title: A mutation in the Tubb4a gene leads to microtubule accumulation with hypomyelination and demyelination.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Sciences, University of Wisconsin-Madison, Madison, WI.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Duncan
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.|Center for Childhood White Matter Disorders, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.affiliation: Department of Medical Sciences, University of Wisconsin-Madison, Madison, WI.
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Radcliff
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI.
authors.forename: John J
authors.initials: JJ
authors.lastname: Moran
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI.
authors.forename: Camila
authors.initials: C
authors.lastname: Lopez-Anido
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI.
authors.forename: Phu
authors.initials: P
authors.lastname: Duong
authors.affiliation: Electron Microscope Facility, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI.
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: August
authors.affiliation: Center for Childhood White Matter Disorders, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.|Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.affiliation: Center for Childhood White Matter Disorders, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands.|Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands.
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI.|Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI.
authors.forename: John
authors.initials: J
authors.lastname: Svaren
mesh_terms: D000818:Animals; D002675:Child, Preschool; D003711:Demyelinating Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D008279:Magnetic Resonance Imaging; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism*; D009900:Optic Nerve / Q000000981:diagnostic imaging*; D051381:Rats; D013116:Spinal Cord / Q000000981:diagnostic imaging*; D014404:Tubulin / Q000235:genetics*; D066127:White Matter / Q000000981:diagnostic imaging*
chemical_list: C582076:TUBB4A protein, human; D014404:Tubulin