TUBB1-related Macrothrombocytopenia

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Inheritance

2

Autosomal dominant inheritance with incomplete penetrance HP:0000006

Most reported disease-associated alleles are heterozygous and segregate in dominant pedigrees, but a carrier may have macrothrombocytopenia, isolated platelet enlargement, or normal platelet count and size.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:34516618 SUPPORT Human Clinical

"Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities."

Directly establishes incomplete penetrance across nine TUBB1 families.

PMID:33400601 SUPPORT Human Clinical

"These findings were consistent with an autosomal dominant inheritance with incomplete penetrance."

Independently documents dominant inheritance with incomplete penetrance.

Variant-specific biallelic allele-burden pattern HP:0000007

In one consanguineous pedigree, p.Gly109Glu produced macrothrombocytopenia in homozygotes; heterozygous relatives generally had increased platelet size alone or normal platelets. This is a variant-specific observation, not evidence that all TUBB1 disease is recessive.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT."

Establishes the biallelic phenotype for this allele.

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Discussions and Knowledge Gaps

4

Which allele-specific, genetic, or environmental factors determine whether a carrier has macrothrombocytopenia, isolated enlargement, or normal traits?

KNOWLEDGE GAP OPEN gap_tubb1_variant_penetrance_and_allele_burden

Attached to

pathophysiology#Variant-Specific Disruption of Beta-1 Tubulin

Rare heterozygous alleles show incomplete penetrance, while p.Gly109Glu caused macrothrombocytopenia only in homozygotes in one family.

Show evidence (3 references)

PMID:34516618 SUPPORT Human Clinical

"These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants."

States the unresolved modifiers.

PMID:32892537 SUPPORT Human Clinical

"Further clinical and functional studies of the newly identified TUBB1 variants may offer important insights into their pathogenicity in macrothrombocytopenia."

Supports caution for newly observed alleles.

PMID:34516618 SUPPORT Human Clinical

"These findings support the hypothesis that upregulation of other β-tubulin isoforms may counteract the β1-tubulin defect."

Identifies compensatory tubulin expression as a candidate modifier, not a proven explanation of incomplete penetrance.

Why do some families show functional platelet abnormalities while other disruptive alleles leave activation, secretion, aggregation, and spreading normal?

KNOWLEDGE GAP OPEN gap_tubb1_platelet_function_heterogeneity

Attached to

pathophysiology#Marginal-Ring and Platelet-Maturation Defect

Structural marginal-ring defects do not predict a single functional phenotype.

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"There seems to be a divergence in the impact of variants on β1-tubulin incorporation into microtubules and on platelet function."

Explicitly identifies the divergence.

Do tissue-specific thresholds or modifiers partition thyroid dysgenesis and macrothrombocytopenia among carriers of the same TUBB1 alleles?

KNOWLEDGE GAP OPEN gap_tubb1_platelet_thyroid_tissue_penetrance

Attached to

pathophysiology#Variant-Specific Disruption of Beta-1 Tubulin pathophysiology#Thyroid Cell Proliferation Defect

The 2025 functional follow-up used the same 289-patient Shandong series reported in 2019. Its four p.Arg318Trp thyroid-agenesis cases had normal platelets, while platelet cohorts have not systematically established the prevalence of thyroid dysgenesis.

Show evidence (1 reference)

PMID:40071799 SUPPORT Human Clinical

"these 4 patients in our study cohort displayed normal platelets"

Documents the thyroid phenotype without a platelet phenotype.

Does impaired p53-dependent DNA-damage surveillance confer meaningful myeloid-malignancy risk across TUBB1 disease or only in particular families?

KNOWLEDGE GAP OPEN gap_tubb1_myeloid_malignancy_generalizability

Attached to

pathophysiology#Attenuated DNA-Damage Response in TUBB1-Deficient Cells

Myeloid malignancy and p.Thr149Pro were identified together in one family; no cited cohort establishes penetrance or excess risk.

Show evidence (1 reference)

PMID:30854628 SUPPORT Human Clinical

"We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P."

Establishes the family observation but not general risk.

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Pathophysiology

5

Variant-Specific Disruption of Beta-1 Tubulin

Disease-associated TUBB1 alleles do not have one uniform molecular effect. Several missense proteins fail to incorporate into microtubules, whereas p.Arg359Trp partly incorporates and has a weaker distribution defect; truncating alleles are also reported. The shared consequence across functionally tested alleles is disturbed beta-1-tubulin organization or dosage, not a universal simple loss-of-function mechanism.

megakaryocyte CL:0000556 platelet CL:0000233

TUBB1 hgnc:16257

Genetic context variant_origin: GERMLINE functional_impact_category: UNKNOWN

Heterozygous missense, frameshift, and nonsense alleles occur with incomplete penetrance. Homozygous p.Gly109Glu shows an allele-burden effect. UNKNOWN is used because assayed alleles differ in incorporation, abundance, and zygosity.

microtubule cytoskeleton organization GO:0000226 ↕ DYSREGULATED

Experimental models

TUBB1 variant-transfected CHO cells CELL LINE Compares molecular effects across multiple missense variants.

Downstream

Marginal-Ring and Platelet-Maturation Defect Disturbed beta-1 tubulin compromises platelet production and structure.

Variant-Dependent Platelet Functional Effects This is an allele- and family-dependent branch rather than an obligate consequence: hyperaggregation or impaired release occurs in selected families, while several other genotypes retain normal tested responses.

Attenuated DNA-Damage Response in TUBB1-Deficient Cells Loss or dysfunction of TUBB1 can attenuate the DNA-damage response in experimental cells, but generalization from the reported family and cell models to all clinical alleles remains unproven.

Thyroid Cell Proliferation Defect The thyroid branch is restricted to particular alleles and incompletely penetrant; p.Arg318Trp reduced TUBB1 abundance and proliferation in a thyroid-cell model.

Show evidence (2 references)

PMID:24344610 SUPPORT In Vitro

"Mutant β1-tubulin was not incorporated into microtubules with endogenous α-tubulin, and α-tubulin expression was decreased in transfected Chinese hamster ovary cells."

Establishes failed incorporation for p.Phe260Ser.

PMID:34516618 SUPPORT In Vitro

"whereas the p.Arg359Trp variant exerted a visible but weaker deleterious effect in β1-tubulin distribution."

