RAB33B-Related Smith-McCort Dysplasia 2

Mendelian MONDO:0014087 Pathograph 5 Show in embeddings browser Smith-McCort dysplasia Skeletal Dysplasia RAB protein disorder

RAB33B-related Smith-McCort dysplasia 2 is a rare autosomal recessive spondylo-epi-metaphyseal skeletal dysplasia caused by biallelic RAB33B variants. RAB33B encodes a Golgi-localized Rab GTPase involved in Golgi vesicle trafficking and autophagy. Pathogenic variants reduce or destabilize Rab33b, prevent normal Golgi-membrane localization, alter autophagosome formation in cell models, and are linked in a knock-in mouse model to impaired osteoclast function, altered protein glycosylation, and abnormal bone material properties. Clinically, SMC2 resembles Dyggve-Melchior-Clausen skeletal dysplasia radiographically but is distinguished by normal cognition and lack of microcephaly in the classic presentation.

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1
Inheritance
4
Pathophys.
2
Phenotypes
1
Gaps
5
Pathograph
1
Genes
1
Deep Research
🏷

Classifications

👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
RAB33B-related SMC2 is reported in homozygous and compound heterozygous affected individuals and families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:23042644 SUPPORT Human Clinical
"Smith-McCort dysplasia (SMC) is a rare autosomal recessive spondylo-epi-metaphyseal dysplasia"
The RAB33B case report defines SMC as an autosomal recessive skeletal dysplasia.
PMID:28127940 SUPPORT Human Clinical
"Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*)."
Homozygous and compound heterozygous RAB33B pathogenic variants support autosomal recessive inheritance.
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Discussions and Knowledge Gaps

1
Does the Rab33b Lys46Gln knock-in mouse capture the disease-relevant human skeletal mechanism broadly enough to infer the SMC2 pathograph, or does its partial, male-restricted phenotype mean that human chondrocyte, osteoclast, and glycosylation biology require additional model systems?
HUMAN MODEL MISMATCH OPEN gap_rab33b_mouse_partial_recapitulation
Attached to
pathophysiology#Osteoclast and protein-glycosylation dysfunction pathophysiology#Spondyloepimetaphyseal skeletal dysplasia
The Rab33b knock-in mouse provides the strongest functional bridge from RAB33B Golgi/autophagy dysfunction to bone resorption and glycosylation defects, but the same paper reports incomplete and sex-specific phenotypic recapitulation. That makes the mouse evidence valuable for mechanism directionality while leaving uncertainty about which skeletal-cell defects drive the progressive human spondylo-epi-metaphyseal phenotype.
Proposed experiments
Isogenic RAB33B-deficient human skeletal-cell differentiation models
exp_rab33b_human_skeletal_cell_models
Generate patient-derived or CRISPR-edited human iPSC chondrocyte and osteoclast differentiation systems and compare Golgi localization, autophagosome formation, protein glycosylation, matrix production, and bone-resorption readouts against rescued and wild-type controls.
Sex- and age-stratified Rab33b knock-in skeletal phenotyping
exp_rab33b_mouse_sex_age_series
Extend the Rab33b Lys46Gln mouse analysis across both sexes and multiple developmental ages with vertebral, growth-plate, osteoclast, and glycosylation readouts to test whether the human phenotype is missed because of timing, skeletal site, or sex-specific expressivity.
Show evidence (1 reference)
PMID:37359363 SUPPORT Model Organism
"The mouse model only reproduced some of the features of the human disease and was sex-specific, manifesting in male but not female mice."
The model paper itself identifies the mismatch that motivates this open discussion.
⚙

