This entry is scoped to the MONDO:0100144 TUBB2B p.Arg390Gln-specific entity, not to every disorder historically described as Uner Tan syndrome. The defining report identified a biallelic p.Arg390Gln substitution in a consanguineous family with three affected individuals. All three had habitual quadrupedal locomotion and severe cerebellar hypoplasia, and none had the basal ganglia malformations reported in other TUBB2B-associated disease. Variant assays found intact beta-tubulin folding, alpha/beta-heterodimer assembly, and incorporation of variant-containing heterodimers into microtubule polymers. A homologous yeast TUB2-390Q model grew normally under basal conditions but was more sensitive to microtubule-depolymerizing drugs. These measurements support a mild perturbation of microtubule function but do not establish a specific functional-impact class in the developing human brain, exclude every possible dominant-negative effect, explain recessivity, or resolve the intermediates leading to cerebellar hypoplasia. The allele, inheritance, and anatomical pattern distinguish this entity from de novo TUBB2B-related complex cortical dysplasia and from the genetically heterogeneous CAMRQ disorders that can also include quadrupedal gait.
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Conditions with similar clinical presentations that must be differentiated from Uner Tan Syndrome:
name: Uner Tan Syndrome
creation_date: "2026-08-20T18:20:00Z"
category: Mendelian
synonyms:
- recessive quadrupedalism
disease_term:
preferred_term: Uner Tan Syndrome
term:
id: MONDO:0100144
label: Uner Tan Syndrome
description: >-
This entry is scoped to the MONDO:0100144 TUBB2B p.Arg390Gln-specific entity,
not to every disorder historically described as Uner Tan syndrome. The
defining report identified a biallelic p.Arg390Gln substitution in a
consanguineous family with three affected individuals. All three had habitual
quadrupedal locomotion and severe cerebellar hypoplasia, and none had the basal
ganglia malformations reported in other TUBB2B-associated disease.
Variant assays found intact beta-tubulin folding, alpha/beta-heterodimer
assembly, and incorporation of variant-containing heterodimers into
microtubule polymers. A homologous yeast TUB2-390Q model grew normally under
basal conditions but was more sensitive to microtubule-depolymerizing drugs.
These measurements support a mild perturbation of microtubule function but do
not establish a specific functional-impact class in the developing human
brain, exclude every possible dominant-negative effect, explain recessivity,
or resolve the intermediates leading to cerebellar hypoplasia.
The allele, inheritance, and anatomical pattern distinguish this entity from
de novo TUBB2B-related complex cortical dysplasia and from the genetically
heterogeneous CAMRQ disorders that can also include quadrupedal gait.
parents:
- hereditary neurological disease
- congenital nervous system disorder
references:
- reference: PMID:28013290
title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
- reference: PMID:19465910
title: Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.
- reference: PMID:41080462
title: A mutational hotspot in TUBB2A associated with impaired heterodimer formation and severe brain developmental disorders.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The reported consanguineous family carried a biallelic TUBB2B p.Arg390Gln
substitution. This supports autosomal recessive inheritance for this
allele-specific entity but does not by itself explain the molecular dosage
mechanism.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Analysis of a consanguineous UTS family identified a biallelic TUBB2B
mutation, resulting in a p.R390Q amino acid substitution.
explanation: >-
Establishes the biallelic variant and family context.
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The TUBB2B mutation described here represents an unusual recessive mode of
inheritance for missense-mediated tubulinopathies
explanation: >-
The authors explicitly interpret the reported inheritance as recessive.
pathophysiology:
- name: TUBB2B p.Arg390Gln-Associated Microtubule-Function Perturbation
role: TRIGGER
biological_scale: MOLECULAR
description: >-
The biallelic p.Arg390Gln substitution is the molecular trigger. Assays found
no detectable defect in three measured steps: beta-tubulin folding,
alpha/beta-heterodimer assembly, and incorporation into microtubule polymers.
A homologous yeast model showed normal basal growth but increased sensitivity
to microtubule-depolymerizing drugs. The human neural-cell consequence and
precise functional class remain unresolved.
genetic_context:
functional_impact_category: UNKNOWN
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
allele_type: missense
description: >-
Homozygous p.Arg390Gln. Intact performance in the assayed steps and a mild
yeast challenge phenotype do not establish partial loss of function, prove
haplosufficiency, or exclude unmeasured dominant-negative or other effects
in human neurodevelopment.
genes:
- preferred_term: TUBB2B
term:
id: hgnc:30829
label: TUBB2B
biological_processes:
- preferred_term: microtubule cytoskeleton organization
term:
id: GO:0000226
label: microtubule cytoskeleton organization
modifier: DYSREGULATED
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
explanation: >-
Directly reports intact performance in the three assayed biochemical and
assembly steps; it does not test every possible variant effect.
