{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:05:51Z","timestamp":1791295551209,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,5,9]],"date-time":"2017-05-09T00:00:00Z","timestamp":1494288000000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000071","name":"National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["NS075269"],"award-info":[{"award-number":["NS075269"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["U54 HD090256"],"award-info":[{"award-number":["U54 HD090256"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Our goal was to define the genetic cause of the profound hypomyelination in the\n                      <jats:italic>taiep<\/jats:italic>\n                      rat model and determine its relevance to human white matter disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Based on previous localization of the\n                      <jats:italic>taiep<\/jats:italic>\n                      mutation to rat chromosome 9, we tested whether the mutation resided within the\n                      <jats:italic>Tubb4a<\/jats:italic>\n                      (\u03b2\u2010tubulin 4A) gene, because mutations in the\n                      <jats:italic>TUBB4A<\/jats:italic>\n                      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\u2010year\u2010old rats by light and electron microscopy. Cerebral white matter from a patient with\n                      <jats:italic>TUBB4A<\/jats:italic>\n                      Asn414Lys mutation and magnetic resonance imaging evidence of severe hypomyelination were studied similarly.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      As the\n                      <jats:italic>taiep<\/jats:italic>\n                      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\n                      <jats:italic>Tubb4a<\/jats:italic>\n                      (p.Ala302Thr) was found in homozygous\n                      <jats:italic>taiep<\/jats:italic>\n                      samples. A similar hypomyelination associated with increased oligodendrocyte numbers and arrays of microtubules in oligodendrocytes was demonstrated in the human patient sample.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>taiep<\/jats:italic>\n                      rat is the first animal model of\n                      <jats:italic>TUBB4<\/jats:italic>\n                      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\n                      <jats:italic>TUBB4A<\/jats:italic>\n                      mutation and leukodystrophy confirms the usefulness of\n                      <jats:italic>taiep<\/jats:italic>\n                      as a model of the human disease. Ann Neurol 2017;81:690\u2013702\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24930","type":"journal-article","created":{"date-parts":[[2017,4,10]],"date-time":"2017-04-10T04:43:04Z","timestamp":1491799384000},"page":"690-702","source":"Crossref","is-referenced-by-count":65,"title":["A mutation in the\n                    <i>Tubb4a<\/i>\n                    gene leads to microtubule accumulation with hypomyelination and demyelination"],"prefix":"10.1002","volume":"81","author":[{"given":"Ian D.","family":"Duncan","sequence":"first","affiliation":[{"name":"Department of Medical Sciences University of Wisconsin\u2013Madison Madison WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Bugiani","sequence":"additional","affiliation":[{"name":"Department of Pathology VU University Medical Center Amsterdam the Netherlands"},{"name":"Center for Childhood White Matter Disorders Amsterdam Neuroscience, VU University 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