Supports variant-to-variant differences in incorporation.

Marginal-Ring and Platelet-Maturation Defect

Patient platelets can lose or disorganize the beta-1-tubulin marginal ring. Patient-derived megakaryocytes show variant- and penetrance-dependent impairment of proplatelet formation, and circulating preplatelets show impaired final maturation.

megakaryocyte CL:0000556 platelet CL:0000233

platelet formation GO:0030220 ↓ DECREASED

Experimental models

Patient-derived CD34-positive megakaryocytes PRIMARY CELL CULTURE Reproduces impaired maturation and proplatelet formation.

Animal models

Tubb1 knockout mouse Mouse (Mus musculus) partially recapitulates Reproduces impaired proplatelet formation and macrothrombocytopenia.

Downstream

Macrothrombocytopenia Reduced production and maturation yield fewer, larger platelets.

Giant Platelets Defective maturation generates large and giant platelets.

Abnormal Bleeding Bleeding is a variable clinical consequence; the available cohort does not resolve whether severity tracks platelet count, platelet size, or qualitative platelet function.

Show evidence (2 references)

PMID:24344610 SUPPORT Human Clinical

"A circumferential marginal microtubule band was undetectable, whereas microtubules were frayed and disorganized in every platelet from the affected individuals."

Direct cytological evidence from p.Phe260Ser patient platelets.

PMID:34516618 SUPPORT In Vitro

"The deleterious functional effect of TUBB1 variants (p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu) is strongly supported by the finding of impaired MK maturation and proplatelet formation by MKs differentiated from CD34+ cell from thrombocytopenic carriers of these mutations."

Links three variants to impaired patient-derived megakaryocytes.

Thyroid Cell Proliferation Defect

The recurrent heterozygous p.Arg318Trp allele occurs in independent thyroid-dysgenesis cohorts. In human thyroid cells it reduced TUBB1 abundance and significantly inhibited proliferation. Its effect on wound-healing migration was not significant, so impaired migration is not asserted as the human cellular mechanism.

TUBB1 hgnc:16257

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN

The allele is associated with thyroid dysgenesis and has functional effects in thyroid cells, but the authors describe susceptibility and call for further mechanistic work.

thyroid gland development GO:0030878 ↕ DYSREGULATED

Experimental models

p.Arg318Trp-transfected human thyroid cells CELL LINE Reproduces reduced abundance and proliferation, but not significant migration.

Downstream

Congenital Hypothyroidism Associated with Thyroid Dysgenesis Reduced proliferation is a candidate route to thyroid agenesis.

Show evidence (2 references)

PMID:40071799 SUPPORT In Vitro

"The c.952C>T mutant decreased the expression of TUBB1 in both mRNA and protein level, and inhibited the proliferation of thyroid cells significantly."

Supports reduced expression and proliferation.

PMID:40071799 SUPPORT In Vitro

"Also, c.952C>T mutant showed restrain effects on the migration, although there was no stistical significance."

Prevents treating impaired migration as established.

Variant-Dependent Platelet Functional Effects

Platelet agglutination, granule release, and low-dose agonist responses are abnormal in some TUBB1 families, but activation, secretion, aggregation, and spreading remain nearly normal with several other alleles. The evidence therefore supports an allele- or context-dependent functional branch rather than a necessary consequence of marginal-ring disruption.

platelet CL:0000233

Downstream

Variable Platelet-Function Abnormalities Functional abnormalities occur in selected families while other carriers retain normal tested responses.

Show evidence (2 references)

PMID:33400601 SUPPORT Human Clinical

"Affected individuals within the family demonstrated impaired platelet aggregation and/or release functions."

Establishes the functional branch in the p.Arg318Trp family.

PMID:34516618 SUPPORT Human Clinical

"Moreover, homozygous and heterozygous carriers of p.Gly109Glu showed normal platelet aggregation response to different agonists"

Supports the node's allele-dependent qualification by documenting a genotype with normal aggregation.

Attenuated DNA-Damage Response in TUBB1-Deficient Cells

In a thrombocytopenia family with myeloid malignancy, TUBB1 deficiency was associated experimentally with reduced nuclear p53 accumulation, pro-apoptotic transcription, and apoptosis after genotoxic stress. This is a plausible genome-instability route, not an established universal malignancy phenotype.

TUBB1 hgnc:16257

Experimental models

TUBB1-deficient DNA-damage cell model CELL LINE Reproduces failure to eliminate DNA-damaged cells.

Show evidence (1 reference)

PMID:30854628 SUPPORT In Vitro

"We found that the nuclear accumulation of p53 (also termed TP53) and the expression of pro-apoptotic genes triggered by genotoxic stress were blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB1."

States the measured DNA-damage-response defects.

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Pathograph

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Phenotypes

5

Blood 4

Macrothrombocytopenia HP:0040185

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"Thrombocytopenia, defined as platelet count below the normal healthy volunteer range (n = 107; 142-359 × 109/L), was in general moderate (median, 76; range, 57-134 × 109/L) and associated with increased platelet size (mean platelet volume [MPV], 13.3-15.0 fL; normal, 9.0-12.8 fL; Table 1)."

Direct cohort evidence for the combined count-and-size phenotype.

Giant Platelets HP:0001902

Show evidence (2 references)

PMID:34516618 SUPPORT Human Clinical

"Variable platelet size was observed with large (arrows) and giant (cross) platelets."

Directly documents large and giant circulating platelets.

PMID:34516618 SUPPORT Human Clinical

"In this family, several subjects across 3 generations displayed increased MPV, but only the 2 probands were thrombocytopenic (≈60 × 109/L at electronic counting), although they did not have excessive bleeding, including at childbirths and miscarriage (II.1). Microscopic platelet counting44 was..."

Supports the observed microscopic count and size distribution underlying the caution about automated counting of very large platelets.

Abnormal Bleeding HP:0001892

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"The index probands were referred for possible IPD because of lifelong macrothrombocytopenia although, for most of them, this was not associated with a relevant bleeding tendency (ISTH-BAT mean score ± standard deviation [SD]: 1.10 ± 2.07; median, 0; range, 0-8; Table 1)."

Directly quantifies the usually low but variable bleeding burden.