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal
conditions, but did result in increased sensitivity to
microtubule-depolymerizing drugs, indicative of a mild impact of this
mutation on microtubule function.
explanation: >-
Shows a challenge-dependent phenotype in a homologous yeast model rather
than a direct readout in developing human neural tissue.
downstream:
- target: Cerebellar Developmental Abnormality
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The report links the tubulin variant to cerebellar hypoplasia, but the
intervening neural cell types, developmental stages, and cellular events
were not resolved.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The TUBB2B mutation described here represents an unusual recessive mode
of inheritance for missense-mediated tubulinopathies and reinforces the
sensitivity of the developing cerebellum to microtubule defects.
explanation: >-
This is the authors' disease-level inference, not a directly mapped
cellular pathway from the variant to the anatomical finding.
- name: Cerebellar Developmental Abnormality
biological_scale: TISSUE
description: >-
Severe cerebellar hypoplasia was present in all three affected individuals.
The source interprets this pattern as evidence that the developing
cerebellum is sensitive to microtubule defects, but it does not identify a
selectively affected cerebellar cell type or prove a tissue-specific
threshold mechanism.
biological_processes:
- preferred_term: cerebellum development
term:
id: GO:0021549
label: cerebellum development
modifier: DYSREGULATED
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to the identifying quadrupedal locomotion, all three patients
showed severe cerebellar hypoplasia.
explanation: >-
Establishes the structural cerebellar finding in the complete reported
affected set.
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
reinforces the sensitivity of the developing cerebellum to microtubule
defects
explanation: >-
Records the authors' interpretation while preserving its inferential
source type.
downstream:
- target: Cerebellar Hypoplasia
description: >-
The developmental abnormality is observed structurally as cerebellar
hypoplasia.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all three patients showed severe cerebellar hypoplasia
explanation: >-
Directly connects the cerebellar developmental node to the reported
anatomical phenotype.
- target: Habitual Quadrupedal Locomotion
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The co-occurrence of quadrupedal locomotion and severe cerebellar
hypoplasia motivates an emerging hypothesis that cerebellar developmental
abnormality contributes to the locomotor phenotype through unresolved
intermediates. This edge does not assert that cerebellar hypoplasia
directly causes the gait pattern or identify a single causal route.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In addition to the identifying quadrupedal locomotion, all three patients
showed severe cerebellar hypoplasia.
explanation: >-
The source establishes co-occurrence in three affected individuals, not
causation. OTHER records that the proposed link is an explicit
disease-level inference rather than a demonstrated mechanistic route.
phenotypes:
- name: Habitual Quadrupedal Locomotion
category: Neurologic
frequency: 3/3 affected individuals in the reported family
description: >-
Quadrupedal locomotion was the identifying locomotor phenotype in all three
reported affected individuals. It is recorded descriptively; the available
evidence does not establish a single causal path from cerebellar hypoplasia
to this locomotor strategy.
phenotype_term:
preferred_term: Cerebellar ataxia associated with quadrupedal gait
term:
id: HP:0009878
label: Cerebellar ataxia associated with quadrupedal gait
notes: >-
HP:0009878 is the exact HPO concept for cerebellar ataxia associated with
quadrupedal gait. Neither this term nor the curated source supports
evolutionary-hierarchy descriptions of affected people.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition to the identifying quadrupedal locomotion, all three patients
showed severe cerebellar hypoplasia.
explanation: >-
Names quadrupedal locomotion as the identifying feature in all three
affected individuals.
- name: Cerebellar Hypoplasia
category: Neurologic
frequency: 3/3 affected individuals in the reported family
severity: SEVERE
description: >-
Severe cerebellar hypoplasia was reported in all three affected individuals.
