A mutation in theTubb4agene leads to microtubule accumulation with hypomyelination and demyelination (original) (raw)
2017, Annals of Neurology
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 if the mutation resided within the Tubb4a (β-tubulin 4A) gene, since mutations in the TUBB4A gene have been described in patients with CNS 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 MRI evidence of severe hypomyelination was 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
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