Variable Platelet-Function Abnormalities Abnormal platelet function HP:0011869

Show evidence (3 references)

PMID:33400601 SUPPORT Human Clinical

"Moreover, impaired platelet agglutination in response to ristocetin was detected in the patient's brother. Half of the family members harboring the p.R318W mutation displayed significantly decreased external release of p-selectin by stimulated platelets."

Documents two abnormalities in one p.Arg318Trp family.

PMID:30446499 SUPPORT Human Clinical

"In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists"

Documents the hyperaggregation result in the thyroid-ascertained families.

PMID:34516618 SUPPORT Human Clinical

"The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes."

Supports the phenotype's explicit non-universality by documenting several genotypes with negligible functional effects.

Endocrine 1

Congenital Hypothyroidism Associated with Thyroid Dysgenesis HP:0000851

Show evidence (3 references)

PMID:30446499 SUPPORT Human Clinical

"We identified three novel TUBB1 gene mutations that co-segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort."

Establishes familial co-segregation and the original association.

PMID:31642429 SUPPORT Human Clinical

"Among the 289 children with CH and TD, 4 (1.4%) were found to have a c.952C>T(p.R318W) heterozygous mutation in the TUBB1 gene"

Replicates the association; classification remained potentially pathogenic.

PMID:40071799 SUPPORT Human Clinical

"all 4 patients harbouring the c.952C>T mutation showed thyroid agenesis, underscoring its detrimental effect on cell survival during thyroid development. Notably, these 4 patients in our study cohort displayed normal platelets"

Documents thyroid agenesis and tissue-discordant penetrance.

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Genetic Associations

1

TUBB1 (Causative)

Gene: TUBB1 (beta-1 tubulin, class VI) hgnc:16257

Show evidence (2 references)

PMID:34516618 SUPPORT Human Clinical

"Microtubules are assembled by heterodimers of α and β-tubulin, and β1-tubulin, encoded by TUBB1, is the predominant β-tubulin isoform in megakaryocytes (MKs) and platelets."

Supports the platelet-lineage context without claiming exclusivity.

PMID:30446499 SUPPORT Human Clinical

"TUBB1 gene is expressed in the developing and adult thyroid in humans and mice."

Establishes expression in the second relevant tissue.

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Diagnosis

2

Blood count, blood smear, and platelet tubulin assessment

Count and size should be interpreted together and confirmed on a smear because automated counters may miss giant platelets. Beta-1-tubulin immunofluorescence can show an absent or disorganized marginal ring.

laboratory procedure NCIT:C25294

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"Venous blood samples were drawn into EDTA and sodium citrate for the different studies (complete blood count [CBC], immature platelet fraction [%IPF], blood smear and immunofluorescence, functional studies, electron microscopy, CD34+ cell isolation and MK cultures, DNA, and RNA)."

Documents the phenotyping modalities used in the largest series.

Molecular testing with segregation and functional interpretation

Sequence findings should be integrated with phenotype, segregation, allele burden, and functional evidence. Incomplete penetrance complicates family interpretation, and prediction algorithms alone are insufficient.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:34516618 SUPPORT Human Clinical

"In silico algorithms of prediction are not reliable enough when analyzing TUBB1 variants, ratifying the importance of clinical information and biological evaluation when establishing the pathogenicity of such variants."

Supports integrated interpretation rather than prediction alone.

🧫

Experimental Models

4

TUBB1 variant-transfected CHO cells CELL_LINE

CHO cells expressing wild-type or mutant TUBB1 compare beta-1-tubulin incorporation and distribution, but do not reproduce megakaryocyte biology.

Publication

PMID:34516618

Pathograph links

Variant-Specific Disruption of Beta-1 Tubulin recapitulates fidelity: moderate Compares molecular effects across multiple missense variants.

Limitations: CHO cells are neither human nor megakaryocytic and use overexpression.

Show evidence (1 reference)

PMID:34516618 SUPPORT In Vitro

"Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network."

Establishes the model and molecular readout.

Show evidence (1 reference)

PMID:34516618 SUPPORT In Vitro

"Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network."

Establishes the transfected-cell model.

Patient-derived CD34-positive megakaryocytes PRIMARY_CELL_CULTURE

Peripheral-blood CD34-positive cells from carriers were differentiated into megakaryocytes to test maturation and proplatelet formation.

Publication

PMID:34516618

Pathograph links

Marginal-Ring and Platelet-Maturation Defect recapitulates fidelity: high Reproduces impaired maturation and proplatelet formation.

Limitations: In-vitro formation does not fully represent platelet release in vivo, and results differed by carrier phenotype.

Show evidence (1 reference)

PMID:34516618 SUPPORT In Vitro

"TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes."

States the model's principal phenotype.

Show evidence (1 reference)

PMID:34516618 SUPPORT In Vitro

"TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes."

Establishes the patient-derived model.

p.Arg318Trp-transfected human thyroid cells CELL_LINE

Immortalized Nthy-ori 3.1 thyroid cells expressing p.Arg318Trp were assayed for TUBB1 abundance, proliferation, and scratch-wound migration.

Publication

PMID:40071799

Pathograph links

Thyroid Cell Proliferation Defect partially recapitulates fidelity: moderate Reproduces reduced abundance and proliferation, but not significant migration.

Limitations: An immortalized, plasmid-transfected line does not model embryonic thyroid morphogenesis; the scratch assay lacks a matrix environment.

Show evidence (1 reference)

PMID:40071799 SUPPORT In Vitro

"Functional experimental results indicated that the c.952C>T mutant dominantly affects gene expression and proliferation of thyroid cells."

Supports the expression and proliferation readouts.

Show evidence (1 reference)

PMID:40071799 SUPPORT In Vitro

"We performed real-time polymerase chain reaction (RT-PCR), western blot, Cell Counting Kit 8 (CCK8), and wound healing assay to evaluate the effect of TUBB1 c.952C>T on gene expression, cell proliferation, and migration."

Defines the model and assays.

TUBB1-deficient DNA-damage cell model CELL_LINE

TUBB1-deficient cells were exposed to genotoxic stress to test p53 accumulation, pro-apoptotic transcription, and apoptosis.

