Affinage

TUBB2A

Tubulin beta-2A chain · UniProt Q13885

Length
445 aa
Mass
49.9 kDa
Annotated
2026-06-10
16 papers in source corpus 5 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TUBB2A encodes a beta-tubulin isotype that incorporates into alpha/beta-tubulin heterodimers, and pathogenic de novo variants converge on disrupting heterodimer formation, microtubule dynamics, and spindle morphology in ways that scale with cortical malformation severity (PMID:24702957, PMID:41872443). Distinct surfaces of the protein carry distinct consequences: variants in a conserved loop predicted to contact the alpha-tubulin-bound GTP impair the intradimer interface and correct heterodimer assembly (PMID:24702957), while a variant at the longitudinal E-site interface destabilizes heterodimer binding at that contact (PMID:41080462); variants at or near the dimer interface produce the most pronounced effects on microtubule morphology/dynamics and the most severe cortical phenotypes (PMID:41872443). A separate solvent-exposed residue (Asp417) lies at the kinesin motor-binding surface, and its mutation selectively abolishes binding to the neuron-specific kinesin KIF1A while leaving microtubule assembly intact, additionally disrupting mitotic spindle bipolarity and M-phase progression (PMID:29547997). In neurons, TUBB2A acts downstream of FGF13, which binds it directly and promotes microtubule stability and mitochondrial function in a TUBB2A-dependent manner (PMID:41808420).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2014 Medium

    Established that TUBB2A coding variants are not silent but mechanistically impair tubulin heterodimer formation, linking the gene to microtubule dysfunction at the intradimer/GTP interface.

    Evidence in vitro tubulin/microtubule functional assay with in silico modeling of de novo patient variants

    PMID:24702957

    Open questions at the time
    • Single lab in vitro plus modeling; no reconstituted heterodimer structure
    • Did not test effects on neuronal microtubule networks
    • GTP-loop association inferred from modeling, not direct biochemistry
  2. 2018 High

    Resolved that different TUBB2A surfaces have separable functional roles by showing a kinesin-binding-site variant (D417N) selectively abolishes KIF1A binding while preserving microtubule assembly, distinct from interface variants that impair the spindle.

    Evidence in vitro KIF1A binding assay, structural modeling, and cellular overexpression with mitotic spindle and cell-cycle readouts

    PMID:29547997

    Open questions at the time
    • KIF1A-dependent synaptic vesicle transport defect inferred, not directly measured in neurons
    • Overexpression rather than knock-in/endogenous context
    • Mechanism linking spindle defect to cortical phenotype unestablished
  3. 2025 Low

    Identified Arg391 at the longitudinal E-site interface as a recurrent mutational hotspot, extending the interface-disruption model to a second critical heterodimer contact.

    Evidence whole-exome sequencing and computational modeling of the heterodimer interface

    PMID:41080462

    Open questions at the time
    • Computational modeling only, no experimental reconstitution or in vitro validation
    • No cellular phenotyping of the variant
    • Heterodimer destabilization predicted, not measured
  4. 2026 Medium

    Generalized the genotype-phenotype relationship by showing across eight variants that those at/near the dimer interface most strongly perturb microtubule morphology and dynamics and correlate with the most severe cortical malformation (pachygyria).

    Evidence TUBB2A-FLAG/EGFP overexpression in HEK293T cells with spindle morphology and microtubule dynamics assays

    PMID:41872443

    Open questions at the time
    • Overexpression in a non-neuronal cell line
    • Genotype-phenotype correlation is associative across a variant set
    • No endogenous neuronal validation
  5. 2026 Medium

    Placed TUBB2A in a neuronal pathway by demonstrating direct FGF13 binding and TUBB2A-dependent control of microtubule stability and mitochondrial function.

    Evidence reciprocal co-immunoprecipitation, overexpression/knockdown in an AD mouse model, mitochondrial membrane potential and ultrastructural readouts

    PMID:41808420

    Open questions at the time
    • Single lab; binding interface on TUBB2A not mapped
    • Mechanism by which FGF13-TUBB2A binding regulates mitochondrial transport not resolved
    • Disease relevance limited to one mouse model context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How interface-disrupting variants mechanistically translate microtubule/spindle defects into specific cortical malformation patterns, and whether FGF13-TUBB2A coupling operates through KIF1A-dependent transport, remain unresolved.
  • No structure of mutant heterodimers
  • No endogenous/knock-in neuronal disease model integrating spindle, transport, and mitochondrial phenotypes
  • Link between FGF13 pathway and KIF1A motor function untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 3
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2
Partners
FGF13KIF1A
Complex memberships
alpha/beta-tubulin heterodimer

