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

Cas Simons, Nicole I Wolf, Nathan McNeil, Ljubica Caldovic, Joseph M Devaney, Asako Takanohashi, Joanna Crawford, Kelin Ru, Sean M Grimmond, David Miller, et al. (2013) AMERICAN JOURNAL OF HUMAN GENETICS. 92(5). p.767-773
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 alpha-tubulin and beta-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.
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author
organization
alternative title
A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum
year
type
journalArticle (original)
publication status
published
subject
keyword
VARIANTS, FRAMEWORK, DNA-SEQUENCING DATA, H-ABC
journal title
AMERICAN JOURNAL OF HUMAN GENETICS
Am. J. Hum. Genet.
volume
92
issue
5
pages
767 - 773
Web of Science type
Article
Web of Science id
000318582800011
JCR category
GENETICS & HEREDITY
JCR impact factor
10.987 (2013)
JCR rank
9/165 (2013)
JCR quartile
1 (2013)
ISSN
0002-9297
DOI
10.1016/j.ajhg.2013.03.018
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
4329321
handle
http://hdl.handle.net/1854/LU-4329321
date created
2014-03-12 11:19:56
date last changed
2016-12-19 15:45:49
@article{4329321,
  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 alpha-tubulin and beta-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.},
  author       = {Simons, Cas and Wolf, Nicole I and McNeil, Nathan and Caldovic, Ljubica and Devaney, Joseph M and Takanohashi, Asako and Crawford, Joanna and Ru, Kelin and Grimmond, Sean M and Miller, David and Tonduti, Davide and Schmidt, Johanna L and Chudnow, Robert S and Van Coster, Rudy and Lagae, Lieven and Kisler, Jill and Sperner, J{\"u}rgen and van der Knaap, Marjo S and Schiffmann, Raphael and Taft, Ryan J and Vanderver, Adeline},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keyword      = {VARIANTS,FRAMEWORK,DNA-SEQUENCING DATA,H-ABC},
  language     = {eng},
  number       = {5},
  pages        = {767--773},
  title        = {A de novo mutation in the \ensuremath{\beta}-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2013.03.018},
  volume       = {92},
  year         = {2013},
}

Chicago
Simons, Cas, Nicole I Wolf, Nathan McNeil, Ljubica Caldovic, Joseph M Devaney, Asako Takanohashi, Joanna Crawford, et al. 2013. “A De Novo Mutation in the Β-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.
APA
Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., et al. (2013). A de novo mutation in the β-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.
Vancouver
1.
Simons C, Wolf NI, McNeil N, Caldovic L, Devaney JM, Takanohashi A, et al. A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum. AMERICAN JOURNAL OF HUMAN GENETICS. 2013;92(5):767–73.
MLA
Simons, Cas, Nicole I Wolf, Nathan McNeil, et al. “A De Novo Mutation in the Β-tubulin Gene TUBB4A Results in the Leukoencephalopathy Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum.” AMERICAN JOURNAL OF HUMAN GENETICS 92.5 (2013): 767–773. Print.