TUBB8-related Oocyte Maturation Defect

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Inheritance

2

Autosomal dominant inheritance HP:0000006

The founding four-generation family showed autosomal-dominant transmission, and additional affected individuals carried paternally inherited or de novo heterozygous missense variants. Dominant-negative function is asserted only for the assayed heterozygous missense variants, not for every reported TUBB8 variant. No penetrance value is assigned.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:26789871 SUPPORT Human Clinical

"We sequenced the exomes of five members of a four-generation family, three of whom had infertility due to oocyte meiosis I arrest."

The multigenerational family established autosomal-dominant transmission.

PMID:26789871 SUPPORT Human Clinical

"These mutations interfere with human oocyte maturation and are either inherited paternally as an autosomal dominant or arise de novo (Figure 1 and Table 1)."

The founding report explicitly describes paternal autosomal-dominant and de novo occurrence.

Autosomal recessive inheritance HP:0000007

A selected infertility cohort reported five families with recessive inheritance: three with homozygous variants and two with compound-heterozygous variants. This clinical observation supports a recessive mode, but does not by itself assign a common functional impact to the biallelic alleles. No penetrance value is assigned.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"Five families showed a recessive inheritance pattern, including families 6, 9, and 10 that were identified with a homozygous variant and families 1 and 7 that were identified with compound heterozygous variant (Fig.1and Table1)."

Directly supports separate homozygous and compound-heterozygous recessive observations.

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Discussions and Knowledge Gaps

2

Which TUBB8 variants act by reducing the tubulin dimer pool and which by impairing nucleation, and does the HDAC6-inhibition rescue work only for the latter?

KNOWLEDGE GAP OPEN gap_tubb8_variant_stratification_for_rescue

Attached to

pathophysiology#Reduced Alpha/Beta-Tubulin Heterodimer Yield pathophysiology#D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation treatments#HDAC6 inhibition to restore spindle microtubule acetylation (preclinical)

This gap is unusually actionable, because the answer decides who a candidate therapy could help. The mechanistic study is explicit that dimer-pool reduction is the main etiology but leaves large numbers of variants unexplained, and it resolves three of those unexplained variants as nucleation defects acting through EB1 and CKAP5/TACC3. The rescue was demonstrated for one of them, D417N. Whether HDAC6 inhibition restores spindle assembly in a variant whose primary problem is too little heterodimer - rather than a heterodimer that cannot nucleate properly - is untested, and there is reason to doubt it: stabilizing existing microtubules does not create tubulin that was never folded. Stratifying the reported TUBB8 variant spectrum by mechanism class, then testing the rescue in a pool-reduction variant, would establish whether this is a therapy for a subset or for the disorder.

Show evidence (2 references)

PMID:39834092 SUPPORT In Vitro

"The main etiology is the dramatic reduction of tubulin α/β dimer, but still large numbers of variants remain unexplained."

Establishes that the variant spectrum splits by mechanism and that the split is not yet mapped.

PMID:39834092 SUPPORT In Vitro

"These rescue results shed light on the strategy to treat meiotic defects in a certain group of TUBB8 mutated patients."

The rescue is scoped to a group of patients, which is exactly the group this gap asks to define.

Do the conditional human-TUBB8-D417N mouse and acute oocyte-expression systems reproduce endogenous heterozygous human disease well enough to transfer the EB1/CKAP5/TACC3, Ran-GTP, acetylation, or HDAC6-rescue findings to patient oocytes?

HUMAN MODEL MISMATCH OPEN gap_tubb8_human_model_fidelity

Attached to

animal_models#Oocyte-specific human TUBB8-D417N conditional knock-in mouse experimental_models#Ex vivo human GV-oocyte TUBB8 missense mRNA microinjection experimental_models#Ex vivo mouse-oocyte TUBB8 expression and HDAC6-inhibitor rescue experimental_models#Cell-free TUBB8 heterodimer folding and assembly assay pathophysiology#D417N Model-Defined Reduction of TUBB8-EB1 Binding pathophysiology#D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation pathophysiology#D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling

TUBB8 is primate-specific, yet the most detailed D417N pathway and every HDAC6-rescue result come from engineered mouse oocytes or other experimental systems. Human GV-oocyte microinjection uses the relevant cell type but is an acute overexpression assay, not an endogenous patient genotype. These models establish testable proximal mechanisms while leaving human target validity, safety, embryo competence, pregnancy, and live-birth benefit unresolved.

Show evidence (2 references)

PMID:39834092 SUPPORT Model Organism

"To elucidate the deleterious effect of the human TUBB8 pathogenic variants in vivo, we generated oocyte-specific knock-in mouse models that mimic the equivalent human missense variants."

Establishes that the detailed in vivo route comes from a mouse model.

PMID:39834092 SUPPORT In Vitro

"Although our study focused on treating oocytes carrying missense variants rather than directly treating patients, upon further investigation of safety and efficacy, it may be plausible to administer treatment to patients using liposomes containing HDAC6 inhibitors as potential therapeutic..."

Explicitly distinguishes model-oocyte rescue from patient treatment.

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Pathophysiology

10

Functionally Assayed Heterozygous Missense TUBB8 Variants

The founding study assayed seven heterozygous missense variants using heterodimer-assembly reactions, cultured cells, yeast, and mouse and human oocytes. Those tested variants disrupted microtubule behavior and oocyte spindle assembly with dominant-negative effects. This category is not extended to unassayed variants, frameshift alleles, or biallelic genotypes.

oocyte CL:0000023

TUBB8 hgnc:20773

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

Dominant-negative function is limited to heterozygous missense variants for which the cited study performed functional assays.

Downstream

Reduced Alpha/Beta-Tubulin Heterodimer Yield Several assayed missense variants impair folding or assembly and diminish heterodimer yield.

D417N Model-Defined Reduction of TUBB8-EB1 Binding D417N retains heterodimer yield but reduces TUBB8-EB1 binding in model systems.

D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling D417N perturbs the Ran-GTP, TPX2, and NuMA spindle-assembly route in model systems.

Loss of Stable Acetylated Spindle Microtubules in D417N Models D417N model oocytes also show reduced microtubule acetylation and increased HDAC6, without establishing that the EB1 or Ran-GTP route causes this state.

Show evidence (3 references)

PMID:26789871 SUPPORT In Vitro

"TUBB8 expression is unique to oocytes and the early embryo, in which this gene accounts for almost all the expressed β-tubulin."

Establishes the oocyte and early-embryo expression context.

PMID:26789871 SUPPORT In Vitro

"The mutations affect chaperone-dependent folding and assembly of the α/β-tubulin heterodimer, disrupt microtubule behavior on expression in cultured cells"

Biochemical and cultured-cell assays support variant effects on heterodimer assembly and microtubule behavior; the model-organism and ex vivo oocyte systems are curated separately below.

PMID:26789871 SUPPORT In Vitro

"TUBB8 mutations have dominant-negative effects that disrupt microtubule behavior and oocyte meiotic spindle assembly and maturation, causing female infertility."

The explicit dominant-negative statement behind this node's functional_impact_category.

Clinically Observed Heterozygous TUBB8 Genotypes with Unresolved Variant-Level Function

The 2021 selected infertility cohort found that most detected variants were heterozygous, but only a minority of the wider reported variant spectrum had functional assays. Some variants were maternally inherited or observed in a fertile sister. The clinical genotype association is retained without assigning dominant-negative, loss-of-function, or other functional impact to an unassayed allele.

TUBB8 hgnc:20773

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS

Heterozygous clinical observations lacking variant-level functional confirmation; no functional_impact_category is inferred.

Downstream

Poor Fertilization Heterozygous variants were observed among patients with poor fertilization, but the allele-specific route was not functionally established.

Zygotic Cleavage Failure Heterozygous variants were observed in the cleavage-failure spectrum without a common demonstrated molecular route.

Embryo Developmental Arrest Heterozygous variants were observed in embryo-arrest families, with variable phenotypes and incomplete variant-level functional evidence.

Formation of Multiple Pronuclei During Fertilization Multiple-pronuclear fertilization occurred in selected heterozygous families, but a shared allele-specific mechanism was not established.

Show evidence (2 references)

PMID:33970371 SUPPORT Human Clinical

"Most of the variants (22/29) were heterozygous; however, some of the inheritance patterns were unknown due to the absence of DNA samples from parents."

Supports the heterozygous clinical category while documenting incomplete segregation information.

PMID:33970371 SUPPORT Human Clinical

"Among the variants identified, we found five (p.A196T, p.T232S, p.A302T, p.R320H, and p.A411D) in six embryonic arrest families (20, 22, 24, 25, 26, and 32) that were maternally inherited or were also detected in a fertile sister in the proband (Fig. 1)."

Shows why maternal transmission cannot be converted into a penetrance assertion and why variant interpretation must remain cautious.

Homozygous TUBB8 Genotypes

Homozygous TUBB8 variants were reported in three families in a selected infertility cohort. This trigger records the observed genotype separately and does not infer its functional impact.

TUBB8 hgnc:20773

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS

Clinically observed homozygous genotypes; no functional_impact_category is assigned without allele-specific assays.

Downstream

Zygotic Cleavage Failure The homozygous families fall within the cohort's cleavage-failure group; the mechanistic intermediates were not established.

Formation of Multiple Pronuclei During Fertilization Multiple-pronuclear fertilization was observed in homozygous family 10; the route from that genotype to the fertilization phenotype is unresolved.

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"Five families showed a recessive inheritance pattern, including families 6, 9, and 10 that were identified with a homozygous variant and families 1 and 7 that were identified with compound heterozygous variant (Fig.1and Table1)."

Identifies the three homozygous families.

Compound-Heterozygous TUBB8 Genotypes

Compound-heterozygous TUBB8 variants were reported in two families in the same selected cohort. This is a distinct biallelic trigger with no inferred shared functional impact.

