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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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, Davide Tonduti, Johanna L. Schmidt, Robert S. Chudnow, Rudy van Coster, Lieven Lagae, Jill Kisler, Jürgen Sperner, Marjo S. van der Knaap, Raphael Schiffmann, Ryan J. Taft, Adeline Vanderver The American Journal of Human Genetics Volume 92, Issue 5, Pages 767-773 (May 2013) DOI: 10.1016/j.ajhg.2013.03.018 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 MRI Findings in H-ABC Axial T2-weighted images (first three columns) and sagittal T1-weighted images (fourth column) of individual HA107 at the age of 3.5 years (A–D), individual HA27 at 21 years (E–H), and an unaffected individual at 14 years (I–L). We included the unaffected individual to demonstrate the low signal on T2-weighted images of normal myelinated white matter, the normal volume of the putamen, and the normal volume of the cerebellum. Note the relatively high T2 signal of the cerebral white matter in the two affected individuals (A, B, E, and F); this indicates lack of myelin. No putamen is visible in the affected individuals (B and F) (arrows are where the putamen should be). The cerebellar atrophy is already present in the younger individual (D) but is worse in the older individual (H). The American Journal of Human Genetics 2013 92, 767-773DOI: (10.1016/j.ajhg.2013.03.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 The Highly Conserved TUBB4A Residue Asp249 Sits at the Intradimer Interface of α-Tubulin and β-Tubulin (A) The genomic structure of TUBB4A shows the region encoding Arg2 in exon 1 and the region encoding Asp249 in exon 4. (B) Multiple-sequence alignment of a section of four human β-tubulins, a zebrafish β-tubulin, and the Saccharomyces cerevisiae β-tubulin. Residue Asp249 is marked in bold text, residues that form the T7 loop are boxed, and asterisks indicate invariant residues. Sequences are labeled with their Uniprot ID. (C) Structure of bovine tubulin heterodimer.19 Guanosine triphosphate (GTP; green) can be seen bound at the interface of α-tubulin (magenta) and β-tubulin (blue). Residue Asp249 is shown as red spheres, its interacting partner Arg2 is shown as blue spheres, and the remainder of the T7 loop is shown in yellow. (D) A magnified view of the intradimer interface demonstrates the roll of Asp249 in coordinating the interaction between the T7 loop and the α-tubulin-bound GTP. The American Journal of Human Genetics 2013 92, 767-773DOI: (10.1016/j.ajhg.2013.03.018) Copyright © 2013 The American Society of Human Genetics Terms and Conditions