The denominator describes the single reported family and must not be treated
as a population frequency estimate.
phenotype_term:
preferred_term: Cerebellar hypoplasia
term:
id: HP:0001321
label: Cerebellar hypoplasia
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all three patients showed severe cerebellar hypoplasia
explanation: >-
Reports the finding and severity in the complete affected set.
imaging_findings:
- name: Reported Absence of Basal Ganglia Malformation
modality: OTHER
frequency: 3/3 affected individuals in the reported family
description: >-
None of the three affected individuals had the basal ganglia malformations
described as typical of other TUBB2B mutations. This is a negative structural
finding, not a positive abnormal-basal-ganglia phenotype and not a validated
pathognomonic test.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
None, however, displayed the basal ganglia malformations typically
associated with TUBB2B mutations.
explanation: >-
Directly supports the explicitly negative finding; SUPPORT applies to the
absence statement itself.
genetic:
- name: TUBB2B
association: Causative
gene_term:
preferred_term: TUBB2B (beta-tubulin 2B)
term:
id: hgnc:30829
label: TUBB2B
notes: >-
This association is variant- and inheritance-specific: the curated entity is
anchored to biallelic p.Arg390Gln. It should not be generalized to every
biallelic TUBB2B finding or merged with de novo TUBB2B
cortical-malformation disease without separate evidence.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Analysis of a consanguineous UTS family identified a biallelic TUBB2B
mutation, resulting in a p.R390Q amino acid substitution.
explanation: >-
Identifies TUBB2B and the specific biallelic substitution in the reported
family.
diagnosis:
- name: Molecular Identification of Biallelic TUBB2B p.Arg390Gln
presence: Biallelic TUBB2B p.Arg390Gln in an individual with a compatible phenotype
results: >-
Identification of the biallelic p.Arg390Gln substitution supports assignment
to this allele-specific MONDO entity.
description: >-
Quadrupedal gait and cerebellar hypoplasia are not gene-specific. Molecular
identification of the biallelic TUBB2B p.Arg390Gln substitution distinguishes
this entity from de novo TUBB2B cortical-malformation disease and from
other genetic causes of a similar clinical pattern. Evidence is limited to
one reported family, so this is a scope boundary rather than a validated
diagnostic performance claim.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Analysis of a consanguineous UTS family identified a biallelic TUBB2B
mutation, resulting in a p.R390Q amino acid substitution.
explanation: >-
Supports molecular definition by the biallelic p.Arg390Gln finding.
differential_diagnoses:
- name: TUBB2B-Related Complex Cortical Dysplasia with Other Brain Malformations 7
disease_term:
preferred_term: complex cortical dysplasia with other brain malformations 7
term:
id: MONDO:0012399
label: complex cortical dysplasia with other brain malformations 7
description: >-
This differential shares TUBB2B but is associated with de novo variants and
a cortical-malformation pattern rather than the biallelic
p.Arg390Gln-specific entity curated here.
distinguishing_features:
- De novo TUBB2B variants with bilateral asymmetrical polymicrogyria favor complex cortical dysplasia with other brain malformations 7.
- Biallelic p.Arg390Gln with severe cerebellar hypoplasia and no reported basal ganglia malformation favors this entry.
evidence:
- reference: PMID:19465910
reference_title: Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four
individuals and a 27-gestational-week fetus with bilateral asymmetrical
polymicrogyria.
explanation: >-
Establishes the de novo inheritance and cortical-malformation pattern of
the same-gene differential.
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
None, however, displayed the basal ganglia malformations typically
associated with TUBB2B mutations.
explanation: >-
Supports the reported anatomical distinction from typical TUBB2B disease.
- name: Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndromes
disease_term:
preferred_term: cerebellar ataxia, intellectual disability, and dysequilibrium
term:
id: MONDO:0009133
label: cerebellar ataxia, intellectual disability, and dysequilibrium
description: >-
The CAMRQ umbrella covers genetically heterogeneous autosomal recessive
cerebellar disorders, including separately curated VLDLR-, WDR81-, CA8-, and
ATP8A2-related subtypes. Some historical uses of the Uner Tan eponym overlap
this broader clinical group; molecular diagnosis is needed to preserve the
disease boundary.
distinguishing_features:
- A causal finding in VLDLR, WDR81, CA8, or ATP8A2 favors the corresponding CAMRQ subtype.
