RGD Reference Report - A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. - Rat Genome Database

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A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination.

Authors: Duncan, Ian D  Bugiani, Marianna  Radcliff, Abigail B  Moran, John J  Lopez-Anido, Camila  Duong, Phu  August, Benjamin K  Wolf, Nicole I  van der Knaap, Marjo S  Svaren, John 
Citation: Duncan ID, etal., Ann Neurol. 2017 May;81(5):690-702. doi: 10.1002/ana.24930. Epub 2017 May 9.
RGD ID: 150429639
Pubmed: PMID:28393430   (View Abstract at PubMed)
PMCID: PMC5495199   (View Article at PubMed Central)
DOI: DOI:10.1002/ana.24930   (Journal Full-text)


OBJECTIVE: Our 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.
METHODS: Based 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.
RESULTS: As 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.
INTERPRETATION: The 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TUBB4AHumandemyelinating disease  ISOTubb4a (Rattus norvegicus)DNA:missense mutation:cds:p.Ala302Thr (rat)RGD 
Taiep/DunRatdemyelinating disease  IAGP progressive with ageRGD 
Tubb4aRatdemyelinating disease  IAGP DNA:missense mutation:cds:p.Ala302Thr (rat)RGD 
Tubb4aMousedemyelinating disease  ISOTubb4a (Rattus norvegicus)DNA:missense mutation:cds:p.Ala302Thr (rat)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Taiep/DunRatdemyelination  IAGP progressive with ageRGD 
Tubb4aRatdemyelination  IAGP DNA:missense mutation:cds:p.Ala302Thr ratRGD 
Taiep/DunRattremors  IAGP progressive with ageRGD 
Tubb4aRattremors  IAGP DNA:missense mutation:cds:p.Ala302Thr ratRGD 
Objects Annotated

Genes (Rattus norvegicus)
Tubb4a  (tubulin, beta 4A class IVa)

Genes (Mus musculus)
Tubb4a  (tubulin, beta 4A class IVA)

Genes (Homo sapiens)
TUBB4A  (tubulin beta 4A class IVa)

Strains
Taiep/Dun  (NA)


Additional Information