TUBB8 hgnc:20773

Genetic context variant_origin: GERMLINE zygosity: COMPOUND_HETEROZYGOUS

Clinically observed compound-heterozygous genotypes; no functional_impact_category is assigned without allele-specific assays.

Downstream

Mixed Oocyte Maturation Arrest One compound-heterozygous family had mixed germinal-vesicle/metaphase-I arrest; no molecular route is inferred.

Zygotic Cleavage Failure One compound-heterozygous family was in the cleavage-failure group; no molecular route is inferred.

Formation of Multiple Pronuclei During Fertilization Multiple-pronuclear fertilization was observed in compound-heterozygous family 1; no common functional impact is inferred for the two alleles.

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"Five families showed a recessive inheritance pattern, including families 6, 9, and 10 that were identified with a homozygous variant and families 1 and 7 that were identified with compound heterozygous variant (Fig.1and Table1)."

Identifies the two compound-heterozygous families.

Reduced Alpha/Beta-Tubulin Heterodimer Yield

Biochemical assays of the founding missense-variant set showed a spectrum of folding and heterodimer-assembly defects, with most variants diminishing the yield of assembled alpha/beta-tubulin heterodimer. D417N is explicitly kept outside this route because its folding kinetics and heterodimer yield were comparable to wild type in the later biochemical study.

oocyte CL:0000023

tubulin heterodimer assembly GO:0007021 ↓ DECREASED

Experimental models

Cell-free TUBB8 heterodimer folding and assembly assay OTHER The assay directly measures variant-specific heterodimer formation.

Downstream

Defective Oocyte Meiotic Spindle Assembly A reduced functional heterodimer pool can compromise construction of the meiotic spindle.

Show evidence (2 references)

PMID:26789871 SUPPORT In Vitro

"These data reveal a range of heterodimer assembly defects caused by the TUBB8 mutations, in some cases attributable to changes in the equilibria that govern the de novo assembly of heterodimers 24, in others pointing to misfolding, and in most cases leading to a diminished yield of assembled..."

Biochemical evidence for variant-dependent folding and heterodimer-yield defects.

PMID:39834092 SUPPORT In Vitro

"Our data revealed no differences in translational efficiency in vitro, the kinetics of folding, or the yield of α/β-heterodimer formation compared to the wild type (Figure 2H and I)."

D417N is a demonstrated exception and must not be routed through reduced heterodimer yield.

D417N Model-Defined Reduction of TUBB8-EB1 Binding

In conditional human-TUBB8-D417N mouse oocytes and complementary ex vivo or biochemical systems, D417N reduced EB1 abundance at microtubule plus ends and reduced TUBB8-EB1 affinity. This interaction defect is model-defined and variant-specific; it is not presented as demonstrated in patient oocytes or as a shared route for all TUBB8 variants.

oocyte CL:0000023

TUBB8 hgnc:20773

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS

Human TUBB8 p.D417N expressed in model systems; functional conclusions are specific to this assayed missense variant and experimental context.

Animal models

Oocyte-specific human TUBB8-D417N conditional knock-in mouse Mouse partially recapitulates The conditional model reproduces reduced EB1 signal and D417N-associated spindle and maturation readouts studied in the paper.

Downstream

D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation The study links loss of stable EB1 binding to disrupted interaction between microtubule plus ends and the CKAP5 nucleator in D417N model oocytes.

Show evidence (2 references)

PMID:39834092 SUPPORT Model Organism

"Our findings demonstrated a significant decrease in EB1 expression within D417N oocytes compared to WT, consistent with our previous observations from in vitro microinjection (Figure 2J and K)."

Immunofluorescence in the conditional mouse model supports reduced EB1 at microtubule plus ends in D417N oocytes.

PMID:39834092 SUPPORT In Vitro

"In addition, co-immunoprecipitation assays investigating the TUBB8-EB1 interaction demonstrated a sharp decline in their affinity caused by the D417N missense variant (Figure 2L)."

Biochemical evidence for the D417N-specific reduction in EB1 affinity.

D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation

D417N mouse oocytes showed aberrant CKAP5 and TACC3 localization and impaired microtubule nucleation. CKAP5 abundance and TUBB8-CKAP5 binding were unchanged, so this node records regulator mislocalization rather than loss of CKAP5. These findings remain specific to the engineered model context.

oocyte CL:0000023

TUBB8 hgnc:20773

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS

Human TUBB8 p.D417N expressed in model systems; functional conclusions are specific to this assayed missense variant and experimental context.

microtubule nucleation GO:0007020 ↓ DECREASED

Animal models

Oocyte-specific human TUBB8-D417N conditional knock-in mouse Mouse partially recapitulates The conditional model reproduces CKAP5/TACC3 mislocalization and impaired microtubule-nucleation readouts in D417N oocytes.

Downstream

Defective Oocyte Meiotic Spindle Assembly CKAP5/TACC3 mislocalization and impaired nucleation disrupt construction of the meiotic spindle in D417N model oocytes.

Show evidence (2 references)

PMID:39834092 SUPPORT Model Organism

"Quantitative analysis revealed significantly impaired perinuclear distribution of CKAP5 in D417N oocytes compared to WT oocytes at the GVBD and pro-metaphase I stages (Figure 3E)."

Directly supports abnormal CKAP5 localization in D417N mouse oocytes.

PMID:39834092 SUPPORT Model Organism

"As expected, similar peripheral accumulation was observed for TACC3 in D417N oocytes, indicating impaired microtubule nucleation and spindle assembly caused by the D417N missense variant (Figure S4B)."

Supports abnormal TACC3 localization and the associated nucleation defect in D417N mouse oocytes.

D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling

D417N mouse oocytes showed a reduced and disrupted Ran-GTP gradient, reduced TPX2, and failed NuMA localization at spindle poles. Complementary co-immunoprecipitation measured reduced D417N affinity for active Ran. This parallel spindle-assembly route is model-defined and variant-specific.

oocyte CL:0000023

TUBB8 hgnc:20773

Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS

Human TUBB8 p.D417N expressed in model systems; functional conclusions are specific to this assayed missense variant and experimental context.

Animal models

Oocyte-specific human TUBB8-D417N conditional knock-in mouse Mouse partially recapitulates The conditional model reproduces the altered Ran-GTP, TPX2, and NuMA spindle-assembly readouts studied in D417N oocytes.

Downstream

Defective Oocyte Meiotic Spindle Assembly The attenuated Ran-GTP route reduces spindle-assembly-factor activity and disrupts meiotic spindle assembly in D417N model oocytes.

Show evidence (3 references)

PMID:39834092 SUPPORT Model Organism

"While a distinct ring-shape of active Ran localised around chromosomes after GVBD was clearly observed in WT oocytes, this ring was severely disrupted and the overall Ran-GTP expression was largely decreased by the presence of the D417N missense variant (Figures 4A and B and S7)."

Supports attenuation of the Ran-GTP gradient in D417N mouse oocytes.

PMID:39834092 SUPPORT In Vitro

"Furthermore, co-immunoprecipitation assays using HeLa cells revealed that compared to WT, the D417N missense variant exhibited reduced affinity for Ran-GTP (active-Ran) (Figure 4C)."

Biochemical evidence supports reduced affinity between D417N TUBB8 and active Ran.

PMID:39834092 SUPPORT Model Organism

"Consistent with low expressions of Ran-GTP, TPX2 in D417N mutant oocytes was significantly decreased and led to the failure of NuMA to localise at the spindle poles (Figure 4D-G)."

Directly supports reduced TPX2 and failed NuMA pole localization in D417N mouse oocytes.

Loss of Stable Acetylated Spindle Microtubules in D417N Models

Conditional D417N mouse oocytes showed reduced acetylated tubulin and increased HDAC6, alongside short or broken microtubules. This node is limited to the D417N model evidence and serves as the target of the ex vivo HDAC6-inhibitor rescue; it is not a human biomarker or demonstrated patient treatment mechanism.

oocyte CL:0000023

Experimental models

Ex vivo mouse-oocyte TUBB8 expression and HDAC6-inhibitor rescue PRIMARY CELL CULTURE The ex vivo mouse-oocyte assay reproduces the acetylation deficit and demonstrates rescue of selected cellular readouts after HDAC6 inhibition.

Animal models

Oocyte-specific human TUBB8-D417N conditional knock-in mouse Mouse partially recapitulates The D417N mouse oocytes show reduced microtubule acetylation and increased HDAC6, enabling ex vivo rescue experiments.

Downstream

Defective Oocyte Meiotic Spindle Assembly Loss of stable microtubules accompanies abnormal spindle assembly in the D417N model.

Show evidence (1 reference)

PMID:39834092 SUPPORT Model Organism

"Stable microtubule was largely abolished on the spindle of TUBB8-D417N oocytes, reflected by reduced tubulin acetylation and accumulated HDAC6."

Directly supports the acetylation and HDAC6 state in D417N model oocytes.

Defective Oocyte Meiotic Spindle Assembly

Absent, misshapen, or disorganized meiotic spindles are observed in patient oocytes with maturation arrest and reproduced by expression of selected human TUBB8 variants in mouse and human oocytes. This node supports the metaphase-I-arrest presentation only; later fertilization, cleavage, and embryo-arrest presentations are not routed through it.

oocyte CL:0000023

meiotic spindle organization GO:0000212 ↕ DYSREGULATED

Experimental models

Ex vivo human GV-oocyte TUBB8 missense mRNA microinjection PRIMARY CELL CULTURE The ex vivo assay reproduces defective spindle assembly in human oocytes.

Downstream

Metaphase I Oocyte Maturation Arrest Failure to form a competent meiotic spindle prevents completion of meiosis I in the maturation-arrest presentation.