Pathophysiology

4
RAB33B Golgi Rab GTPase deficiency
Biallelic RAB33B variants impair a Golgi-localized Rab GTPase required for vesicle trafficking and autophagy-associated membrane events.
RAB33B hgnc:16075
Golgi vesicle transport GO:0048193 ⚠ ABNORMAL autophagy GO:0006914 ⚠ ABNORMAL
Golgi apparatus GO:0005794
Downstream
Rab33b protein instability and Golgi mislocalization Disease-causing Rab33b variants reduce protein abundance or prevent normal accumulation on Golgi membranes.
Show evidence (2 references)
PMID:23042644 SUPPORT Human Clinical
"identification of a missense mutation in RAB33B, another Golgi protein involved in retrograde transport of Golgi vesicles."
Human genetic evidence links RAB33B and its Golgi retrograde transport role to SMC.
PMID:31408960 SUPPORT Other
"Rab33b is a protein that localises to the Golgi apparatus and has suggested functions in both membrane trafficking and autophagic processes."
The review places Rab33b at the Golgi and in membrane-trafficking and autophagy biology.
Rab33b protein instability and Golgi mislocalization
Mutant Rab33b proteins are unstable, prematurely degraded, and fail to accumulate normally on Golgi membranes, reducing Golgi trafficking and autophagy functions.
Golgi organization GO:0007030 ⚠ ABNORMAL autophagy GO:0006914 ↓ DECREASED
Downstream
Osteoclast and protein-glycosylation dysfunction
Show evidence (2 references)
PMID:41506134 SUPPORT In Vitro
"all of these mutants show subcellular mislocalisation and fail to accumulate on Golgi membranes."
Cell-culture expression of five disease-causing variants supports Golgi mislocalization.
PMID:41506134 SUPPORT In Vitro
"overexpression of the single amino acid substitution variants in cells induced for autophagy causes a severe reduction in the number of autophagosomes"
Functional experiments support impaired autophagosome formation for missense variants.
Osteoclast and protein-glycosylation dysfunction
Golgi/autophagy dysfunction in RAB33B-related SMC disrupts skeletal-tissue homeostasis through impaired osteoclast function and altered protein glycosylation in skeletal and other tissues.
osteoclast CL:0000092
bone resorption GO:0045453 ↓ DECREASED protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL protein O-linked glycosylation GO:0006493 ⚠ ABNORMAL
Downstream
Spondyloepimetaphyseal skeletal dysplasia
Show evidence (2 references)
PMID:37359363 SUPPORT Model Organism
"suggesting a bone resorption defect."
The RAB33B knock-in mouse model showed a bone phenotype interpreted as a resorption defect.
PMID:37359363 SUPPORT Model Organism
"disturbed protein glycosylation in cells contributing to skeletal formation"
Lectin staining findings support altered protein glycosylation in skeletal disease-relevant cells.
Spondyloepimetaphyseal skeletal dysplasia
The tissue-level result is a Smith-McCort skeletal dysplasia with spondylo-epi-metaphyseal involvement and characteristic lacy iliac changes, typically without intellectual disability or microcephaly.
Show evidence (2 references)
PMID:23042644 SUPPORT Human Clinical
"skeletal features identical to those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly."
The RAB33B report defines the SMC phenotype and its distinction from DMC.
PMID:28127940 SUPPORT Human Clinical
"This report ascertains the pathogenic relationship between RAB33B and SMC."
Additional patients strengthen the RAB33B-SMC causal association.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for RAB33B-Related Smith-McCort Dysplasia 2 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
Spondyloepimetaphyseal dysplasia Skeletal dysplasia HP:0002652
Smith-McCort dysplasia is distinguished from Dyggve-Melchior-Clausen dysplasia by normal cognition and no microcephaly; those are exclusion context rather than positive phenotype assertions.
Show evidence (2 references)
PMID:23042644 SUPPORT Human Clinical
"spondylo-epi-metaphyseal dysplasia with skeletal features identical to those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal intelligence and no microcephaly."
The original RAB33B report supports the skeletal dysplasia phenotype and documents the normal-intelligence/no-microcephaly distinction.
PMID:28127940 SUPPORT Human Clinical
"skeletal phenotypes characterized by spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia."
HP:0002652 is used as a broad HPO mapping for this spondylo-epi-metaphyseal dysplasia pattern.
Growth 1
Short stature Short stature HP:0004322
Show evidence (1 reference)
PMID:37359363 SUPPORT Human Clinical
"including short neck and trunk, p latyspondyly, hyperlordosis, various joint abnormalities, and short bones"
The review of SMC clinical findings supports short stature as a skeletal-growth phenotype.
🧬