Publication

PMID:30854628

Pathograph links

Attenuated DNA-Damage Response in TUBB1-Deficient Cells recapitulates fidelity: moderate Reproduces failure to eliminate DNA-damaged cells.

Limitations: The abstract does not establish reproduction of the heterozygous patient genotype or malignancy risk across pedigrees.

Show evidence (1 reference)

PMID:30854628 SUPPORT In Vitro

"DNA damage response was severely attenuated by loss of TUBB1."

States the central result.

Show evidence (1 reference)

PMID:30854628 SUPPORT In Vitro

"apoptosis after DNA damage was diminished by knockdown of TUBB1."

Establishes the perturbation and readout.

🐁

Animal Models

1

Tubb1 knockout mouse

Tubb1-null mice reproduce impaired platelet production and macrothrombocytopenia and show abnormal thyroid development and secretion.

Species

Mouse (Mus musculus)

Genotype

Homozygous Tubb1 knockout

Publication

PMID:30446499

Pathograph links

Marginal-Ring and Platelet-Maturation Defect partially recapitulates fidelity: moderate Reproduces impaired proplatelet formation and macrothrombocytopenia.

Limitations: A homozygous null differs from heterozygous human alleles with incomplete penetrance and variant-specific effects.

Show evidence (1 reference)

PMID:34516618 SUPPORT Model Organism

"β1-tubulin knockout mice display impaired proplatelet formation and macrothrombocytopenia."

Identifies the reproduced platelet features.

Show evidence (1 reference)

PMID:30446499 SUPPORT Model Organism

"In mice, Tubb1 knock-out disrupted microtubule integrity by preventing β1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion."

Establishes the null model.

{ }

Source YAML

click to show

name: TUBB1-related Macrothrombocytopenia
creation_date: "2026-08-20T17:15:00Z"
category: Mendelian
disease_term:
preferred_term: macrothrombocytopenia, isolated, 1, autosomal dominant
term:
id: MONDO:0800047
label: macrothrombocytopenia, isolated, 1, autosomal dominant
description: >-
TUBB1-related macrothrombocytopenia is an inherited platelet disorder caused
by functionally consequential TUBB1 variants. Beta-1 tubulin is the
predominant beta-tubulin isoform in megakaryocytes and platelets. It supports
proplatelet formation and the marginal microtubule ring that maintains
platelet shape. Pathogenic alleles can alter incorporation or abundance of
beta-1 tubulin, disrupt the marginal ring and late platelet maturation, and
produce lifelong macrothrombocytopenia or isolated platelet enlargement.

The disorder is usually heterozygous with autosomal dominant transmission,
but platelet-trait penetrance is incomplete. One p.Gly109Glu pedigree showed
a clear allele-burden effect: macrothrombocytopenia occurred in homozygotes,
whereas heterozygotes generally had only enlarged or normal platelets.
Bleeding was mild or absent in most individuals in the largest cohort, and
automated counters can underestimate platelet number when platelets are very
large.