- Biallelic TUBB2B p.Arg390Gln favors the MONDO:0100144 entity curated here.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Analysis of a consanguineous UTS family identified a biallelic TUBB2B
mutation, resulting in a p.R390Q amino acid substitution.
explanation: >-
Supports the TUBB2B p.Arg390Gln side of the differential. The broader CAMRQ
taxonomy is an ontology and cross-record assertion, as stated below.
notes: >-
This is an ontology and cross-record scope assertion. Source-level evidence
for the four CAMRQ subtypes remains in the separately curated
Cerebellar_Ataxia_Intellectual_Disability_and_Dysequilibrium record and is not
duplicated here.
treatments: []
experimental_models:
- name: TUBB2B p.Arg390Gln Folding, Heterodimer-Assembly, and Polymer-Incorporation Assays
description: >-
Variant-focused assays tested beta-tubulin folding, alpha/beta-heterodimer
assembly, and incorporation of variant-containing heterodimers into
microtubule polymers. All three measured steps were intact; the assays do not
model developing neural tissue or establish that every microtubule function
is normal.
experimental_model_type: OTHER
conditions:
- TUBB2B p.Arg390Gln compared with wild-type protein in folding, heterodimer-assembly, and polymer-incorporation assays
publication: PMID:28013290
modeled_mechanisms:
- target: TUBB2B p.Arg390Gln-Associated Microtubule-Function Perturbation
description: >-
Tests three candidate molecular failure points and finds no detectable
impairment in those specific readouts.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
explanation: >-
Connects the assay model to the specific measured aspects of the trigger
node.
findings:
- statement: >-
p.Arg390Gln did not measurably impair folding, heterodimer assembly, or
incorporation into microtubule polymers.
supporting_text: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
explanation: >-
Supports the negative result for each of the three measured assay steps.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
explanation: >-
Defines the measured in-vitro system and its negative results.
- name: Saccharomyces cerevisiae TUB2-390Q Drug-Sensitivity Model
description: >-
A homologous 390Q substitution in yeast TUB2 produced normal basal growth but
increased sensitivity to microtubule-depolymerizing drugs. This provides a
model-organism challenge readout of microtubule function, not a human neural
developmental model.
experimental_model_type: OTHER
organism:
preferred_term: Saccharomyces cerevisiae
term:
id: NCBITaxon:4932
label: Saccharomyces cerevisiae
conditions:
- TUB2-390Q under basal growth conditions
- TUB2-390Q challenged with microtubule-depolymerizing drugs
publication: PMID:28013290
modeled_mechanisms:
- target: TUBB2B p.Arg390Gln-Associated Microtubule-Function Perturbation
description: >-
Models the homologous substitution and reveals a phenotype only under a
microtubule-destabilizing challenge.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal
conditions, but did result in increased sensitivity to
microtubule-depolymerizing drugs, indicative of a mild impact of this
mutation on microtubule function.
explanation: >-
Connects the homologous yeast challenge phenotype to the molecular
perturbation node.
findings:
- statement: >-
TUB2-390Q preserved basal growth but increased sensitivity to
microtubule-depolymerizing drugs.
supporting_text: >-
The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal
conditions, but did result in increased sensitivity to
microtubule-depolymerizing drugs, indicative of a mild impact of this
mutation on microtubule function.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal
conditions, but did result in increased sensitivity to
microtubule-depolymerizing drugs, indicative of a mild impact of this
mutation on microtubule function.
explanation: >-
Supports the stated basal-growth and drug-sensitivity finding.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The 390Q mutation in S. cerevisiae TUB2 did not affect growth under basal
conditions, but did result in increased sensitivity to
microtubule-depolymerizing drugs, indicative of a mild impact of this
mutation on microtubule function.
explanation: >-
Directly reports the basal and challenged phenotypes of the yeast model.
datasets: []
clinical_trials: []
discussions:
- discussion_id: gap_uner_tan_arg390_versus_tubb2a_arg391
prompt: >-
Which of substitution chemistry, tubulin-isotype context, and zygosity
explains the different observations for TUBB2B p.Arg390Gln and TUBB2A
p.Arg391His?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#TUBB2B p.Arg390Gln-Associated Microtubule-Function Perturbation
rationale: >-
TUBB2B p.Arg390Gln leaves the assayed folding, heterodimer-assembly, and
polymer-incorporation steps intact and is reported in the biallelic state.
The structurally corresponding TUBB2A p.Arg391His variant is heterozygous and
computationally predicted to weaken heterodimer formation. These records do
not isolate residue substitution, isotype background, or allele dosage.