Abnormality of Chromosome Segregation In the large-polar-body patient cases, abnormal spindle morphology or localization accompanied directly demonstrated chromosome-segregation errors; this edge is limited to that maturation-stage context.

Show evidence (3 references)

PMID:26789871 SUPPORT Human Clinical

"Almost all oocytes harvested during these attempts were arrested at the MI stage, and none had a visible spindle (Table 1, Figure 2C-E)."

Direct observation of absent visible spindles in patient oocytes with metaphase-I arrest.

PMID:26789871 SUPPORT In Vitro

"Finally, to further validate the effects of the mutation, we microinjected TUBB8 S176L and D417N mutant RNAs into human GV oocytes. Consistent with the phenotypes observed in mouse oocytes, we found severely or completely impaired spindle assembly (Figure 4C)."

Ex vivo human-oocyte microinjection reproduces defective spindle assembly for two assayed variants.

PMID:39834092 SUPPORT Model Organism

"About 75% of D417N oocytes are arrested at the metaphase I stage accompanied by an abnormal spindle (Figure 2E and F)."

The conditional D417N mouse model independently supports abnormal spindle assembly with metaphase-I arrest.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Genitourinary 3

Metaphase I Oocyte Maturation Arrest HP:0031516

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:26789871 SUPPORT Human Clinical

"We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families."

Directly establishes metaphase-I oocyte arrest in affected families.

Mixed Oocyte Maturation Arrest HP:6001356

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"The retrieved oocytes had been through germinal vesicle (GV)/metaphase I (MI) mixed arrest in families 1-3 and poor fertilization in family 4."

Directly supports a mixed GV/MI maturation-arrest presentation.

Female Infertility HP:0008222

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"All of the 32 individuals from independent and hitherto uncharacterized families with primary female infertility underwent two to three failed IVF/ICSI attempts in our centre or at other hospitals despite a normal menstrual cycle, endocrine level, and karyotype."

Directly documents primary infertility and recurrent assisted-reproduction failure in the selected clinical cohort.

Prenatal and Birth 3

Zygotic Cleavage Failure HP:0033336

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"Nearly all the 2PN zygotes were arrested before the first cleavage, even after two extra days of cultivation (families 5-13)."

Direct observation of failure before first zygotic cleavage.

Embryo Developmental Arrest HP:0020003

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"All the other families presented with embryonic arrest, and although 1-2 usable embryos were produced, these embryos failed to form blastocysts during subsequent culture or establish pregnancy after transfer."

Directly supports preimplantation embryo developmental arrest.

Formation of Multiple Pronuclei During Fertilization HP:4000008

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"We also observed various abnormalities in the fertilized zygotes or embryos; there were problems such as high proportion of abnormal fertilization including 1PN (single pronucleus formation in zygotes) and MPN (multi-pronucleus formation in zygotes) (frequency>0.5, in families 1, 2, 8, 10, 12,..."

Directly documents multiple-pronuclear fertilization abnormalities.

Cellular 1

Abnormality of Chromosome Segregation HP:0002916

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"Both the PB and the oocyte exhibited abnormal chromosome compositions, including partial chromosome trisomy or monosomy (Fig. 2b)."

Direct chromosome analysis supports segregation abnormalities.

Other 1

Poor Fertilization

Sequelae: Female Infertility

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"The retrieved oocytes had been through germinal vesicle (GV)/metaphase I (MI) mixed arrest in families 1-3 and poor fertilization in family 4."

Directly supports poor fertilization as an alternative presentation.

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Genetic Associations

1

TUBB8 (Causative)

Gene: TUBB8 (beta-tubulin 8) hgnc:20773

Show evidence (2 references)

PMID:26789871 SUPPORT Human Clinical

"We identified seven mutations in the primate-specific gene TUBB8 that were responsible for oocyte meiosis I arrest in 7 of the 24 families."

Founding evidence that TUBB8 mutations cause the disorder, and that it is a primate-specific gene.

PMID:33970371 SUPPORT Human Clinical

"However, it should be noted that the evidence for the pathogenicity of theseTUBB8variant has been obtained using a variety of different means, including in vitro functional verification, morphological observation of the spindle, pedigree segregation analysis, and the genetic detection of probands."

Supports conservative, variant-level interpretation rather than treating every reported allele as equivalently proven.

💊

Medical Actions

3

Oocyte donation

Category: Therapeutic Action: Therapeutic Procedure NCIT:C49236

Donor oocytes may be a feasible reproductive option for selected patients whose TUBB8 variants are classified as likely pathogenic and whose repeated ART failure is attributable to the oocyte. The source offers this as a present option rather than reporting a controlled outcome study; it is not a treatment of the patient's variant and is not generalized to VUS carriers.

Show evidence (1 reference)

PMID:33970371 SUPPORT Human Clinical

"For these patients with the LP variants, donor eggs may be the most feasible method at present."

Supports only a qualified recommendation for patients with likely-pathogenic variants; it does not provide efficacy estimates.

Genetic counseling after TUBB8 variant detection

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling should distinguish autosomal-dominant from autosomal-recessive observations, review parental and familial segregation, and explain that reported TUBB8 variants vary in evidentiary strength and phenotype. A VUS or an allele found in a fertile relative should not be used alone to predict infertility, embryo outcome, or treatment response. This record does not infer incomplete penetrance.

Show evidence (2 references)

PMID:33970371 SUPPORT Human Clinical

"Our study expands the spectrum of TUBB8 variants, particularly for embryonic arrest. Together with the extant knowledge of TUBB8 variants, this study provides a foundation for the genetic counselling of female infertility."

Directly identifies genetic counseling as an intended use.

PMID:33970371 SUPPORT Human Clinical

"We further analysed the correlation between phenotype and genotype, and we found 17 variants that caused different phenotypes under the same variant."

Supports explicit counseling about variable phenotype by variant.

HDAC6 inhibition to restore spindle microtubule acetylation (preclinical)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: tubastatin A CHEBI:94186 Histone Deacetylase Inhibitor NCIT:C1946

Platform: Small molecule

Model-only, variant-limited rescue. Cultured oocytes from the conditional human-TUBB8-D417N mouse and mouse oocytes acutely expressing selected human TUBB8 variants were treated with tubacin or tubastatin A. Spindle morphology, microtubule acetylation, and polar-body extrusion improved in selected model conditions. No affected patient received an HDAC6 inhibitor, and the study provides no human efficacy, safety, dosing, pregnancy, or live-birth data.

Mechanism Target:

RESTORES Loss of Stable Acetylated Spindle Microtubules in D417N Models — Ex vivo HDAC6 inhibition restores acetylation and spindle readouts in the D417N mouse-oocyte model; this target link does not assert a human effect.

Show evidence (1 reference)

PMID:39834092 SUPPORT In Vitro

"More importantly, selective inhibition of HDAC6 by culturing TUBB8-D417N oocytes with Tubacin or Tubastatin A showed morphologically normal spindle and drastically recovered polar-body extrusion rate."

Reports structural and polar-body-extrusion rescue in cultured model oocytes.

Show evidence (1 reference)

PMID:39834092 SUPPORT In Vitro

"These rescue results shed light on the strategy to treat meiotic defects in a certain group of TUBB8 mutated patients."

The authors' own subset language is retained while the lack of patient treatment data is made explicit.

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Diagnosis

1

Selected molecular testing for recurrent IVF/ICSI failure

Exome sequencing or a female-infertility panel containing TUBB8 can be considered after recurrent IVF/ICSI failure characterized by oocyte maturation arrest, poor fertilization, cleavage failure, or early embryo arrest. The cited evidence comes from a selected research cohort and does not establish population screening. Results require segregation review and variant-level classification; a VUS should not be treated as a confirmed diagnosis solely because it occurs in TUBB8.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:33970371 SUPPORT Human Clinical

"We performed whole exome sequencing to screen for candidate variants in 100 infertile female subjects and 100 controls who were able to conceive naturally."

Establishes WES as the testing method used in the selected cohort.

PMID:33970371 SUPPORT Human Clinical

"So far, 16 of the reported 102TUBB8variants have been examined in in vitro functional assays"

Supports the warning that only a minority of the reported spectrum had been examined in functional assays.

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Experimental Models

3

Ex vivo human GV-oocyte TUBB8 missense mRNA microinjection PRIMARY_CELL_CULTURE

Human GV oocytes were microinjected with S176L or D417N TUBB8 RNA and showed severely impaired spindle assembly. The relevant human cell type is used, but acute mRNA overexpression is not an endogenous heterozygous genotype and the assay covers only two variants.

Cell source

Donated human germinal-vesicle oocytes cultured ex vivo

Culture

Acute mRNA microinjection followed by meiotic maturation culture

Publication

PMID:26789871

Pathograph links

Defective Oocyte Meiotic Spindle Assembly partially recapitulates fidelity: low The ex vivo assay reproduces defective spindle assembly in human oocytes.

Limitations: Acute RNA microinjection can produce nonphysiologic expression; the oocytes are outside their ovarian context, and maturation or pregnancy outcomes cannot be assessed.

Show evidence (1 reference)

PMID:26789871 SUPPORT In Vitro

"Finally, to further validate the effects of the mutation, we microinjected TUBB8 S176L and D417N mutant RNAs into human GV oocytes. Consistent with the phenotypes observed in mouse oocytes, we found severely or completely impaired spindle assembly (Figure 4C)."

Directly supports the ex vivo human-oocyte spindle readout.

Show evidence (1 reference)

PMID:26789871 SUPPORT In Vitro

"Finally, to further validate the effects of the mutation, we microinjected TUBB8 S176L and D417N mutant RNAs into human GV oocytes."

Establishes the experimental system.