Genetic Associations

1
RAB33B biallelic pathogenic variants (Loss of function mutation)
Gene: RAB33B hgnc:16075 relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:28127940 SUPPORT Human Clinical
"Recently, RAB33B (OMIM 605950) has been identified as the second gene for SMC."
The report identifies RAB33B as the second Smith-McCort dysplasia gene.
{ }

Source YAML

click to show 
name: RAB33B-Related Smith-McCort Dysplasia 2
creation_date: "2026-07-06T12:00:00Z"
category: Mendelian
description: >-
  RAB33B-related Smith-McCort dysplasia 2 is a rare autosomal recessive
  spondylo-epi-metaphyseal skeletal dysplasia caused by biallelic RAB33B
  variants. RAB33B encodes a Golgi-localized Rab GTPase involved in Golgi
  vesicle trafficking and autophagy. Pathogenic variants reduce or destabilize
  Rab33b, prevent normal Golgi-membrane localization, alter autophagosome
  formation in cell models, and are linked in a knock-in mouse model to impaired
  osteoclast function, altered protein glycosylation, and abnormal bone
  material properties. Clinically, SMC2 resembles Dyggve-Melchior-Clausen
  skeletal dysplasia radiographically but is distinguished by normal cognition
  and lack of microcephaly in the classic presentation.
disease_term:
  preferred_term: Smith-McCort dysplasia 2
  term:
    id: MONDO:0014087
    label: Smith-McCort dysplasia 2
parents:
- Smith-McCort dysplasia
- Skeletal Dysplasia
- RAB protein disorder
synonyms:
- SMC2
- Smith-McCort dysplasia due to RAB33B deficiency
- RAB33B deficiency
- RAB33B-related spondyloepimetaphyseal dysplasia
external_assertions:
- name: OMIM Smith-McCort dysplasia 2 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:615222
  description: OMIM phenotype identifier for RAB33B-related Smith-McCort dysplasia 2.
classifications:
  icimd_category:
  - classification_value: vesicular_trafficking
    notes: >-
      WP-068 classification 19.6.70.01: Complex Molecule and Organelle
      Metabolism, disorders of organelle biogenesis, dynamics and interactions,
      disorders of vesicular trafficking.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    RAB33B-related SMC2 is reported in homozygous and compound heterozygous
    affected individuals and families.
  evidence:
  - reference: PMID:23042644
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Smith-McCort dysplasia (SMC) is a rare autosomal recessive
      spondylo-epi-metaphyseal dysplasia
    explanation: >-
      The RAB33B case report defines SMC as an autosomal recessive skeletal
      dysplasia.
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present three SMC patients with four novel pathogenic variants in
      RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for
      c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG
      (p.G17Vfs*58) and c.490C>T (p.Q164*).
    explanation: >-
      Homozygous and compound heterozygous RAB33B pathogenic variants support
      autosomal recessive inheritance.
pathophysiology:
- name: RAB33B Golgi Rab GTPase deficiency
  description: >-
    Biallelic RAB33B variants impair a Golgi-localized Rab GTPase required for
    vesicle trafficking and autophagy-associated membrane events.
  genes:
  - preferred_term: RAB33B
    term:
      id: hgnc:16075
      label: RAB33B
  biological_processes:
  - preferred_term: Golgi vesicle transport
    modifier: ABNORMAL
    term:
      id: GO:0048193
      label: Golgi vesicle transport
  - preferred_term: autophagy
    modifier: ABNORMAL
    term:
      id: GO:0006914
      label: autophagy
  locations:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  evidence:
  - reference: PMID:23042644
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identification of a missense mutation in RAB33B, another Golgi protein
      involved in retrograde transport of Golgi vesicles.
    explanation: >-
      Human genetic evidence links RAB33B and its Golgi retrograde transport
      role to SMC.
  - reference: PMID:31408960
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Rab33b is a protein that localises to the Golgi apparatus and has
      suggested functions in both membrane trafficking and autophagic processes.
    explanation: >-
      The review places Rab33b at the Golgi and in membrane-trafficking and
      autophagy biology.
  downstream:
  - target: Rab33b protein instability and Golgi mislocalization
    causal_link_type: DIRECT
    description: >-
      Disease-causing Rab33b variants reduce protein abundance or prevent normal
      accumulation on Golgi membranes.
    evidence:
    - reference: PMID:23042644
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we report a novel RAB33B mutation in a second SMC case that leads
        to a marked reduction of the protein
      explanation: >-
        Protein studies in a second SMC case support reduced Rab33b abundance.
- name: Rab33b protein instability and Golgi mislocalization
  description: >-
    Mutant Rab33b proteins are unstable, prematurely degraded, and fail to
    accumulate normally on Golgi membranes, reducing Golgi trafficking and
    autophagy functions.
  biological_processes:
  - preferred_term: Golgi organization
    modifier: ABNORMAL
    term:
      id: GO:0007030
      label: Golgi organization
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:41506134
