ArticleAnnals of neurology2017
A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination.
Article in Annals of neurology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 59 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- The role of genetics and molecular mechanisms in early onset scoliosis.Journal of clinical orthopaedics and trauma · 2026Review
- The tubulin code in acute ischemic stroke: post-translational reprogramming of the neuronal cytoskeleton and implications for phase-specific neuroprotection.Frontiers in neuroscience · 2026Review
- A scoping review of stem cell models of leukodystrophies: advances in understanding pathophysiological mechanisms.NPJ genomic medicine · 2025Article
- KIF1C-related disorders: spastic ataxia or hypomyelinating leukodystrophy? A paradigm of classification ambiguity.Neurogenetics · 2025Article
- QSI and DTI of Inherited White Matter Disorders in Rat Spinal Cord: Early Detection and Comparison with Quantitative Electron Microscopy Findings.Diagnostics (Basel, Switzerland) · 2025Article
- Multi-Omics Analysis of Hippocampus in Rats Administered Trimethyltin Chloride.Neurotoxicity research · 2025Article
- Association between microenvironment-related genes and prognosis of primary central nervous system lymphoma.EJHaem · 2024Article
- Article
- Zinc-Finger Protein ZFP488 Regulates the Timing of Oligodendrocyte Myelination and Remyelination.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- LncRNA TubAR complexes with TUBB4A and TUBA1A to promote microtubule assembly and maintain myelination.Cell discovery · 2024Article
- Single prolonged stress induces behavior and transcriptomic changes in the medial prefrontal cortex to increase susceptibility to anxiety-like behavior in rats.Frontiers in psychiatry · 2024Article
- Article
- Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs).Neurology international · 2023Review
- Gross Motor Function in Pediatric OnsetJournal of child neurology · 2023Article
- Gene expression and locomotor recovery in adult rats with spinal cord injury and plasma-synthesized polypyrrole/iodine application combined with a mixed rehabilitation scheme.Frontiers in neurology · 2023Article
- Characterization of sperm motility and testosterone secretion in theAnimal reproduction · 2023Article
- H-ABC tubulinopathy revealed by label-free second harmonic generation microscopy.Scientific reports · 2022Article
- Functional Investigation of TUBB4A Variants Associated with Different Clinical Phenotypes.Molecular neurobiology · 2022Article
- H-ABC- and dystonia-causingScience advances · 2022Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
objectiveOur goal was to define the genetic cause of the profound hypomyelination in the taiep rat model and determine its relevance to human white matter disease.
methodsBased on previous localization of the taiep mutation to rat chromosome 9, we tested whether the mutation resided within the Tubb4a (β-tubulin 4A) gene, because mutations in the TUBB4A gene have been described in patients with central nervous system hypomyelination. To determine whether accumulation of microtubules led to progressive demyelination, we analyzed the spinal cord and optic nerves of 2-year-old rats by light and electron microscopy. Cerebral white matter from a patient with TUBB4A Asn414Lys mutation and magnetic resonance imaging evidence of severe hypomyelination were studied similarly.
resultsAs the taiep rat ages, there is progressive loss of myelin in the brain and dorsal column of the spinal cord associated with increased oligodendrocyte numbers with accumulation of microtubules. This accumulation involved the entire cell body and distal processes of oligodendrocytes, but there was no accumulation of microtubules in axons. A single point mutation in Tubb4a (p.Ala302Thr) was found in homozygous taiep samples. A similar hypomyelination associated with increased oligodendrocyte numbers and arrays of microtubules in oligodendrocytes was demonstrated in the human patient sample.
interpretationThe taiep rat is the first animal model of TUBB4 mutations in humans and a novel system in which to test the mechanism of microtubule accumulation. The finding of microtubule accumulation in a patient with a TUBB4A mutation and leukodystrophy confirms the usefulness of taiep as a model of the human disease. Ann Neurol 2017;81:690-702.
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