pathophysiology:
- name: Accelerated Catabolism of Vitamin D Metabolites
  description: >-
    The variant enzyme oxidizes calcitriol far more efficiently than wild-type
    CYP3A4, and more efficiently than CYP24A1, the physiological inactivator. The
    active hormone and its precursor are cleared before they can act. Because the
    defect is in the degradation limb, giving more substrate does not help: the
    same enzyme destroys the supplement, which is the feature that separates this
    disorder from every other member of the series.
  role: trigger
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: CYP3A4 Vitamin D Metabolite Oxidation
    term:
      id: GO:0008395
      label: steroid hydroxylase activity
    modifier: GAIN_OF_FUNCTION
  biological_processes:
  - preferred_term: Vitamin D Catabolism
    term:
      id: GO:0042359
      label: vitamin D metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro, the mutant CYP3A4 oxidized 1,25-dihydroxyvitamin D with 10-fold
      greater activity than WT CYP3A4 and 2-fold greater activity than CYP24A1,
      the principal inactivator of vitamin D metabolites.
    explanation: >-
      Quantifies the gain of catabolic function against both wild-type enzyme and
      the physiological inactivator.
  downstream:
  - target: Hormone Deficiency Despite Intact Synthesis
    causal_link_type: DIRECT
    description: >-
      Accelerated clearance depletes both metabolites without any defect in their
      production.
- name: Hormone Deficiency Despite Intact Synthesis
  description: >-
    Serum 25-hydroxyvitamin D and calcitriol are both low, mimicking nutritional
    deficiency or a synthetic block, while the synthetic enzymes are normal.
    Vitamin D receptor signalling in the intestine falls and the calciopenic
    cascade follows. This is the disorder-specific instance of the module's
    calciopenic trigger arm, entered from the catabolic side.
  role: central_effector
  biological_scale: ORGANISM
  conforms_to: "defective_skeletal_mineralization#Calciopenic Substrate Deficiency"
  cell_types:
  - preferred_term: Enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: Vitamin D Receptor Signaling
    term:
      id: GO:0070561
      label: vitamin D receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Records the low levels of both metabolites together with resistance to both
      parent and activated vitamin D.
  downstream:
  - target: Defective Skeletal Mineralization
    causal_link_type: DIRECT
    description: >-
      Reduced calcium and phosphate supply lowers the calcium-phosphate product at
      the mineralization front.
- name: Defective Skeletal Mineralization
  description: >-
    Early-onset rickets that responds poorly to conventional vitamin D and
    calcitriol dosing.
  role: effector
  biological_scale: TISSUE
  conforms_to: "defective_skeletal_mineralization#Impaired Hydroxyapatite Deposition at the Mineralization Front"
  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
  locations:
  - preferred_term: Bone
    term:
      id: UBERON:0001474
      label: bone element
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Documents early-onset rickets as the presenting skeletal phenotype.
phenotypes:
- category: Skeletal
  name: Rickets
  description: Early-onset rickets resistant to both parent and activated vitamin D.
  phenotype_term:
    preferred_term: Rickets
    term:
      id: HP:0002748
      label: Rickets
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Names rickets as the presenting feature in both reported patients.
- category: Biochemical
  name: Low circulating vitamin D metabolites
  phenotype_term:
    preferred_term: Decreased circulating vitamin D concentration
    term:
      id: HP:0100512
      label: Decreased circulating vitamin D concentration
  evidence:
  - reference: PMID:29461981
    reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe two unrelated patients with early-onset rickets, reduced
      serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
      1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
      activated forms of vitamin D.
    explanation: >-
      Reports reduced levels of both vitamin D metabolites.
treatments:
- name: Vitamin D and Calcitriol Replacement (Resistant)
  description: >-
    Recorded as a treatment whose defining feature is that it FAILS. Because the
    lesion is in the degradation limb, the variant enzyme destroys supplied
    hormone as fast as it is given, so both parent vitamin D and activated
    calcitriol meet deficient responsiveness. This is what singles type 3 out
    within the series: in types 1A and 1B the hormone that is missing can simply
    be supplied, whereas here supplying it is defeated by the lesion itself. No
    effective regimen is asserted - the two reported patients are the entire
    clinical evidence base, and inventing a dosing recommendation from them would
    exceed what the source supports.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: calcitriol
      term:
        id: CHEBI:17823
        label: calcitriol
    - preferred_term: cholecalciferol
      term:
        id: CHEBI:28940
        label: calciol
  target_mechanisms:
  - target: Accelerated Catabolism of Vitamin D Metabolites
    treatment_effect: MODULATES
    description: >-
      Supplying parent or activated vitamin D raises substrate flux into the same
      accelerated catabolic pathway rather than correcting it, which is why the
      response is deficient rather than absent.
    evidence:
    - reference: PMID:29461981
      reference_title: CYP3A4 mutation causes vitamin D-dependent rickets type 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we describe two unrelated patients with early-onset rickets, reduced
        serum levels of the vitamin D metabolites 25-hydroxyvitamin D and
        1,25-dihydroxyvitamin D, and deficient responsiveness to parent and
        activated forms of vitamin D.
      explanation: >-
        Reports deficient responsiveness to both parent and activated vitamin D,
        the therapeutic consequence of the catabolic gain of function.
notes: >-
  Evidence for this disorder rests on two unrelated patients sharing one recurrent
  de novo variant, plus in vitro enzymology. No cohort or prevalence data are
  asserted here. The pharmacological corollary - that CYP3A4-inducing drugs might
  phenocopy the mechanism - is a plausible extension of the same biology but is
  not curated as a claim of this entry.