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      all of these mutants show subcellular mislocalisation and fail to
      accumulate on Golgi membranes.
    explanation: >-
      Cell-culture expression of five disease-causing variants supports Golgi
      mislocalization.
  - reference: PMID:41506134
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      overexpression of the single amino acid substitution variants in cells
      induced for autophagy causes a severe reduction in the number of
      autophagosomes
    explanation: >-
      Functional experiments support impaired autophagosome formation for
      missense variants.
  downstream:
  - target: Osteoclast and protein-glycosylation dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - altered Golgi-dependent protein processing
    - impaired autophagy-associated membrane trafficking
    evidence:
    - reference: PMID:37359363
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data reveal a potential novel role of RAB33B in osteoclast function
        and protein glycosylation and their dysregulation in SMC
      explanation: >-
        The knock-in mouse model connects RAB33B dysfunction to osteoclast and
        glycosylation abnormalities.
- name: Osteoclast and protein-glycosylation dysfunction
  description: >-
    Golgi/autophagy dysfunction in RAB33B-related SMC disrupts skeletal-tissue
    homeostasis through impaired osteoclast function and altered protein
    glycosylation in skeletal and other tissues.
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: bone resorption
    modifier: DECREASED
    term:
      id: GO:0045453
      label: bone resorption
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  - preferred_term: protein O-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  evidence:
  - reference: PMID:37359363
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "suggesting a bone resorption defect."
    explanation: >-
      The RAB33B knock-in mouse model showed a bone phenotype interpreted as a
      resorption defect.
  - reference: PMID:37359363
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      disturbed protein glycosylation in cells contributing to skeletal
      formation
    explanation: >-
      Lectin staining findings support altered protein glycosylation in skeletal
      disease-relevant cells.
  downstream:
  - target: Spondyloepimetaphyseal skeletal dysplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - abnormal bone resorption
    - altered bone material properties
    evidence:
    - reference: PMID:28127940
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Both disorders share the same skeletal phenotypes characterized by
        spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia.
      explanation: >-
        This clinical review of RAB33B-associated SMC supports the core skeletal
        phenotype.
- name: Spondyloepimetaphyseal skeletal dysplasia
  description: >-
    The tissue-level result is a Smith-McCort skeletal dysplasia with
    spondylo-epi-metaphyseal involvement and characteristic lacy iliac changes,
    typically without intellectual disability or microcephaly.
  evidence:
  - reference: PMID:23042644
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal features identical to those of Dyggve-Melchior-Clausen syndrome
      (DMC) but with normal intelligence and no microcephaly.
    explanation: >-
      The RAB33B report defines the SMC phenotype and its distinction from DMC.
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report ascertains the pathogenic relationship between RAB33B and SMC."
    explanation: >-
      Additional patients strengthen the RAB33B-SMC causal association.
phenotypes:
- category: Musculoskeletal
  name: Spondyloepimetaphyseal dysplasia
  phenotype_term:
    preferred_term: Skeletal dysplasia
    term:
      id: HP:0002652
      label: Skeletal dysplasia
  description: >-
    The more specific clinical/radiographic pattern is
    spondylo-epi-metaphyseal dysplasia.
  notes: >-
    Smith-McCort dysplasia is distinguished from Dyggve-Melchior-Clausen
    dysplasia by normal cognition and no microcephaly; those are exclusion
    context rather than positive phenotype assertions.
  evidence:
  - reference: PMID:23042644
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      spondylo-epi-metaphyseal dysplasia with skeletal features identical to
      those of Dyggve-Melchior-Clausen syndrome (DMC) but with normal
      intelligence and no microcephaly.
    explanation: >-
      The original RAB33B report supports the skeletal dysplasia phenotype and
      documents the normal-intelligence/no-microcephaly distinction.
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      skeletal phenotypes characterized by spondylo-epi-metaphyseal dysplasia
      with distinctive lacy ilia.
    explanation: >-
      HP:0002652 is used as a broad HPO mapping for this
      spondylo-epi-metaphyseal dysplasia pattern.
- category: Growth
  name: Short stature
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  description: >-
    Short trunk dwarfism and short neck/trunk are typical Smith-McCort dysplasia
    skeletal-growth features.
  evidence:
  - reference: PMID:37359363