Ex vivo mouse-oocyte TUBB8 expression and HDAC6-inhibitor rescue PRIMARY_CELL_CULTURE

Mouse GV oocytes expressing human TUBB8 variants, including oocytes from the conditional D417N model, were cultured with selective HDAC6 inhibitors. The system measures spindle morphology, acetylation, and polar-body extrusion but does not test treatment in a patient or an intact reproductive cycle.

Cell source

Mouse germinal-vesicle oocytes cultured ex vivo

Culture

Human TUBB8 mRNA microinjection or conditional-model oocytes with inhibitor exposure

Publication

PMID:39834092

Pathograph links

Loss of Stable Acetylated Spindle Microtubules in D417N Models partially recapitulates fidelity: low The ex vivo mouse-oocyte assay reproduces the acetylation deficit and demonstrates rescue of selected cellular readouts after HDAC6 inhibition.

Limitations: Species context, acute expression for some variants, ex vivo culture, and absence of fertilization, embryo-development, pregnancy, and safety endpoints preclude human efficacy inference.

Show evidence (1 reference)

PMID:39834092 SUPPORT In Vitro

"More importantly, selective inhibition of HDAC6 by culturing TUBB8-D417N oocytes with Tubacin or Tubastatin A showed morphologically normal spindle and drastically recovered polar-body extrusion rate."

Supports rescue only in cultured model oocytes.

Show evidence (1 reference)

PMID:39834092 SUPPORT In Vitro

"Although our study focused on treating oocytes carrying missense variants rather than directly treating patients, upon further investigation of safety and efficacy, it may be plausible to administer treatment to patients using liposomes containing HDAC6 inhibitors as potential therapeutic..."

Explicitly confirms that patients were not treated.

Cell-free TUBB8 heterodimer folding and assembly assay OTHER

Cell-free translation and tubulin-chaperone assembly assays measure whether a tested TUBB8 variant changes folding kinetics or assembled heterodimer yield. The assay separates reduced-yield variants from D417N but cannot reproduce oocyte spindle architecture or clinical outcome.

Culture

In vitro translation and non-denaturing gel analysis

Publication

PMID:26789871

Pathograph links

Reduced Alpha/Beta-Tubulin Heterodimer Yield partially recapitulates fidelity: low The assay directly measures variant-specific heterodimer formation.

Limitations: A cell-free reaction omits oocyte-specific protein abundance, spatial organization, microtubule-associated proteins, spindle architecture, and developmental outcomes.

Show evidence (1 reference)

PMID:26789871 SUPPORT In Vitro

"These data reveal a range of heterodimer assembly defects caused by the TUBB8 mutations, in some cases attributable to changes in the equilibria that govern the de novo assembly of heterodimers 24, in others pointing to misfolding, and in most cases leading to a diminished yield of assembled..."

Direct biochemical measurement of heterodimer assembly.

Show evidence (1 reference)

PMID:39834092 SUPPORT In Vitro

"Our data revealed no differences in translational efficiency in vitro, the kinetics of folding, or the yield of α/β-heterodimer formation compared to the wild type (Figure 2H and I)."

Demonstrates that D417N does not belong in the reduced-yield route.

🐁

Animal Models

1

Oocyte-specific human TUBB8-D417N conditional knock-in mouse

A Cre-lox conditional model expresses human TUBB8-D417N in mouse oocytes. It reproduces abnormal spindle assembly, reduced polar-body extrusion, altered EB1/CKAP5/TACC3 and Ran-GTP readouts, and reduced tubulin acetylation. Because TUBB8 is primate-specific and the host oocyte and tubulin-isotype environment are murine, the model is assigned low translational fidelity.

Species

Mouse

Genotype

Conditional oocyte-specific human TUBB8 p.D417N knock-in driven by Gdf9-Cre

Genes

TUBB8 hgnc:20773

Publication

PMID:39834092

Pathograph links

D417N Model-Defined Reduction of TUBB8-EB1 Binding partially recapitulates fidelity: low The conditional model reproduces reduced EB1 signal and D417N-associated spindle and maturation readouts studied in the paper.

Limitations: Human TUBB8 is conditionally introduced into a mouse oocyte, which lacks an endogenous equivalent expression program; only D417N is modeled and no patient oocyte establishes that the full regulator chain occurs in humans.

Show evidence (1 reference)

PMID:39834092 SUPPORT Model Organism

"Therefore, we generated oocyte-specific expressed wild-type TUBB8-WT flox/flox; Gdf9-Cre (hereafter referred to as WT) and TUBB8-D417N flox/flox; Gdf9-Cre (hereafter referred to as D417N) mice (Figures 2A and S1E)."

Establishes the conditional human-TUBB8 mouse model.

D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation partially recapitulates fidelity: low The conditional model reproduces CKAP5/TACC3 mislocalization and impaired microtubule-nucleation readouts in D417N oocytes.

Limitations: The engineered mouse-oocyte context may not reproduce regulator abundance, localization, or nucleation in endogenous heterozygous patient oocytes.

D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling partially recapitulates fidelity: low The conditional model reproduces the altered Ran-GTP, TPX2, and NuMA spindle-assembly readouts studied in D417N oocytes.

Limitations: The engineered mouse-oocyte context does not establish that this route is active in endogenous heterozygous patient oocytes.

Loss of Stable Acetylated Spindle Microtubules in D417N Models partially recapitulates fidelity: low The D417N mouse oocytes show reduced microtubule acetylation and increased HDAC6, enabling ex vivo rescue experiments.

Limitations: Acetylation and HDAC6 were measured in the engineered mouse-oocyte system; neither is established as a patient biomarker or validated human target.

Show evidence (1 reference)

PMID:39834092 SUPPORT Model Organism

"Stable microtubule was largely abolished on the spindle of TUBB8-D417N oocytes, reflected by reduced tubulin acetylation and accumulated HDAC6."

Supports the model-specific acetylation and HDAC6 phenotype.

Show evidence (1 reference)

PMID:39834092 SUPPORT Model Organism

"About 75% of D417N oocytes are arrested at the metaphase I stage accompanied by an abnormal spindle (Figure 2E and F)."

Establishes the central maturation and spindle phenotype.

{ }

Source YAML

click to show

name: TUBB8-related Oocyte Maturation Defect
creation_date: "2026-08-20T17:00:00Z"
updated_date: "2026-08-25T21:23:22Z"
category: Mendelian
disease_term:
  preferred_term: oocyte maturation defect 2
  term:
    id: MONDO:0021573
    label: oocyte maturation defect 2
description: >-
  TUBB8-related oocyte maturation defect is a female-infertility disorder caused
  by variants in the primate-specific beta-tubulin isotype expressed
  predominantly in oocytes and early embryos. Its clinical spectrum is broader
  than metaphase-I arrest alone: selected IVF/ICSI cohorts include metaphase-I or
  mixed germinal-vesicle/metaphase-I maturation arrest, poor fertilization,
  zygotic cleavage failure, and preimplantation embryo arrest. These are
  alternative presentations; fertilization, cleavage, and embryo arrest are not
  modeled as consequences of metaphase-I arrest.

  Autosomal-dominant disease is supported by paternally transmitted and de novo
  heterozygous missense variants. Dominant-negative function is restricted here
  to the heterozygous missense variants tested in functional assays. A later
  cohort also reported homozygous and compound-heterozygous genotypes, supporting
  an autosomal-recessive mode without establishing one shared molecular effect
  for all biallelic alleles. Maternally inherited variants and variants observed
  in fertile relatives make variant-level interpretation and counseling
  important; this entry does not infer incomplete penetrance from those
  observations.

