John Svaren, PhD – Slide of the Week

John Svaren, PhD - Slide of the Week

Title: Mutations in the TUBB4A Gene Cause a Hypomyelinating Leukodystrophy

Legend: A) White matter abnormities in a patient with a mutation in the beta 4 tubulin gene (Tubb4a), which causes hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). B) The taiep rat exhibits a dramatic loss of myelin (stained in blue) at 3 months with virtual absence at later timepoints. C) The taiep mutation in the Tubb4a gene was identified in the rat chromosomal interval by using a binding profile of the Sox10 transcription factor, which is critical for myelination of the nervous system. Binding sites for the Sox10 transcription factor are highlighted in blue. D) The taiep mutation occurs in Ala302 in the TUBB4A protein. Other TUBB4A mutations causing  H-ABC are shown, including the N414 mutation associated with the patient shown in panel A.

Citation: Duncan ID, Bugiani M, Radcliff AB, Moran JJ, Lopez-Anido C, Duong P, August BK, Wolf NI, van der Knaap MS, Svaren J. A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination. Ann Neurol. 2017 May;81(5):690-702. PubMed PMID:  28393430; PubMed Central PMCID: PMC5495199

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.  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 TUBB4A 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.

About the Lab: The Svaren laboratory is focused on the transcriptional and epigenetic regulation of myelination. Myelin is a vital constituent of the nervous system that increases the speed of action potentials and also provides trophic support for the long axons that project from neurons. Their studies are centered on the myelin-producing cells of the peripheral nervous system, called Schwann cells. The Svaren lab has focused on elucidating regulation of gene networks during Schwann cell development and response to injury. They have also recently found a novel role of the polycomb repressive complex 2, an epigenetic regulator, in controlling the regenerative responses of Schwann cells after peripheral nerve injury.

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