Platelet-function effects are not uniform. Hyperaggregation or impaired
agglutination and release has been reported in particular families, whereas
several other variants had negligible effects on activation, secretion,
aggregation, or spreading. Separately, heterozygous TUBB1 variants have been
associated with congenital hypothyroidism due to thyroid dysgenesis. This is
recorded as an incompletely penetrant allelic association rather than a core
feature of the MONDO-defined isolated platelet disorder: four
thyroid-agenesis cases carrying p.Arg318Trp had normal platelets.
parents:
- hereditary disease
- blood platelet disease
references:
- reference: PMID:24344610
title: TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.
- reference: PMID:30446499
title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
- reference: PMID:34516618
title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
- reference: PMID:32892537
title: Identification of novel TUBB1 variants in patients with macrothrombocytopenia.
- reference: PMID:30854628
title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
- reference: PMID:33400601
title: Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.
- reference: PMID:31642429
title: "[TUBB1 mutation in children with congenital hypothyroidism and thyroid dysgenesis in Shandong, China]."
- reference: PMID:40071799
title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
inheritance:
- name: Autosomal dominant inheritance with incomplete penetrance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Most reported disease-associated alleles are heterozygous and segregate in
dominant pedigrees, but a carrier may have macrothrombocytopenia, isolated
platelet enlargement, or normal platelet count and size.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Segregation studies showed incomplete penetrance of these variants for
platelet traits. Indeed, most carriers showed macrothrombocytopenia, some
only increased platelet size, and a minority had no abnormalities.
explanation: Directly establishes incomplete penetrance across nine TUBB1 families.
- reference: PMID:33400601
reference_title: Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings were consistent with an autosomal dominant inheritance
with incomplete penetrance.
explanation: Independently documents dominant inheritance with incomplete penetrance.
- name: Variant-specific biallelic allele-burden pattern
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
In one consanguineous pedigree, p.Gly109Glu produced
macrothrombocytopenia in homozygotes; heterozygous relatives generally had
increased platelet size alone or normal platelets. This is a
variant-specific observation, not evidence that all TUBB1 disease is
recessive.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moreover, only homozygous carriers of the p.Gly109Glu variant displayed
macrothrombocytopenia, highlighting the importance of allele burden in
the phenotypic expression of TUBB1-RT.
explanation: Establishes the biallelic phenotype for this allele.
pathophysiology:
- name: Variant-Specific Disruption of Beta-1 Tubulin
role: TRIGGER
biological_scale: MOLECULAR
description: >-
Disease-associated TUBB1 alleles do not have one uniform molecular effect.
Several missense proteins fail to incorporate into microtubules, whereas
p.Arg359Trp partly incorporates and has a weaker distribution defect;
truncating alleles are also reported. The shared consequence across
functionally tested alleles is disturbed beta-1-tubulin organization or
dosage, not a universal simple loss-of-function mechanism.
genetic_context:
functional_impact_category: UNKNOWN
variant_origin: GERMLINE
description: >-
Heterozygous missense, frameshift, and nonsense alleles occur with
incomplete penetrance. Homozygous p.Gly109Glu shows an allele-burden
effect. UNKNOWN is used because assayed alleles differ in incorporation,
abundance, and zygosity.
genes:
- preferred_term: TUBB1
term: {id: "hgnc:16257", label: TUBB1}
cell_types:
- preferred_term: megakaryocyte
term: {id: "CL:0000556", label: megakaryocyte}
- preferred_term: platelet
term: {id: "CL:0000233", label: platelet}
biological_processes:
- preferred_term: microtubule cytoskeleton organization
term: {id: "GO:0000226", label: microtubule cytoskeleton organization}
modifier: DYSREGULATED
evidence:
- reference: PMID:24344610
reference_title: TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Mutant β1-tubulin was not incorporated into microtubules with endogenous
α-tubulin, and α-tubulin expression was decreased in transfected Chinese
hamster ovary cells.
explanation: Establishes failed incorporation for p.Phe260Ser.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
whereas the p.Arg359Trp variant exerted a visible but weaker deleterious
effect in β1-tubulin distribution.
explanation: Supports variant-to-variant differences in incorporation.
downstream:
- target: Marginal-Ring and Platelet-Maturation Defect
description: Disturbed beta-1 tubulin compromises platelet production and structure.
- target: Variant-Dependent Platelet Functional Effects
description: >-
This is an allele- and family-dependent branch rather than an obligate
consequence: hyperaggregation or impaired release occurs in selected
families, while several other genotypes retain normal tested responses.
evidence:
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TUBB1 mutations caused the formation of macroplatelets and
hyperaggregation of human platelets after stimulation by low doses of
agonists
explanation: >-
Supports the functional branch in the reported families; PARTIAL
reflects that the effect is not shared by all tested alleles.
- target: Attenuated DNA-Damage Response in TUBB1-Deficient Cells
description: >-
Loss or dysfunction of TUBB1 can attenuate the DNA-damage response in
experimental cells, but generalization from the reported family and cell
models to all clinical alleles remains unproven.
evidence:
- reference: PMID:30854628
reference_title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: DNA damage response was severely attenuated by loss of TUBB1.
explanation: >-
Supports the experimental branch; PARTIAL reflects uncertain clinical
generalizability.
- target: Thyroid Cell Proliferation Defect
description: >-
The thyroid branch is restricted to particular alleles and incompletely
penetrant; p.Arg318Trp reduced TUBB1 abundance and proliferation in a
thyroid-cell model.
evidence:
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional experimental results indicated that the c.952C>T mutant
dominantly affects gene expression and proliferation of thyroid cells.
explanation: >-
Connects the gene-level trigger to the allele-restricted thyroid branch.
- name: Marginal-Ring and Platelet-Maturation Defect
biological_scale: CELLULAR
description: >-
Patient platelets can lose or disorganize the beta-1-tubulin marginal ring.
Patient-derived megakaryocytes show variant- and penetrance-dependent
impairment of proplatelet formation, and circulating preplatelets show
impaired final maturation.
cell_types:
- preferred_term: megakaryocyte
term: {id: "CL:0000556", label: megakaryocyte}
- preferred_term: platelet
term: {id: "CL:0000233", label: platelet}
biological_processes:
- preferred_term: platelet formation
term: {id: "GO:0030220", label: platelet formation}
modifier: DECREASED
evidence:
- reference: PMID:24344610
reference_title: TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A circumferential marginal microtubule band was undetectable, whereas
microtubules were frayed and disorganized in every platelet from the
affected individuals.
explanation: Direct cytological evidence from p.Phe260Ser patient platelets.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The deleterious functional effect of TUBB1 variants (p.Arg359Trp,
p.Gly269Asp, and p.Gly109Glu) is strongly supported by the finding of
impaired MK maturation and proplatelet formation by MKs differentiated
from CD34+ cell from thrombocytopenic carriers of these mutations.
explanation: Links three variants to impaired patient-derived megakaryocytes.
downstream:
- target: Macrothrombocytopenia
description: Reduced production and maturation yield fewer, larger platelets.
- target: Giant Platelets
description: Defective maturation generates large and giant platelets.
- target: Abnormal Bleeding
description: >-
Bleeding is a variable clinical consequence; the available cohort does
not resolve whether severity tracks platelet count, platelet size, or
qualitative platelet function.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The index probands were referred for possible IPD because of lifelong
macrothrombocytopenia although, for most of them, this was not associated
with a relevant bleeding tendency (ISTH-BAT mean score ± standard
deviation [SD]: 1.10 ± 2.07; median, 0; range, 0-8; Table 1).
explanation: >-
Supports low average bleeding burden with substantial individual
variability; PARTIAL reflects the unresolved mechanistic route.
- name: Thyroid Cell Proliferation Defect
role: TRIGGER
biological_scale: CELLULAR
description: >-
The recurrent heterozygous p.Arg318Trp allele occurs in independent
thyroid-dysgenesis cohorts. In human thyroid cells it reduced TUBB1
abundance and significantly inhibited proliferation. Its effect on
wound-healing migration was not significant, so impaired migration is not
asserted as the human cellular mechanism.
genetic_context:
functional_impact_category: UNKNOWN
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
allele_type: missense
description: >-
The allele is associated with thyroid dysgenesis and has functional
effects in thyroid cells, but the authors describe susceptibility and call
for further mechanistic work.
genes:
- preferred_term: TUBB1
term: {id: "hgnc:16257", label: TUBB1}
biological_processes:
- preferred_term: thyroid gland development
term: {id: "GO:0030878", label: thyroid gland development}
modifier: DYSREGULATED
evidence:
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The c.952C>T mutant decreased the expression of TUBB1 in both mRNA and
protein level, and inhibited the proliferation of thyroid cells
significantly.
explanation: Supports reduced expression and proliferation.
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Also, c.952C>T mutant showed restrain effects on the migration, although