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 De novo variants in TUBB2A (p.N247K and p.A248V) affecting adjacent amino acids in a conserved loop impair tubulin heterodimer formation and microtubule function in vitro. In silico modeling predicted that the affected loop directly associates with the alpha-tubulin-bound GTP molecule, impairing the intradimer interface and correct formation of the alpha/beta-tubulin heterodimer. In vitro tubulin/microtubule functional assay combined with in silico structural modeling; de novo variant identification in patients American journal of human genetics Medium 24702957
2018 A missense mutation in TUBB2A (p.D417N) at a solvent-exposed residue at the kinesin motor binding site impairs binding to KIF1A (a neuron-specific kinesin required for transport of synaptic vesicle precursors), as confirmed by in vitro binding assay and structural analysis. Overexpression of TUBB2AD417N disrupts mitotic spindle bipolarity and morphology and affects M phase entry and length. In contrast, TUBB2AD417N retains the ability to assemble into microtubules. Additionally, the previously reported TUBB2AA248V mutant does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. In vitro KIF1A binding assay, structural modeling, overexpression in cells with mitotic spindle and cell cycle analysis Human molecular genetics High 29547997
2025 A recurrent heterozygous TUBB2A variant (p.Arg391His) affects a conserved residue within the longitudinal E-site heterodimer interface. Computational modeling demonstrated that this variant disrupts alpha/beta-tubulin heterodimer formation by impairing binding stability at this critical interaction site, identifying Arg391 as a mutational hotspot for disrupted tubulin dynamics. Whole-exome sequencing, structural/computational modeling of heterodimer interface Frontiers in cellular neuroscience Low 41080462
2026 Four novel and four previously reported TUBB2A variants all affected the morphology of the spindle apparatus and dynamics of microtubules when expressed in HEK293T cells. Variants located at or near the alpha/beta-tubulin dimer interface exerted a pronounced influence on microtubule morphology and dynamics and were associated with more severe cortical phenotypes (pachygyria). TUBB2A-FLAG and TUBB2A-EGFP plasmid overexpression in HEK293T cells; spindle morphology and microtubule dynamics assays Scientific reports Medium 41872443
2026 FGF13 directly binds TUBB2A as confirmed by co-immunoprecipitation. FGF13 overexpression enhances microtubule stability and mitochondrial function in hippocampal neurons, and these protective effects are reversed by TUBB2A knockdown, placing TUBB2A downstream of FGF13 in a pathway linking microtubule stability to mitochondrial transport and function in neurons. DNA methylation-mediated silencing of FGF13 reduces its binding to TUBB2A. Co-immunoprecipitation, western blotting, overexpression and knockdown in AD mouse model, flow cytometry for mitochondrial membrane potential, transmission electron microscopy FASEB journal Medium 41808420

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 De novo mutations in the beta-tubulin gene TUBB2A cause simplified gyral patterning and infantile-onset epilepsy. American journal of human genetics 92 24702957
2018 Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy. Human molecular genetics 37 29547997
2020 Defining the phenotypical spectrum associated with variants in TUBB2A. Journal of medical genetics 27 32571897
2020 Identification of TUBB2A by quantitative proteomic analysis as a novel biomarker for the prediction of distant metastatic breast cancer. Clinical proteomics 21 32489334
2016 De Novo TUBB2A Variant Presenting With Anterior Temporal Pachygyria. Journal of child neurology 21 27770045
2020 De novo mutations of TUBB2A cause infantile-onset epilepsy and developmental delay. Journal of human genetics 18 32203252
2017 De novo pathogenic variant in TUBB2A presenting with arthrogryposis multiplex congenita, brain abnormalities, and severe developmental delay. American journal of medical genetics. Part A 15 28840640
2020 Expanding the Phenotype of TUBB2A-Related Tubulinopathy: Three Cases of a Novel, Heterozygous TUBB2A Pathogenic Variant p.Gly98Arg. Molecular syndromology 13 33776625
2020 Circular RNA circ_C16orf62 Suppresses Cell Growth in Gastric Cancer by miR-421/Tubulin beta-2A Chain (TUBB2A) Axis. Medical science monitor : international medical journal of experimental and clinical research 7 33006960
2025 Integrated analysis of single-cell RNA-seq and spatial transcriptomics to identify the lactylation-related protein TUBB2A as a potential biomarker for glioblastoma in cancer cells by machine learning. Frontiers in immunology 6 40642071
2023 Identification of TUBB2A as a Cancer-Immunity Cycle-Related Therapeutic Target in Triple-Negative Breast Cancer. Molecular biotechnology 5 37742297
2025 A mutational hotspot in TUBB2A associated with impaired heterodimer formation and severe brain developmental disorders. Frontiers in cellular neuroscience 1 41080462
2024 [Genetic analysis of a family with epilepsy accompanied by developmental delay and brain deformity due to a de novo variant of TUBB2A gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 38311557
2022 Generation of an induced pluripotent stem cell line (DHMCi009-A) from an individual with TUBB2A tubulinopathy. Stem cell research 1 35930870
2026 Hypermethylation of FGF13 Reduces Microtubule Stability via Interaction With TUBB2A to Promote Mitochondrial Dysfunction in Alzheimer's Disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41808420
2026 TUBB2A related epilepsy: novel variants and genotype-phenotype correlation. Scientific reports 0 41872443

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