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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

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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.
Keywords
VARIANTS, FRAMEWORK, DNA-SEQUENCING DATA, H-ABC

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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.
@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},
}

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