there was no stistical significance.
explanation: Prevents treating impaired migration as established.
downstream:
- target: Congenital Hypothyroidism Associated with Thyroid Dysgenesis
description: Reduced proliferation is a candidate route to thyroid agenesis.
- name: Variant-Dependent Platelet Functional Effects
biological_scale: CELLULAR
description: >-
Platelet agglutination, granule release, and low-dose agonist responses are
abnormal in some TUBB1 families, but activation, secretion, aggregation,
and spreading remain nearly normal with several other alleles. The evidence
therefore supports an allele- or context-dependent functional branch rather
than a necessary consequence of marginal-ring disruption.
cell_types:
- preferred_term: platelet
term: {id: "CL:0000233", label: platelet}
evidence:
- reference: PMID:33400601
reference_title: Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Affected individuals within the family demonstrated impaired platelet
aggregation and/or release functions.
explanation: Establishes the functional branch in the p.Arg318Trp family.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moreover, homozygous and heterozygous carriers of p.Gly109Glu showed
normal platelet aggregation response to different agonists
explanation: >-
Supports the node's allele-dependent qualification by documenting a
genotype with normal aggregation.
downstream:
- target: Variable Platelet-Function Abnormalities
description: >-
Functional abnormalities occur in selected families while other carriers
retain normal tested responses.
- name: Attenuated DNA-Damage Response in TUBB1-Deficient Cells
biological_scale: CELLULAR
description: >-
In a thrombocytopenia family with myeloid malignancy, TUBB1 deficiency was
associated experimentally with reduced nuclear p53 accumulation,
pro-apoptotic transcription, and apoptosis after genotoxic stress. This is
a plausible genome-instability route, not an established universal
malignancy phenotype.
genes:
- preferred_term: TUBB1
term: {id: "hgnc:16257", label: TUBB1}
evidence:
- reference: PMID:30854628
reference_title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We found that the nuclear accumulation of p53 (also termed TP53) and the
expression of pro-apoptotic genes triggered by genotoxic stress were
blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA
damage was diminished by knockdown of TUBB1.
explanation: States the measured DNA-damage-response defects.
phenotypes:
- name: Macrothrombocytopenia
description: >-
Lifelong thrombocytopenia with increased platelet size is defining. Counts
were generally moderately reduced, and most individuals in the largest
series had little or no clinically relevant bleeding.
phenotype_term:
preferred_term: Macrothrombocytopenia
term: {id: "HP:0040185", label: Macrothrombocytopenia}
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thrombocytopenia, defined as platelet count below the normal healthy
volunteer range (n = 107; 142-359 × 109/L), was in general moderate
(median, 76; range, 57-134 × 109/L) and associated with increased platelet
size (mean platelet volume [MPV], 13.3-15.0 fL; normal, 9.0-12.8 fL;
Table 1).
explanation: Direct cohort evidence for the combined count-and-size phenotype.
- name: Giant Platelets
description: >-
Smears show a broad size distribution with large and occasional giant
platelets. Electronic counts can be lower than microscopic counts when very
large platelets are present.
phenotype_term:
preferred_term: Giant platelets
term: {id: "HP:0001902", label: Giant platelets}
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Variable platelet size was observed with large (arrows) and giant (cross)
platelets.
explanation: Directly documents large and giant circulating platelets.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this family, several subjects across 3 generations displayed increased
MPV, but only the 2 probands were thrombocytopenic (≈60 × 109/L at
electronic counting), although they did not have excessive bleeding,
including at childbirths and miscarriage (II.1). Microscopic platelet
counting44 was ≈100 × 109/L in both siblings, with more than 20% of large
platelets (mean platelet diameter, [MPD] > 5 µm) and occasional giant
platelets (MPD > 6 µm; Figure 1B).
explanation: >-
Supports the observed microscopic count and size distribution underlying
the caution about automated counting of very large platelets.
- name: Abnormal Bleeding
description: >-
Bleeding is not a consistent core feature. Most probands in the largest
series had no clinically relevant bleeding tendency and the median ISTH-BAT
score was zero, but the observed score range reached eight, documenting
clinically meaningful bleeding in some individuals.
phenotype_term:
preferred_term: Abnormal bleeding
term: {id: "HP:0001892", label: Abnormal bleeding}
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The index probands were referred for possible IPD because of lifelong
macrothrombocytopenia although, for most of them, this was not associated
with a relevant bleeding tendency (ISTH-BAT mean score ± standard
deviation [SD]: 1.10 ± 2.07; median, 0; range, 0-8; Table 1).
explanation: Directly quantifies the usually low but variable bleeding burden.
- name: Variable Platelet-Function Abnormalities
description: >-
Qualitative dysfunction is variant- and family-dependent. The p.Arg318Trp
family included impaired ristocetin agglutination and reduced stimulated
p-selectin release, whereas other variants had negligible functional effects.
phenotype_term:
preferred_term: Abnormal platelet function
term: {id: "HP:0011869", label: Abnormal platelet function}
evidence:
- reference: PMID:33400601
reference_title: Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moreover, impaired platelet agglutination in response to ristocetin was
detected in the patient's brother. Half of the family members harboring
the p.R318W mutation displayed significantly decreased external release
of p-selectin by stimulated platelets.
explanation: Documents two abnormalities in one p.Arg318Trp family.
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, TUBB1 mutations caused the formation of macroplatelets and
hyperaggregation of human platelets after stimulation by low doses of
agonists
explanation: >-
Documents the hyperaggregation result in the thyroid-ascertained families.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin
incorporation into the microtubular marginal ring in platelets but had a
negligible effect on platelet activation, secretion, or spreading,
suggesting that β1-tubulin is dispensable for these processes.
explanation: >-
Supports the phenotype's explicit non-universality by documenting several
genotypes with negligible functional effects.
- name: Congenital Hypothyroidism Associated with Thyroid Dysgenesis
description: >-
This is a replicated TUBB1 allelic association but not a required feature of
the isolated platelet disorder. The 2025 functional follow-up re-examined
the same 289-patient Shandong series reported in 2019; its four
p.Arg318Trp cases all had thyroid agenesis and normal platelets.
phenotype_term:
preferred_term: Congenital hypothyroidism
term: {id: "HP:0000851", label: Congenital hypothyroidism}
evidence:
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified three novel TUBB1 gene mutations that co-segregated with TD
in three distinct families leading to 1.1% of TUBB1 mutations in TD study
cohort.
explanation: Establishes familial co-segregation and the original association.
- reference: PMID:31642429
reference_title: "[TUBB1 mutation in children with congenital hypothyroidism and thyroid dysgenesis in Shandong, China]."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Among the 289 children with CH and TD, 4 (1.4%) were found to have a
c.952C>T(p.R318W) heterozygous mutation in the TUBB1 gene
explanation: Replicates the association; classification remained potentially pathogenic.
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all 4 patients harbouring the c.952C>T mutation showed thyroid agenesis,
underscoring its detrimental effect on cell survival during thyroid
development. Notably, these 4 patients in our study cohort displayed
normal platelets
explanation: Documents thyroid agenesis and tissue-discordant penetrance.
genetic:
- name: TUBB1
association: Causative
gene_term:
preferred_term: TUBB1 (beta-1 tubulin, class VI)
term: {id: "hgnc:16257", label: TUBB1}
notes: >-
Beta-1 tubulin is predominant in megakaryocytes and platelets. TUBB1 is also
expressed in developing and adult thyroid, but involvement differs among
alleles and families.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Microtubules are assembled by heterodimers of α and β-tubulin, and
β1-tubulin, encoded by TUBB1, is the predominant β-tubulin isoform in
megakaryocytes (MKs) and platelets.
explanation: Supports the platelet-lineage context without claiming exclusivity.
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TUBB1 gene is expressed in the developing and adult thyroid in humans and
mice.
explanation: Establishes expression in the second relevant tissue.
diagnosis:
- name: Blood count, blood smear, and platelet tubulin assessment
description: >-
Count and size should be interpreted together and confirmed on a smear
because automated counters may miss giant platelets. Beta-1-tubulin
immunofluorescence can show an absent or disorganized marginal ring.
diagnosis_term:
preferred_term: laboratory procedure
term: {id: "NCIT:C25294", label: Laboratory Procedure}
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Venous blood samples were drawn into EDTA and sodium citrate for the
different studies (complete blood count [CBC], immature platelet fraction
[%IPF], blood smear and immunofluorescence, functional studies, electron
microscopy, CD34+ cell isolation and MK cultures, DNA, and RNA).
explanation: Documents the phenotyping modalities used in the largest series.
- name: Molecular testing with segregation and functional interpretation
description: >-
Sequence findings should be integrated with phenotype, segregation, allele
burden, and functional evidence. Incomplete penetrance complicates family
interpretation, and prediction algorithms alone are insufficient.
diagnosis_term:
preferred_term: Genetic Testing
term: {id: "NCIT:C15709", label: Genetic Testing}
