Title: A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum
Authors: Simons, Cas ×
Wolf, Nicole I
McNeil, Nathan
Caldovic, Ljubica
Devaney, Joseph M
Takanohashi, Asako
Crawford, Joanna
Ru, Kelin
Grimmond, Sean M
Miller, David
Tonduti, Davide
Schmidt, Johanna L
Chudnow, Robert S
van Coster, Rudy
Lagae, Lieven
Kisler, Jill
Sperner, Jürgen
van der Knaap, Marjo S
Schiffmann, Raphael
Taft, Ryan J
Vanderver, Adeline #
Issue Date: May-2013
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:92 issue:5 pages:767-73
Article number: 10.1016/j.ajhg.2013.03.018
Abstract: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hereditary leukoencephalopathy that was originally identified by MRI pattern analysis, and it has thus far defied all attempts at identifying the causal mutation. Only 22 cases are published in the literature to date. We performed exome sequencing on five family trios, two family quartets, and three single probands, which revealed that all eleven H-ABC-diagnosed individuals carry the same de novo single-nucleotide TUBB4A mutation resulting in nonsynonymous change p.Asp249Asn. Detailed investigation of one of the family quartets with the singular finding of an H-ABC-affected sibling pair revealed maternal mosaicism for the mutation, suggesting that rare de novo mutations that are initially phenotypically neutral in a mosaic individual can be disease causing in the subsequent generation. Modeling of TUBB4A shows that the mutation creates a nonsynonymous change at a highly conserved asparagine that sits at the intradimer interface of α-tubulin and β-tubulin, and this change might affect tubulin dimerization, microtubule polymerization, or microtubule stability. Consistent with H-ABC's clinical presentation, TUBB4A is highly expressed in neurons, and a recent report has shown that an N-terminal alteration is associated with a heritable dystonia. Together, these data demonstrate that a single de novo mutation in TUBB4A results in H-ABC.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Brain & Metabolism Section (-)
× corresponding author
# (joint) last author

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