A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum

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, Juergen, van der Knaap, Marjo S., Schiffmann, Raphael, Taft, Ryan J. and Vanderver, Adeline (2013) A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. American Journal of Human Genetics, 92 5: 767-773. doi:10.1016/j.ajhg.2013.03.018


 
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Author 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, Juergen
van der Knaap, Marjo S.
Schiffmann, Raphael
Taft, Ryan J.
Vanderver, Adeline
Title A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum
Formatted title
A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
1537-6605
Publication date 2013-05
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.03.018
Volume 92
Issue 5
Start page 767
End page 773
Total pages 7
Place of publication Cambridge, MA, United States
Publisher Cell Press
Collection year 2014
Language eng
Formatted 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
Keyword DNA-Sequencing Data
H-ABC
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
 
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