  Functional work supports variant-dependent disruption of tubulin folding,
  heterodimer yield, microtubule behavior, and meiotic spindle assembly. The
  EB1-CKAP5/TACC3, Ran-GTP, tubulin-acetylation, and HDAC6 routes were defined in
  systems expressing human TUBB8-D417N, including a conditional mouse model, and
  are therefore recorded as model-derived rather than established human
  mechanisms. HDAC6 inhibition rescued selected mutant mouse oocytes ex vivo but
  has no demonstrated efficacy or safety in affected patients.
parents:
- hereditary disease
- female reproductive system disease
references:
- reference: PMID:26789871
  title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
- reference: PMID:39834092
  title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
- reference: PMID:33970371
  title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    The founding four-generation family showed autosomal-dominant transmission,
    and additional affected individuals carried paternally inherited or de novo
    heterozygous missense variants. Dominant-negative function is asserted only
    for the assayed heterozygous missense variants, not for every reported TUBB8
    variant. No penetrance value is assigned.
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We sequenced the exomes of five members of a four-generation family, three
      of whom had infertility due to oocyte meiosis I arrest.
    explanation: >-
      The multigenerational family established autosomal-dominant transmission.
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These mutations interfere with human oocyte maturation and are either
      inherited paternally as an autosomal dominant or arise de novo (Figure 1
      and Table 1).
    explanation: >-
      The founding report explicitly describes paternal autosomal-dominant and
      de novo occurrence.
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A selected infertility cohort reported five families with recessive
    inheritance: three with homozygous variants and two with
    compound-heterozygous variants. This clinical observation supports a
    recessive mode, but does not by itself assign a common functional impact to
    the biallelic alleles. No penetrance value is assigned.
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five families showed a recessive inheritance pattern, including families
      6, 9, and 10 that were identified with a homozygous variant and families 1
      and 7 that were identified with compound heterozygous variant (Fig.1and
      Table1).
    explanation: >-
      Directly supports separate homozygous and compound-heterozygous recessive
      observations.
pathophysiology:
- name: Functionally Assayed Heterozygous Missense TUBB8 Variants
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    The founding study assayed seven heterozygous missense variants using
    heterodimer-assembly reactions, cultured cells, yeast, and mouse and human
    oocytes. Those tested variants disrupted microtubule behavior and oocyte
    spindle assembly with dominant-negative effects. This category is not
    extended to unassayed variants, frameshift alleles, or biallelic genotypes.
  genetic_context:
    functional_impact_category: DOMINANT_NEGATIVE
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    description: >-
      Dominant-negative function is limited to heterozygous missense variants
      for which the cited study performed functional assays.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TUBB8 expression is unique to oocytes and the early embryo, in which this
      gene accounts for almost all the expressed β-tubulin.
    explanation: Establishes the oocyte and early-embryo expression context.
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutations affect chaperone-dependent folding and assembly of the
      α/β-tubulin heterodimer, disrupt microtubule behavior on expression in
      cultured cells
    explanation: >-
      Biochemical and cultured-cell assays support variant effects on
      heterodimer assembly and microtubule behavior; the model-organism and ex
      vivo oocyte systems are curated separately below.
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TUBB8 mutations have dominant-negative effects that disrupt microtubule
      behavior and oocyte meiotic spindle assembly and maturation, causing female
      infertility.
    explanation: >-
      The explicit dominant-negative statement behind this node's
      functional_impact_category.
  downstream:
  - target: Reduced Alpha/Beta-Tubulin Heterodimer Yield
    description: >-
      Several assayed missense variants impair folding or assembly and diminish
      heterodimer yield.
  - target: D417N Model-Defined Reduction of TUBB8-EB1 Binding
    description: >-
      D417N retains heterodimer yield but reduces TUBB8-EB1 binding in model
      systems.
  - target: D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling
    description: >-
      D417N perturbs the Ran-GTP, TPX2, and NuMA spindle-assembly route in model
      systems.
  - target: Loss of Stable Acetylated Spindle Microtubules in D417N Models
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      D417N model oocytes also show reduced microtubule acetylation and increased
      HDAC6, without establishing that the EB1 or Ran-GTP route causes this state.
- name: Clinically Observed Heterozygous TUBB8 Genotypes with Unresolved Variant-Level Function
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    The 2021 selected infertility cohort found that most detected variants were
    heterozygous, but only a minority of the wider reported variant spectrum had
    functional assays. Some variants were maternally inherited or observed in a
    fertile sister. The clinical genotype association is retained without
    assigning dominant-negative, loss-of-function, or other functional impact to
    an unassayed allele.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous clinical observations lacking variant-level functional
      confirmation; no functional_impact_category is inferred.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most of the variants (22/29) were heterozygous; however, some of the
      inheritance patterns were unknown due to the absence of DNA samples from
      parents.
    explanation: >-
      Supports the heterozygous clinical category while documenting incomplete
      segregation information.
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among the variants identified, we found five (p.A196T, p.T232S, p.A302T,
      p.R320H, and p.A411D) in six embryonic arrest families (20, 22, 24, 25, 26,
      and 32) that were maternally inherited or were also detected in a fertile
      sister in the proband (Fig. 1).
    explanation: >-
      Shows why maternal transmission cannot be converted into a penetrance
      assertion and why variant interpretation must remain cautious.
  downstream:
  - target: Poor Fertilization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heterozygous variants were observed among patients with poor fertilization,
      but the allele-specific route was not functionally established.
  - target: Zygotic Cleavage Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heterozygous variants were observed in the cleavage-failure spectrum
      without a common demonstrated molecular route.
  - target: Embryo Developmental Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heterozygous variants were observed in embryo-arrest families, with
      variable phenotypes and incomplete variant-level functional evidence.
  - target: Formation of Multiple Pronuclei During Fertilization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Multiple-pronuclear fertilization occurred in selected heterozygous
      families, but a shared allele-specific mechanism was not established.
- name: Homozygous TUBB8 Genotypes
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    Homozygous TUBB8 variants were reported in three families in a selected
    infertility cohort. This trigger records the observed genotype separately
    and does not infer its functional impact.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Clinically observed homozygous genotypes; no functional_impact_category is
      assigned without allele-specific assays.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five families showed a recessive inheritance pattern, including families
      6, 9, and 10 that were identified with a homozygous variant and families 1
      and 7 that were identified with compound heterozygous variant (Fig.1and
      Table1).
    explanation: Identifies the three homozygous families.
  downstream:
  - target: Zygotic Cleavage Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The homozygous families fall within the cohort's cleavage-failure group;
      the mechanistic intermediates were not established.
  - target: Formation of Multiple Pronuclei During Fertilization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Multiple-pronuclear fertilization was observed in homozygous family 10;
      the route from that genotype to the fertilization phenotype is unresolved.
- name: Compound-Heterozygous TUBB8 Genotypes
  role: TRIGGER
  biological_scale: MOLECULAR
  description: >-
    Compound-heterozygous TUBB8 variants were reported in two families in the
    same selected cohort. This is a distinct biallelic trigger with no inferred
    shared functional impact.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: COMPOUND_HETEROZYGOUS
    description: >-
      Clinically observed compound-heterozygous genotypes; no
      functional_impact_category is assigned without allele-specific assays.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five families showed a recessive inheritance pattern, including families
      6, 9, and 10 that were identified with a homozygous variant and families 1
      and 7 that were identified with compound heterozygous variant (Fig.1and
      Table1).
    explanation: Identifies the two compound-heterozygous families.
  downstream:
  - target: Mixed Oocyte Maturation Arrest
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      One compound-heterozygous family had mixed germinal-vesicle/metaphase-I
      arrest; no molecular route is inferred.
  - target: Zygotic Cleavage Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      One compound-heterozygous family was in the cleavage-failure group; no
      molecular route is inferred.
  - target: Formation of Multiple Pronuclei During Fertilization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Multiple-pronuclear fertilization was observed in compound-heterozygous
      family 1; no common functional impact is inferred for the two alleles.
- name: Reduced Alpha/Beta-Tubulin Heterodimer Yield
  biological_scale: MOLECULAR
  description: >-
    Biochemical assays of the founding missense-variant set showed a spectrum of
    folding and heterodimer-assembly defects, with most variants diminishing the
    yield of assembled alpha/beta-tubulin heterodimer. D417N is explicitly kept
    outside this route because its folding kinetics and heterodimer yield were
    comparable to wild type in the later biochemical study.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: tubulin heterodimer assembly
    term:
      id: GO:0007021
      label: tubulin complex assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These data reveal a range of heterodimer assembly defects caused by the
      TUBB8 mutations, in some cases attributable to changes in the equilibria
      that govern the de novo assembly of heterodimers 24, in others pointing to
      misfolding, and in most cases leading to a diminished yield of assembled
      heterodimers.
    explanation: >-
      Biochemical evidence for variant-dependent folding and heterodimer-yield
      defects.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data revealed no differences in translational efficiency in vitro, the
      kinetics of folding, or the yield of α/β-heterodimer formation compared to
      the wild type (Figure 2H and I).
    explanation: >-
      D417N is a demonstrated exception and must not be routed through reduced
      heterodimer yield.
  downstream:
  - target: Defective Oocyte Meiotic Spindle Assembly
    description: >-
      A reduced functional heterodimer pool can compromise construction of the
      meiotic spindle.
- name: D417N Model-Defined Reduction of TUBB8-EB1 Binding
  biological_scale: MOLECULAR
  description: >-
    In conditional human-TUBB8-D417N mouse oocytes and complementary ex vivo or
    biochemical systems, D417N reduced EB1 abundance at microtubule plus ends and
    reduced TUBB8-EB1 affinity. This interaction defect is model-defined and
    variant-specific; it is not presented as demonstrated in patient oocytes or
    as a shared route for all TUBB8 variants.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    description: >-
      Human TUBB8 p.D417N expressed in model systems; functional conclusions are
      specific to this assayed missense variant and experimental context.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our findings demonstrated a significant decrease in EB1 expression within
      D417N oocytes compared to WT, consistent with our previous observations
      from in vitro microinjection (Figure 2J and K).
    explanation: >-
      Immunofluorescence in the conditional mouse model supports reduced EB1 at
      microtubule plus ends in D417N oocytes.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In addition, co-immunoprecipitation assays investigating the TUBB8-EB1
      interaction demonstrated a sharp decline in their affinity caused by the
      D417N missense variant (Figure 2L).
    explanation: >-
      Biochemical evidence for the D417N-specific reduction in EB1 affinity.
  downstream:
  - target: D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation
    causal_link_type: DIRECT
    description: >-
      The study links loss of stable EB1 binding to disrupted interaction between
      microtubule plus ends and the CKAP5 nucleator in D417N model oocytes.
- name: D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation
  biological_scale: CELLULAR
  description: >-
    D417N mouse oocytes showed aberrant CKAP5 and TACC3 localization and impaired
    microtubule nucleation. CKAP5 abundance and TUBB8-CKAP5 binding were unchanged,
    so this node records regulator mislocalization rather than loss of CKAP5.
    These findings remain specific to the engineered model context.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    description: >-
      Human TUBB8 p.D417N expressed in model systems; functional conclusions are
      specific to this assayed missense variant and experimental context.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: microtubule nucleation
    term:
      id: GO:0007020
      label: microtubule nucleation
    modifier: DECREASED
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Quantitative analysis revealed significantly impaired perinuclear
      distribution of CKAP5 in D417N oocytes compared to WT oocytes at the GVBD
      and pro-metaphase I stages (Figure 3E).
    explanation: >-
      Directly supports abnormal CKAP5 localization in D417N mouse oocytes.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As expected, similar peripheral accumulation was observed for TACC3 in
      D417N oocytes, indicating impaired microtubule nucleation and spindle
      assembly caused by the D417N missense variant (Figure S4B).
    explanation: >-
      Supports abnormal TACC3 localization and the associated nucleation defect
      in D417N mouse oocytes.
  downstream:
  - target: Defective Oocyte Meiotic Spindle Assembly
    causal_link_type: DIRECT
    description: >-
      CKAP5/TACC3 mislocalization and impaired nucleation disrupt construction of
      the meiotic spindle in D417N model oocytes.
- name: D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling
  biological_scale: CELLULAR
  description: >-
    D417N mouse oocytes showed a reduced and disrupted Ran-GTP gradient, reduced
    TPX2, and failed NuMA localization at spindle poles. Complementary