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including short neck and trunk, p latyspondyly, hyperlordosis, various
      joint abnormalities, and short bones
    explanation: >-
      The review of SMC clinical findings supports short stature as a
      skeletal-growth phenotype.
genetic:
- name: RAB33B biallelic pathogenic variants
  association: Loss of function mutation
  relationship_type: CAUSATIVE
  presence: Pathogenic
  gene_term:
    preferred_term: RAB33B
    term:
      id: hgnc:16075
      label: RAB33B
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    Reported pathogenic variants include homozygous missense or nonsense alleles
    and compound heterozygous frameshift/nonsense variants, with functional
    evidence for reduced protein, instability, Golgi mislocalization, and
    impaired autophagy.
  evidence:
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recently, RAB33B (OMIM 605950) has been identified as the second gene for
      SMC.
    explanation: >-
      The report identifies RAB33B as the second Smith-McCort dysplasia gene.
diagnosis:
- name: Clinical and Radiographic Recognition
  description: >-
    RAB33B-related SMC2 should be recognized in a child with a
    spondylo-epi-metaphyseal skeletal dysplasia pattern, especially lacy ilia,
    and differentiated from Dyggve-Melchior-Clausen dysplasia by normal
    cognition and absence of microcephaly in the classic presentation.
  diagnosis_term:
    preferred_term: clinical imaging procedure
    term:
      id: MAXO:0000005
      label: clinical imaging procedure
  evidence:
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both disorders share the same skeletal phenotypes characterized by
      spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia.
    explanation: >-
      This RAB33B case series identifies the core radiographic pattern used to
      recognize Smith-McCort dysplasia and its Dyggve-Melchior-Clausen overlap.
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The difference rests on the presence or absence of intellectual
      disability, that is, intellectual disability in DMC and normal cognition
      in SMC.
    explanation: >-
      Normal cognition is the key clinical discriminator from
      Dyggve-Melchior-Clausen dysplasia in this paper's diagnostic framing.
- name: Molecular Confirmation of SMC2
  description: >-
    Molecular diagnosis is confirmed by identifying biallelic pathogenic RAB33B
    variants in a patient with compatible Smith-McCort clinical and radiographic
    findings.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:28127940
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present three SMC patients with four novel pathogenic variants in
      RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for
      c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG
      (p.G17Vfs*58) and c.490C>T (p.Q164*).
    explanation: >-
      The case series supports biallelic RAB33B pathogenic variants as the
      molecular confirmation for SMC2.
discussions:
- discussion_id: gap_rab33b_mouse_partial_recapitulation
  prompt: >-
    Does the Rab33b Lys46Gln knock-in mouse capture the disease-relevant human
    skeletal mechanism broadly enough to infer the SMC2 pathograph, or does its
    partial, male-restricted phenotype mean that human chondrocyte, osteoclast,
    and glycosylation biology require additional model systems?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Osteoclast and protein-glycosylation dysfunction
  - pathophysiology#Spondyloepimetaphyseal skeletal dysplasia
  rationale: >-
    The Rab33b knock-in mouse provides the strongest functional bridge from
    RAB33B Golgi/autophagy dysfunction to bone resorption and glycosylation
    defects, but the same paper reports incomplete and sex-specific phenotypic
    recapitulation. That makes the mouse evidence valuable for mechanism
    directionality while leaving uncertainty about which skeletal-cell defects
    drive the progressive human spondylo-epi-metaphyseal phenotype.
  proposed_experiments:
  - experiment_id: exp_rab33b_human_skeletal_cell_models
    name: Isogenic RAB33B-deficient human skeletal-cell differentiation models
    description: >-
      Generate patient-derived or CRISPR-edited human iPSC chondrocyte and
      osteoclast differentiation systems and compare Golgi localization,
      autophagosome formation, protein glycosylation, matrix production, and
      bone-resorption readouts against rescued and wild-type controls.
  - experiment_id: exp_rab33b_mouse_sex_age_series
    name: Sex- and age-stratified Rab33b knock-in skeletal phenotyping
    description: >-
      Extend the Rab33b Lys46Gln mouse analysis across both sexes and multiple
      developmental ages with vertebral, growth-plate, osteoclast, and
      glycosylation readouts to test whether the human phenotype is missed
      because of timing, skeletal site, or sex-specific expressivity.
  evidence:
  - reference: PMID:37359363
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mouse model only reproduced some of the features of the human disease
      and was sex-specific, manifesting in male but not female mice.
    explanation: >-
      The model paper itself identifies the mismatch that motivates this open
      discussion.
📚