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In silico algorithms of prediction are not reliable enough when analyzing
TUBB1 variants, ratifying the importance of clinical information and
biological evaluation when establishing the pathogenicity of such
variants.
explanation: Supports integrated interpretation rather than prediction alone.
treatments: []
experimental_models:
- name: TUBB1 variant-transfected CHO cells
experimental_model_type: CELL_LINE
description: >-
CHO cells expressing wild-type or mutant TUBB1 compare beta-1-tubulin
incorporation and distribution, but do not reproduce megakaryocyte biology.
publication: PMID:34516618
modeled_mechanisms:
- target: Variant-Specific Disruption of Beta-1 Tubulin
relationship: RECAPITULATES
fidelity: MODERATE
description: Compares molecular effects across multiple missense variants.
limitations: CHO cells are neither human nor megakaryocytic and use overexpression.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin
incorporation into the microtubular network.
explanation: Establishes the model and molecular readout.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin
incorporation into the microtubular network.
explanation: Establishes the transfected-cell model.
- name: Patient-derived CD34-positive megakaryocytes
experimental_model_type: PRIMARY_CELL_CULTURE
description: >-
Peripheral-blood CD34-positive cells from carriers were differentiated into
megakaryocytes to test maturation and proplatelet formation.
publication: PMID:34516618
modeled_mechanisms:
- target: Marginal-Ring and Platelet-Maturation Defect
relationship: RECAPITULATES
fidelity: HIGH
description: Reproduces impaired maturation and proplatelet formation.
limitations: >-
In-vitro formation does not fully represent platelet release in vivo, and
results differed by carrier phenotype.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
TUBB1 variants markedly impaired proplatelet formation from peripheral
blood CD34+ cell-derived megakaryocytes.
explanation: States the model's principal phenotype.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
TUBB1 variants markedly impaired proplatelet formation from peripheral
blood CD34+ cell-derived megakaryocytes.
explanation: Establishes the patient-derived model.
- name: p.Arg318Trp-transfected human thyroid cells
experimental_model_type: CELL_LINE
description: >-
Immortalized Nthy-ori 3.1 thyroid cells expressing p.Arg318Trp were assayed
for TUBB1 abundance, proliferation, and scratch-wound migration.
publication: PMID:40071799
modeled_mechanisms:
- target: Thyroid Cell Proliferation Defect
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Reproduces reduced abundance and proliferation, but not significant migration.
limitations: >-
An immortalized, plasmid-transfected line does not model embryonic thyroid
morphogenesis; the scratch assay lacks a matrix environment.
evidence:
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Functional experimental results indicated that the c.952C>T mutant
dominantly affects gene expression and proliferation of thyroid cells.
explanation: Supports the expression and proliferation readouts.
evidence:
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We performed real-time polymerase chain reaction (RT-PCR), western blot,
Cell Counting Kit 8 (CCK8), and wound healing assay to evaluate the effect
of TUBB1 c.952C>T on gene expression, cell proliferation, and migration.
explanation: Defines the model and assays.
- name: TUBB1-deficient DNA-damage cell model
experimental_model_type: CELL_LINE
description: >-
TUBB1-deficient cells were exposed to genotoxic stress to test p53
accumulation, pro-apoptotic transcription, and apoptosis.
publication: PMID:30854628
modeled_mechanisms:
- target: Attenuated DNA-Damage Response in TUBB1-Deficient Cells
relationship: RECAPITULATES
fidelity: MODERATE
description: Reproduces failure to eliminate DNA-damaged cells.
limitations: >-
The abstract does not establish reproduction of the heterozygous patient
genotype or malignancy risk across pedigrees.
evidence:
- reference: PMID:30854628
reference_title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: DNA damage response was severely attenuated by loss of TUBB1.
explanation: States the central result.
evidence:
- reference: PMID:30854628
reference_title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: apoptosis after DNA damage was diminished by knockdown of TUBB1.
explanation: Establishes the perturbation and readout.
animal_models:
- name: Tubb1 knockout mouse
species: Mouse (Mus musculus)
genotype: Homozygous Tubb1 knockout
publication: PMID:30446499
description: >-
Tubb1-null mice reproduce impaired platelet production and
macrothrombocytopenia and show abnormal thyroid development and secretion.
modeled_mechanisms:
- target: Marginal-Ring and Platelet-Maturation Defect
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Reproduces impaired proplatelet formation and macrothrombocytopenia.
limitations: >-
A homozygous null differs from heterozygous human alleles with incomplete
penetrance and variant-specific effects.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
β1-tubulin knockout mice display impaired proplatelet formation and
macrothrombocytopenia.
explanation: Identifies the reproduced platelet features.
- target: Congenital Hypothyroidism Associated with Thyroid Dysgenesis
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Reproduces abnormal thyroid migration and hormone secretion.
limitations: >-
A mouse null cannot establish the human mechanism of individual
heterozygous alleles.
evidence:
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In mice, Tubb1 knock-out disrupted microtubule integrity by preventing
β1-tubulin incorporation and impaired thyroid migration and thyroid
hormone secretion.
explanation: States the model's thyroid phenotype.
evidence:
- reference: PMID:30446499
reference_title: TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In mice, Tubb1 knock-out disrupted microtubule integrity by preventing
β1-tubulin incorporation and impaired thyroid migration and thyroid
hormone secretion.
explanation: Establishes the null model.
discussions:
- discussion_id: gap_tubb1_variant_penetrance_and_allele_burden
prompt: >-
Which allele-specific, genetic, or environmental factors determine whether
a carrier has macrothrombocytopenia, isolated enlargement, or normal traits?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Variant-Specific Disruption of Beta-1 Tubulin
rationale: >-
Rare heterozygous alleles show incomplete penetrance, while p.Gly109Glu
caused macrothrombocytopenia only in homozygotes in one family.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These novel data expand the genetic spectrum of TUBB1-RT and highlight a
remarkable heterogeneity in its clinical presentation, indicating that
allelic burden or combination with other genetic or environmental factors
modulate the phenotypic impact of rare TUBB1 variants.
explanation: States the unresolved modifiers.
- reference: PMID:32892537
reference_title: Identification of novel TUBB1 variants in patients with macrothrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Further clinical and functional studies of the newly identified TUBB1
variants may offer important insights into their pathogenicity in
macrothrombocytopenia.
explanation: Supports caution for newly observed alleles.
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings support the hypothesis that upregulation of other
β-tubulin isoforms may counteract the β1-tubulin defect.
explanation: >-
Identifies compensatory tubulin expression as a candidate modifier, not a
proven explanation of incomplete penetrance.
- discussion_id: gap_tubb1_platelet_function_heterogeneity
prompt: >-
Why do some families show functional platelet abnormalities while other
disruptive alleles leave activation, secretion, aggregation, and spreading normal?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Marginal-Ring and Platelet-Maturation Defect
rationale: >-
Structural marginal-ring defects do not predict a single functional phenotype.
evidence:
- reference: PMID:34516618
reference_title: Expanding the genetic spectrum of TUBB1-related thrombocytopenia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
There seems to be a divergence in the impact of variants on β1-tubulin
incorporation into microtubules and on platelet function.
explanation: Explicitly identifies the divergence.
- discussion_id: gap_tubb1_platelet_thyroid_tissue_penetrance
prompt: >-
Do tissue-specific thresholds or modifiers partition thyroid dysgenesis and
macrothrombocytopenia among carriers of the same TUBB1 alleles?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Variant-Specific Disruption of Beta-1 Tubulin
- pathophysiology#Thyroid Cell Proliferation Defect
rationale: >-
The 2025 functional follow-up used the same 289-patient Shandong series
reported in 2019. Its four p.Arg318Trp thyroid-agenesis cases had normal
platelets, while platelet cohorts have not systematically established the
prevalence of thyroid dysgenesis.
evidence:
- reference: PMID:40071799
reference_title: Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
these 4 patients in our study cohort displayed normal platelets
explanation: Documents the thyroid phenotype without a platelet phenotype.
- discussion_id: gap_tubb1_myeloid_malignancy_generalizability
prompt: >-
Does impaired p53-dependent DNA-damage surveillance confer meaningful
myeloid-malignancy risk across TUBB1 disease or only in particular families?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Attenuated DNA-Damage Response in TUBB1-Deficient Cells
rationale: >-
Myeloid malignancy and p.Thr149Pro were identified together in one family;
no cited cohort establishes penetrance or excess risk.
evidence:
- reference: PMID:30854628
reference_title: TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We performed whole-exome sequencing of a family with thrombocytopenia and
myeloid malignancy and identified a novel TUBB1 variant, T149P.
explanation: Establishes the family observation but not general risk.
notes: >-
Reviewed 2026-08-26. The disease term is specifically the isolated platelet
disorder. Thyroid dysgenesis is retained as a replicated, incompletely
penetrant allelic association rather than made part of the disease identity.