    co-immunoprecipitation measured reduced D417N affinity for active Ran. This
    parallel spindle-assembly route is model-defined and variant-specific.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    allele_type: missense
    description: >-
      Human TUBB8 p.D417N expressed in model systems; functional conclusions are
      specific to this assayed missense variant and experimental context.
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While a distinct ring-shape of active Ran localised around chromosomes
      after GVBD was clearly observed in WT oocytes, this ring was severely
      disrupted and the overall Ran-GTP expression was largely decreased by the
      presence of the D417N missense variant (Figures 4A and B and S7).
    explanation: >-
      Supports attenuation of the Ran-GTP gradient in D417N mouse oocytes.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, co-immunoprecipitation assays using HeLa cells revealed that
      compared to WT, the D417N missense variant exhibited reduced affinity for
      Ran-GTP (active-Ran) (Figure 4C).
    explanation: >-
      Biochemical evidence supports reduced affinity between D417N TUBB8 and
      active Ran.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with low expressions of Ran-GTP, TPX2 in D417N mutant oocytes
      was significantly decreased and led to the failure of NuMA to localise at
      the spindle poles (Figure 4D-G).
    explanation: >-
      Directly supports reduced TPX2 and failed NuMA pole localization in D417N
      mouse oocytes.
  downstream:
  - target: Defective Oocyte Meiotic Spindle Assembly
    causal_link_type: DIRECT
    description: >-
      The attenuated Ran-GTP route reduces spindle-assembly-factor activity and
      disrupts meiotic spindle assembly in D417N model oocytes.
- name: Loss of Stable Acetylated Spindle Microtubules in D417N Models
  biological_scale: CELLULAR
  description: >-
    Conditional D417N mouse oocytes showed reduced acetylated tubulin and
    increased HDAC6, alongside short or broken microtubules. This node is limited
    to the D417N model evidence and serves as the target of the ex vivo
    HDAC6-inhibitor rescue; it is not a human biomarker or demonstrated patient
    treatment mechanism.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Stable microtubule was largely abolished on the spindle of TUBB8-D417N
      oocytes, reflected by reduced tubulin acetylation and accumulated HDAC6.
    explanation: >-
      Directly supports the acetylation and HDAC6 state in D417N model oocytes.
  downstream:
  - target: Defective Oocyte Meiotic Spindle Assembly
    description: >-
      Loss of stable microtubules accompanies abnormal spindle assembly in the
      D417N model.
- name: Defective Oocyte Meiotic Spindle Assembly
  biological_scale: CELLULAR
  description: >-
    Absent, misshapen, or disorganized meiotic spindles are observed in patient
    oocytes with maturation arrest and reproduced by expression of selected
    human TUBB8 variants in mouse and human oocytes. This node supports the
    metaphase-I-arrest presentation only; later fertilization, cleavage, and
    embryo-arrest presentations are not routed through it.
  cell_types:
  - preferred_term: oocyte
    term:
      id: CL:0000023
      label: oocyte
  biological_processes:
  - preferred_term: meiotic spindle organization
    term:
      id: GO:0000212
      label: meiotic spindle organization
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Almost all oocytes harvested during these attempts were arrested at the MI
      stage, and none had a visible spindle (Table 1, Figure 2C-E).
    explanation: >-
      Direct observation of absent visible spindles in patient oocytes with
      metaphase-I arrest.
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, to further validate the effects of the mutation, we microinjected
      TUBB8 S176L and D417N mutant RNAs into human GV oocytes. Consistent with the
      phenotypes observed in mouse oocytes, we found severely or completely
      impaired spindle assembly (Figure 4C).
    explanation: >-
      Ex vivo human-oocyte microinjection reproduces defective spindle assembly
      for two assayed variants.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      About 75% of D417N oocytes are arrested at the metaphase I stage
      accompanied by an abnormal spindle (Figure 2E and F).
    explanation: >-
      The conditional D417N mouse model independently supports abnormal spindle
      assembly with metaphase-I arrest.
  downstream:
  - target: Metaphase I Oocyte Maturation Arrest
    description: >-
      Failure to form a competent meiotic spindle prevents completion of
      meiosis I in the maturation-arrest presentation.
  - target: Abnormality of Chromosome Segregation
    causal_link_type: DIRECT
    description: >-
      In the large-polar-body patient cases, abnormal spindle morphology or
      localization accompanied directly demonstrated chromosome-segregation
      errors; this edge is limited to that maturation-stage context.
phenotypes:
- name: Metaphase I Oocyte Maturation Arrest
  description: >-
    Retrieved oocytes resume meiosis but remain at metaphase I, fail to extrude
    the first polar body, and do not reach mature metaphase II. This is one
    presentation of the disorder, not a required upstream event for the
    fertilization, cleavage, or embryo-arrest presentations.
  phenotype_term:
    preferred_term: Metaphase I oocyte maturation arrest
    term:
      id: HP:0031516
      label: Metaphase I oocyte maturation arrest
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven mutations in the primate-specific gene TUBB8 that were
      responsible for oocyte meiosis I arrest in 7 of the 24 families.
    explanation: Directly establishes metaphase-I oocyte arrest in affected families.
  sequelae:
  - target: Female Infertility
    description: Complete maturation arrest prevents use of the patient's oocytes.
- name: Mixed Oocyte Maturation Arrest
  description: >-
    Some affected cycles yielded a mixture of germinal-vesicle and metaphase-I
    oocytes rather than uniform metaphase-I arrest. This mixed presentation is
    retained separately because it was observed in the later cohort.
  phenotype_term:
    preferred_term: Mixed oocyte maturation arrest
    term:
      id: HP:6001356
      label: Mixed oocyte maturation arrest
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The retrieved oocytes had been through germinal vesicle (GV)/metaphase I
      (MI) mixed arrest in families 1-3 and poor fertilization in family 4.
    explanation: Directly supports a mixed GV/MI maturation-arrest presentation.
  sequelae:
  - target: Female Infertility
    description: Insufficient oocyte maturation contributes to recurrent ART failure.
- name: Poor Fertilization
  description: >-
    Affected cycles can retrieve mature oocytes yet show a low fertilization
    proportion. No exact HPO term is asserted here; the preferred term preserves
    the cohort-defined clinical category.
  phenotype_term:
    preferred_term: Poor fertilization
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The retrieved oocytes had been through germinal vesicle (GV)/metaphase I
      (MI) mixed arrest in families 1-3 and poor fertilization in family 4.
    explanation: Directly supports poor fertilization as an alternative presentation.
  sequelae:
  - target: Female Infertility
    description: Poor fertilization contributes to recurrent IVF/ICSI failure.
- name: Zygotic Cleavage Failure
  description: >-
    Fertilized two-pronuclear zygotes may fail before the first cleavage despite
    successful oocyte maturation and fertilization. This phenotype is not routed
    through metaphase-I arrest.
  phenotype_term:
    preferred_term: Zygotic cleavage failure
    term:
      id: HP:0033336
      label: Zygotic cleavage failure
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nearly all the 2PN zygotes were arrested before the first cleavage, even
      after two extra days of cultivation (families 5-13).
    explanation: Direct observation of failure before first zygotic cleavage.
  sequelae:
  - target: Female Infertility
    description: Cleavage failure prevents progression to a transferable embryo.
- name: Embryo Developmental Arrest
  description: >-
    Other affected cycles produce cleaved embryos, sometimes including one or
    two initially usable embryos, but development stops before blastocyst
    formation or pregnancy. This later presentation is modeled independently of
    metaphase-I arrest.
  phenotype_term:
    preferred_term: Embryo developmental arrest
    term:
      id: HP:0020003
      label: Embryo developmental arrest
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the other families presented with embryonic arrest, and although 1-2
      usable embryos were produced, these embryos failed to form blastocysts
      during subsequent culture or establish pregnancy after transfer.
    explanation: Directly supports preimplantation embryo developmental arrest.
  sequelae:
  - target: Female Infertility
    description: Arrest before blastocyst formation prevents ongoing pregnancy.
- name: Formation of Multiple Pronuclei During Fertilization
  description: >-
    Abnormally fertilized zygotes with multiple pronuclei were frequent in
    selected families, indicating a fertilization-stage abnormality rather than
    obligatory maturation arrest.
  phenotype_term:
    preferred_term: Formation of multiple pronuclei during fertilization
    term:
      id: HP:4000008
      label: Formation of multiple pronuclei during fertilization
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also observed various abnormalities in the fertilized zygotes or
      embryos; there were problems such as high proportion of abnormal
      fertilization including 1PN (single pronucleus formation in zygotes) and
      MPN (multi-pronucleus formation in zygotes) (frequency>0.5, in families 1,
      2, 8, 10, 12, 17, and 20), or embryonic arrest, with or without severe
      fragmentation (Fig.2cand Table2).
    explanation: Directly documents multiple-pronuclear fertilization abnormalities.
  sequelae:
  - target: Female Infertility
    description: >-
      Frequent abnormal pronuclear formation contributed to failed fertilization
      in the selected recurrent-IVF/ICSI-failure cohort.
- name: Abnormality of Chromosome Segregation
  description: >-
    In patients who extruded abnormally large polar bodies, chromosome analysis
    showed partial trisomy or monosomy in the polar body and oocyte. The finding
    is case-context evidence and is not generalized to every TUBB8 variant.
  phenotype_term:
    preferred_term: Abnormality of chromosome segregation
    term:
      id: HP:0002916
      label: Abnormality of chromosome segregation
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both the PB and the oocyte exhibited abnormal chromosome compositions,
      including partial chromosome trisomy or monosomy (Fig. 2b).
    explanation: Direct chromosome analysis supports segregation abnormalities.
  sequelae:
  - target: Female Infertility
    description: >-
      Segregation errors accompanied abnormal oocyte maturation in selected
      patients with recurrent IVF/ICSI failure; no independent penetrance is
      inferred.
- name: Female Infertility
  description: >-
    Primary female infertility presents as recurrent IVF/ICSI failure caused by
    one of several oocyte, fertilization, zygotic-cleavage, or early-embryo
    outcomes. The available cohorts are selected for severe
    assisted-reproduction failure and do not provide an unselected population
    frequency.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the 32 individuals from independent and hitherto uncharacterized
      families with primary female infertility underwent two to three failed
      IVF/ICSI attempts in our centre or at other hospitals despite a normal
      menstrual cycle, endocrine level, and karyotype.
    explanation: >-
      Directly documents primary infertility and recurrent assisted-reproduction
      failure in the selected clinical cohort.
genetic:
- name: TUBB8
  association: Causative
  gene_term:
    preferred_term: TUBB8 (beta-tubulin 8)
    term:
      id: hgnc:20773
      label: TUBB8
  notes: >-
    A primate-specific beta-tubulin with no mouse orthologue of equivalent
    expression, which constrains modelling: the founding and mechanistic studies
    express human variants in mouse or human oocytes rather than relying on a
    native murine counterpart. The gene-disease relationship is established, but
    pathogenicity remains variant-specific: many reported alleles lack functional
    confirmation, segregation data can be incomplete, and the same variant can
    be associated with different reproductive phenotypes.
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified seven mutations in the primate-specific gene TUBB8 that were
      responsible for oocyte meiosis I arrest in 7 of the 24 families.
    explanation: >-
      Founding evidence that TUBB8 mutations cause the disorder, and that it is a
      primate-specific gene.
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it should be noted that the evidence for the pathogenicity of
      theseTUBB8variant has been obtained using a variety of different means,
      including in vitro functional verification, morphological observation of
      the spindle, pedigree segregation analysis, and the genetic detection of
      probands.
    explanation: >-
      Supports conservative, variant-level interpretation rather than treating
      every reported allele as equivalently proven.
diagnosis:
- name: Selected molecular testing for recurrent IVF/ICSI failure
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Exome sequencing or a female-infertility panel containing TUBB8 can be
    considered after recurrent IVF/ICSI failure characterized by oocyte
    maturation arrest, poor fertilization, cleavage failure, or early embryo
    arrest. The cited evidence comes from a selected research cohort and does not
    establish population screening. Results require segregation review and
    variant-level classification; a VUS should not be treated as a confirmed
    diagnosis solely because it occurs in TUBB8.
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole exome sequencing to screen for candidate variants in
      100 infertile female subjects and 100 controls who were able to conceive
      naturally.
    explanation: Establishes WES as the testing method used in the selected cohort.
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      So far, 16 of the reported 102TUBB8variants have been examined in in
      vitro functional assays
    explanation: >-
      Supports the warning that only a minority of the reported spectrum had
      been examined in functional assays.
treatments:
- name: Oocyte donation
  action_category: THERAPEUTIC
  description: >-
    Donor oocytes may be a feasible reproductive option for selected patients
    whose TUBB8 variants are classified as likely pathogenic and whose repeated
    ART failure is attributable to the oocyte. The source offers this as a
    present option rather than reporting a controlled outcome study; it is not a
    treatment of the patient's variant and is not generalized to VUS carriers.
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For these patients with the LP variants, donor eggs may be the most
      feasible method at present.
    explanation: >-
      Supports only a qualified recommendation for patients with
      likely-pathogenic variants; it does not provide efficacy estimates.
- name: Genetic counseling after TUBB8 variant detection
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counseling should distinguish autosomal-dominant from autosomal-recessive
    observations, review parental and familial segregation, and explain that
    reported TUBB8 variants vary in evidentiary strength and phenotype. A VUS or
    an allele found in a fertile relative should not be used alone to predict
    infertility, embryo outcome, or treatment response. This record does not
    infer incomplete penetrance.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study expands the spectrum of TUBB8 variants, particularly for