References & Deep Research

Deep Research

1
RAB33B-Related Smith-McCort Dysplasia 2 Deep Research Fallback ▸

RAB33B-Related Smith-McCort Dysplasia 2 Deep Research Fallback

Scope

No provider-generated deep research artifact was present on the WP-068 branch. This fallback audit documents the literature scope used to curate and review the RAB33B-related entry from cached PubMed references.

Evidence Scope Used For Curation

  • PMID:23042644 for the RAB33B Smith-McCort dysplasia report, autosomal recessive spondylo-epi-metaphyseal dysplasia, normal intelligence and no microcephaly distinction from Dyggve-Melchior-Clausen syndrome, and reduced Rab33b protein evidence.
  • PMID:28127940 for three additional RAB33B-related SMC patients, novel homozygous and compound-heterozygous variants, and the shared spondylo-epi-metaphyseal phenotype with lacy ilia.
  • PMID:31408960 for RAB33B Golgi localization and membrane-trafficking/autophagy biology.
  • PMID:37359363 for the Rab33b knock-in model linking the disorder to osteoclast dysfunction, protein glycosylation abnormalities, bone resorption defects, and short-trunk/short-bone skeletal-growth features.
  • PMID:41506134 for functional evidence that disease-causing RAB33B variants mislocalize away from Golgi membranes and impair autophagosome formation.

Curation Conclusions

The supported model is biallelic RAB33B dysfunction causing a Golgi Rab GTPase defect with Golgi mislocalization, reduced protein stability, impaired autophagy-associated membrane trafficking, and downstream osteoclast/protein glycosylation abnormalities. The phenotype should focus on spondylo-epi-metaphyseal skeletal dysplasia and short stature while preserving the reported distinction that classic Smith-McCort dysplasia has normal cognition and no microcephaly.