A universal LOSS_OF_FUNCTION label was removed because assayed alleles differ
in incorporation, abundance, and zygosity. Abnormal platelet function is also
explicitly variant- and cohort-dependent.

Unsupported treatment claims were removed. The cited studies do not directly
establish immune-thrombocytopenia treatment avoidance, thyroid screening, or
levothyroxine recommendations for this disorder.

📚

References & Deep Research

References

8

PMID:24344610

TUBB1 mutation disrupting microtubule assembly impairs proplatelet formation and results in congenital macrothrombocytopenia.

No top-level findings curated for this source.

PMID:30446499

TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology.

No top-level findings curated for this source.

PMID:34516618

Expanding the genetic spectrum of TUBB1-related thrombocytopenia.

No top-level findings curated for this source.

PMID:32892537

Identification of novel TUBB1 variants in patients with macrothrombocytopenia.

No top-level findings curated for this source.

PMID:30854628

TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.

No top-level findings curated for this source.

PMID:33400601

Identification of a pathogenic TUBB1 variant in a Chinese family with congenital macrothrombocytopenia through whole genome sequencing.

No top-level findings curated for this source.

PMID:31642429

[TUBB1 mutation in children with congenital hypothyroidism and thyroid dysgenesis in Shandong, China].

No top-level findings curated for this source.

PMID:40071799

Genetic and functional analysis of TUBB1 variants in congenital hypothyroidism.

No top-level findings curated for this source.

TUBB1-related Macrothrombocytopenia

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