      embryonic arrest. Together with the extant knowledge of TUBB8 variants,
      this study provides a foundation for the genetic counselling of female
      infertility.
    explanation: Directly identifies genetic counseling as an intended use.
  - reference: PMID:33970371
    reference_title: The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We further analysed the correlation between phenotype and genotype, and we
      found 17 variants that caused different phenotypes under the same variant.
    explanation: Supports explicit counseling about variable phenotype by variant.
- name: HDAC6 inhibition to restore spindle microtubule acetylation (preclinical)
  action_category: THERAPEUTIC
  description: >-
    Model-only, variant-limited rescue. Cultured oocytes from the conditional
    human-TUBB8-D417N mouse and mouse oocytes acutely expressing selected human
    TUBB8 variants were treated with tubacin or tubastatin A. Spindle morphology,
    microtubule acetylation, and polar-body extrusion improved in selected model
    conditions. No affected patient received an HDAC6 inhibitor, and the study
    provides no human efficacy, safety, dosing, pregnancy, or live-birth data.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tubastatin A
      term:
        id: CHEBI:94186
        label: tubastatin A
    - preferred_term: Histone Deacetylase Inhibitor
      term:
        id: NCIT:C1946
        label: Histone Deacetylase Inhibitor
  target_mechanisms:
  - target: Loss of Stable Acetylated Spindle Microtubules in D417N Models
    treatment_effect: RESTORES
    description: >-
      Ex vivo HDAC6 inhibition restores acetylation and spindle readouts in the
      D417N mouse-oocyte model; this target link does not assert a human effect.
    evidence:
    - reference: PMID:39834092
      reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        More importantly, selective inhibition of HDAC6 by culturing TUBB8-D417N
        oocytes with Tubacin or Tubastatin A showed morphologically normal
        spindle and drastically recovered polar-body extrusion rate.
      explanation: >-
        Reports structural and polar-body-extrusion rescue in cultured model
        oocytes.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These rescue results shed light on the strategy to treat meiotic defects in
      a certain group of TUBB8 mutated patients.
    explanation: >-
      The authors' own subset language is retained while the lack of patient
      treatment data is made explicit.
  notes: >-
    Preclinical mouse-oocyte evidence only as of 2026-08; no human efficacy or
    clinical recommendation is asserted.
animal_models:
- name: Oocyte-specific human TUBB8-D417N conditional knock-in mouse
  species: Mouse
  genotype: Conditional oocyte-specific human TUBB8 p.D417N knock-in driven by Gdf9-Cre
  genes:
  - preferred_term: TUBB8
    term:
      id: hgnc:20773
      label: TUBB8
  publication: PMID:39834092
  description: >-
    A Cre-lox conditional model expresses human TUBB8-D417N in mouse oocytes.
    It reproduces abnormal spindle assembly, reduced polar-body extrusion,
    altered EB1/CKAP5/TACC3 and Ran-GTP readouts, and reduced tubulin acetylation.
    Because TUBB8 is primate-specific and the host oocyte and tubulin-isotype
    environment are murine, the model is assigned low translational fidelity.
  modeled_mechanisms:
  - target: D417N Model-Defined Reduction of TUBB8-EB1 Binding
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The conditional model reproduces reduced EB1 signal and D417N-associated
      spindle and maturation readouts studied in the paper.
    limitations: >-
      Human TUBB8 is conditionally introduced into a mouse oocyte, which lacks an
      endogenous equivalent expression program; only D417N is modeled and no
      patient oocyte establishes that the full regulator chain occurs in humans.
    evidence:
    - reference: PMID:39834092
      reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Therefore, we generated oocyte-specific expressed wild-type TUBB8-WT
        flox/flox; Gdf9-Cre (hereafter referred to as WT) and TUBB8-D417N
        flox/flox; Gdf9-Cre (hereafter referred to as D417N) mice (Figures 2A and
        S1E).
      explanation: Establishes the conditional human-TUBB8 mouse model.
  - target: D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The conditional model reproduces CKAP5/TACC3 mislocalization and impaired
      microtubule-nucleation readouts in D417N oocytes.
    limitations: >-
      The engineered mouse-oocyte context may not reproduce regulator abundance,
      localization, or nucleation in endogenous heterozygous patient oocytes.
  - target: D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The conditional model reproduces the altered Ran-GTP, TPX2, and NuMA
      spindle-assembly readouts studied in D417N oocytes.
    limitations: >-
      The engineered mouse-oocyte context does not establish that this route is
      active in endogenous heterozygous patient oocytes.
  - target: Loss of Stable Acetylated Spindle Microtubules in D417N Models
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The D417N mouse oocytes show reduced microtubule acetylation and increased
      HDAC6, enabling ex vivo rescue experiments.
    limitations: >-
      Acetylation and HDAC6 were measured in the engineered mouse-oocyte system;
      neither is established as a patient biomarker or validated human target.
    evidence:
    - reference: PMID:39834092
      reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Stable microtubule was largely abolished on the spindle of TUBB8-D417N
        oocytes, reflected by reduced tubulin acetylation and accumulated HDAC6.
      explanation: Supports the model-specific acetylation and HDAC6 phenotype.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      About 75% of D417N oocytes are arrested at the metaphase I stage
      accompanied by an abnormal spindle (Figure 2E and F).
    explanation: Establishes the central maturation and spindle phenotype.
experimental_models:
- name: Ex vivo human GV-oocyte TUBB8 missense mRNA microinjection
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Donated human germinal-vesicle oocytes cultured ex vivo
  culture_system: Acute mRNA microinjection followed by meiotic maturation culture
  publication: PMID:26789871
  description: >-
    Human GV oocytes were microinjected with S176L or D417N TUBB8 RNA and showed
    severely impaired spindle assembly. The relevant human cell type is used,
    but acute mRNA overexpression is not an endogenous heterozygous genotype and
    the assay covers only two variants.
  modeled_mechanisms:
  - target: Defective Oocyte Meiotic Spindle Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The ex vivo assay reproduces defective spindle assembly in human oocytes.
    limitations: >-
      Acute RNA microinjection can produce nonphysiologic expression; the oocytes
      are outside their ovarian context, and maturation or pregnancy outcomes
      cannot be assessed.
    evidence:
    - reference: PMID:26789871
      reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Finally, to further validate the effects of the mutation, we microinjected
        TUBB8 S176L and D417N mutant RNAs into human GV oocytes. Consistent with
        the phenotypes observed in mouse oocytes, we found severely or completely
        impaired spindle assembly (Figure 4C).
      explanation: Directly supports the ex vivo human-oocyte spindle readout.
  evidence:
  - reference: PMID:26789871
    reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Finally, to further validate the effects of the mutation, we microinjected
      TUBB8 S176L and D417N mutant RNAs into human GV oocytes.
    explanation: Establishes the experimental system.
- name: Ex vivo mouse-oocyte TUBB8 expression and HDAC6-inhibitor rescue
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: Mouse germinal-vesicle oocytes cultured ex vivo
  culture_system: Human TUBB8 mRNA microinjection or conditional-model oocytes with inhibitor exposure
  publication: PMID:39834092
  description: >-
    Mouse GV oocytes expressing human TUBB8 variants, including oocytes from the
    conditional D417N model, were cultured with selective HDAC6 inhibitors. The
    system measures spindle morphology, acetylation, and polar-body extrusion but
    does not test treatment in a patient or an intact reproductive cycle.
  modeled_mechanisms:
  - target: Loss of Stable Acetylated Spindle Microtubules in D417N Models
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The ex vivo mouse-oocyte assay reproduces the acetylation deficit and
      demonstrates rescue of selected cellular readouts after HDAC6 inhibition.
    limitations: >-
      Species context, acute expression for some variants, ex vivo culture, and
      absence of fertilization, embryo-development, pregnancy, and safety
      endpoints preclude human efficacy inference.
    evidence:
    - reference: PMID:39834092
      reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        More importantly, selective inhibition of HDAC6 by culturing TUBB8-D417N
        oocytes with Tubacin or Tubastatin A showed morphologically normal
        spindle and drastically recovered polar-body extrusion rate.
      explanation: Supports rescue only in cultured model oocytes.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although our study focused on treating oocytes carrying missense variants
      rather than directly treating patients, upon further investigation of
      safety and efficacy, it may be plausible to administer treatment to
      patients using liposomes containing HDAC6 inhibitors as potential
      therapeutic interventions in the future.
    explanation: Explicitly confirms that patients were not treated.
- name: Cell-free TUBB8 heterodimer folding and assembly assay
  experimental_model_type: OTHER
  culture_system: In vitro translation and non-denaturing gel analysis
  publication: PMID:26789871
  description: >-
    Cell-free translation and tubulin-chaperone assembly assays measure whether a
    tested TUBB8 variant changes folding kinetics or assembled heterodimer yield.
    The assay separates reduced-yield variants from D417N but cannot reproduce
    oocyte spindle architecture or clinical outcome.
  modeled_mechanisms:
  - target: Reduced Alpha/Beta-Tubulin Heterodimer Yield
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The assay directly measures variant-specific heterodimer formation.
    limitations: >-
      A cell-free reaction omits oocyte-specific protein abundance, spatial
      organization, microtubule-associated proteins, spindle architecture, and
      developmental outcomes.
    evidence:
    - reference: PMID:26789871
      reference_title: Mutations in TUBB8 and Human Oocyte Meiotic Arrest.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These data reveal a range of heterodimer assembly defects caused by the
        TUBB8 mutations, in some cases attributable to changes in the equilibria
        that govern the de novo assembly of heterodimers 24, in others pointing
        to misfolding, and in most cases leading to a diminished yield of
        assembled heterodimers.
      explanation: Direct biochemical measurement of heterodimer assembly.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data revealed no differences in translational efficiency in vitro, the
      kinetics of folding, or the yield of α/β-heterodimer formation compared to
      the wild type (Figure 2H and I).
    explanation: Demonstrates that D417N does not belong in the reduced-yield route.
discussions:
- discussion_id: gap_tubb8_variant_stratification_for_rescue
  prompt: >-
    Which TUBB8 variants act by reducing the tubulin dimer pool and which by
    impairing nucleation, and does the HDAC6-inhibition rescue work only for the
    latter?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Alpha/Beta-Tubulin Heterodimer Yield
  - pathophysiology#D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation
  - treatments#HDAC6 inhibition to restore spindle microtubule acetylation (preclinical)
  rationale: >-
    This gap is unusually actionable, because the answer decides who a candidate
    therapy could help. The mechanistic study is explicit that dimer-pool
    reduction is the main etiology but leaves large numbers of variants
    unexplained, and it resolves three of those unexplained variants as nucleation
    defects acting through EB1 and CKAP5/TACC3. The rescue was demonstrated for
    one of them, D417N. Whether HDAC6 inhibition restores spindle assembly in a
    variant whose primary problem is too little heterodimer - rather than a
    heterodimer that cannot nucleate properly - is untested, and there is reason
    to doubt it: stabilizing existing microtubules does not create tubulin that
    was never folded. Stratifying the reported TUBB8 variant spectrum by mechanism
    class, then testing the rescue in a pool-reduction variant, would establish
    whether this is a therapy for a subset or for the disorder.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The main etiology is the dramatic reduction of tubulin α/β dimer, but still
      large numbers of variants remain unexplained.
    explanation: >-
      Establishes that the variant spectrum splits by mechanism and that the
      split is not yet mapped.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These rescue results shed light on the strategy to treat meiotic defects in
      a certain group of TUBB8 mutated patients.
    explanation: >-
      The rescue is scoped to a group of patients, which is exactly the group
      this gap asks to define.
- discussion_id: gap_tubb8_human_model_fidelity
  prompt: >-
    Do the conditional human-TUBB8-D417N mouse and acute oocyte-expression
    systems reproduce endogenous heterozygous human disease well enough to
    transfer the EB1/CKAP5/TACC3, Ran-GTP, acetylation, or HDAC6-rescue findings
    to patient oocytes?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#Oocyte-specific human TUBB8-D417N conditional knock-in mouse
  - experimental_models#Ex vivo human GV-oocyte TUBB8 missense mRNA microinjection
  - experimental_models#Ex vivo mouse-oocyte TUBB8 expression and HDAC6-inhibitor rescue
  - experimental_models#Cell-free TUBB8 heterodimer folding and assembly assay
  - pathophysiology#D417N Model-Defined Reduction of TUBB8-EB1 Binding
  - pathophysiology#D417N Model-Defined CKAP5/TACC3 Mislocalization and Impaired Microtubule Nucleation
  - pathophysiology#D417N Model-Defined Attenuation of Ran-GTP Spindle-Assembly Signaling
  rationale: >-
    TUBB8 is primate-specific, yet the most detailed D417N pathway and every
    HDAC6-rescue result come from engineered mouse oocytes or other experimental
    systems. Human GV-oocyte microinjection uses the relevant cell type but is an
    acute overexpression assay, not an endogenous patient genotype. These models
    establish testable proximal mechanisms while leaving human target validity,
    safety, embryo competence, pregnancy, and live-birth benefit unresolved.
  evidence:
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To elucidate the deleterious effect of the human TUBB8 pathogenic variants
      in vivo, we generated oocyte-specific knock-in mouse models that mimic the
      equivalent human missense variants.
    explanation: Establishes that the detailed in vivo route comes from a mouse model.
  - reference: PMID:39834092
    reference_title: "Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Although our study focused on treating oocytes carrying missense variants
      rather than directly treating patients, upon further investigation of
      safety and efficacy, it may be plausible to administer treatment to
      patients using liposomes containing HDAC6 inhibitors as potential
      therapeutic interventions in the future.
    explanation: Explicitly distinguishes model-oocyte rescue from patient treatment.
notes: >-
  Created 2026-08-20 while closing out tubulin-family disease coverage following
  docs/reports/tubulinopathies-grouping-review-2026-08-20.md.