Reciprocal substitutions tested in the same experimental system could help
separate those variables; the current comparison cannot establish an
isotype-specific mechanism by analogy alone.
evidence:
- reference: PMID:28013290
reference_title: Uner Tan syndrome caused by a homozygous TUBB2B mutation affecting microtubule stability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional analysis of the R390Q substitution revealed that it did not
affect the ability of β-tubulin to fold or become assembled into the
α/β-heterodimer, nor did it influence the incorporation of
mutant-containing heterodimers into microtubule polymers.
explanation: >-
Defines the directly assayed TUBB2B side of the comparison.
- reference: PMID:41080462
reference_title: A mutational hotspot in TUBB2A associated with impaired heterodimer formation and severe brain developmental disorders.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
Computational modeling demonstrated that the variant disrupts α/β-tubulin
heterodimer formation, impairing binding stability at this critical
interaction site.
explanation: >-
Defines the computational TUBB2A side and prevents it from being presented
as an experimentally demonstrated cellular effect.
notes: >-
This entry remains separate from TUBB2A/TUBB2B-related Cortical Malformation.
That record maps MONDO:0100144 as skos:relatedMatch, reflecting a reviewed
same-gene boundary rather than a subtype assertion. The existing CAMRQ umbrella
record separately curates CAMRQ1 (VLDLR), CAMRQ2 (WDR81), CAMRQ3 (CA8), and
CAMRQ4 (ATP8A2), correcting the earlier statement that these entities were
uncurated.
The entry is intentionally not a member of the Tubulinopathies grouping. That
grouping currently requires evidence for microtubule-dependent neuronal
migration failure; the cached evidence for this entity supports cerebellar
developmental involvement but does not establish cortical migration failure.
It is likewise not mapped to the cerebellar Purkinje-cell degeneration module:
the documented lesion is developmental hypoplasia, not demonstrated
degeneration.
Curated prose uses affected individuals, intellectual disability where
source-supported, and habitual quadrupedal locomotion. Terms such as primitive,
devolution, reverse evolution, and atavism are not used: the curated evidence
supports a locomotor phenotype and neurodevelopmental disorder, not an
evolutionary hierarchy. The gait is not presented as proof of a single causal
route from cerebellar hypoplasia.
review_notes: >-
Evidence review completed 2026-08-24. The cache for PMID:28013290 remained
content_type abstract_only after sanctioned regeneration, so clinical details
available only in the full article were not promoted into structured or
snippet-backed claims. The modality of the reported structural brain findings
is consequently left unspecified. PMID:19465910 is also abstract-only;
PMID:41080462 is cached as full_text_xml. Every evidence snippet is exact text
from the corresponding cache and its evidence_source reflects human clinical,
in-vitro, model-organism, computational, or author-inference provenance.
Functional-impact classification was changed from PARTIAL_LOSS_OF_FUNCTION to
UNKNOWN. Intact performance in selected assays and mild yeast drug sensitivity
do not prove hypomorphic loss of function, explain recessivity, or exclude
unmeasured mechanisms. The variant-to-cerebellar link is therefore explicitly
INDIRECT_UNKNOWN_INTERMEDIATES, and cerebellar hypoplasia is not asserted to
cause habitual quadrupedal locomotion.
Frequencies are reported only as 3/3 affected individuals in the single family,
not as population estimates. The negative basal-ganglia observation is modeled
as a supported negative structural finding rather than a positive HPO
abnormality with REFUTE evidence. HP:0009878 replaces the nonspecific
gait-ataxia binding because it is the exact HPO term for cerebellar ataxia
associated with quadrupedal gait.
No disorder-specific therapeutic study or management guideline was present in
the reviewed evidence, so unsupported treatment-effect entries were removed.
Exact-name and gene/variant ClinicalTrials.gov searches returned no registered
studies on 2026-08-24; clinical_trials is therefore empty. Disease- and
variant-specific NCBI GDS, SRA, and BioProject searches returned no dedicated
dataset. The full article's dbGaP accession belongs to a broader
controlled-access exome initiative rather than a Uner Tan syndrome-specific
dataset, so datasets is empty and no dbGaP cache was created. A current literature scan did
not provide adequate evidence to expand MONDO:0100144 beyond p.Arg390Gln; a
later biallelic TUBB2B report involved a dual molecular diagnosis and was not
used to lump entities.