  Deliberately NOT a member of the Tubulinopathies grouping and NOT conformed to
  microtubule_dependent_neuronal_migration_failure: the cited cohorts concern
  female reproductive phenotypes rather than a neural tubulinopathy.

  DOMINANT_NEGATIVE is used only on the functionally assayed heterozygous
  missense trigger. Clinically observed unassayed heterozygous, homozygous, and
  compound-heterozygous triggers have no inferred functional impact category.

  Metaphase-I or mixed maturation arrest, poor fertilization, zygotic cleavage
  failure, and embryo developmental arrest are alternative presentations. The
  latter three are never routed through metaphase-I arrest.

  EB1/CKAP5/TACC3, Ran-GTP, acetylation, and HDAC6 claims are model-defined. The
  HDAC6-inhibition rescue has no human efficacy evidence. All evidence snippets
  are quoted from the three existing full-text reference caches; no new reference
  was fetched.

📚

References & Deep Research

References

3

PMID:26789871

Mutations in TUBB8 and Human Oocyte Meiotic Arrest.

No top-level findings curated for this source.

PMID:39834092

Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition.

No top-level findings curated for this source.

PMID:33970371

The comprehensive variant and phenotypic spectrum of TUBB8 in female infertility.

No top-level findings curated for this source.

TUBB8-related Oocyte Maturation Defect

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