A novel TUBB4A mutation G96R identified in a patient with hypomyelinating leukodystrophy onset beyond adolescence

Abstract

The tubulin beta-4A gene (TUBB4A) is associated with two different clinical conditions, dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We identified a novel TUBB4A mutation, c.286G>A (p.G96R), in an adult male patient who suffered neurological symptoms beyond adolescence. This patient shows intermediate clinical features between DYT4 and H-ABC, suggesting that the TUBB4A disorder would constitute a spectrum disorder.

Figure 1

Clinical and molecular information. (a) A T2-weighted axial image of brain MRI indicates high intensity in the white matter. Slightly dilated lateral ventricles may indicate the mild atrophy of the basal ganglia. (b) Electropherograms of Sanger sequencing for the present family. Only the patient shows heterozygous mutation of c.286G>A. (c) Comparison of the amino-acid sequences with different species. The affected residue is conserved among species. (d) Mapping TUBB4A mutations to the 3-D protein crystal structure of the bovine αβ-tubulin heterodimer. The bovine α- and β-tubulins are shown in gray and green, respectively. In this image, β-tubulin is supposed to be encoded by TUBB4A whereas α-tubulin is uncertain. The guanosine triphosphate (GTP), Taxol and guanosine diphosphate (GDP) are marked with brown lines. The locations of the mutated residues are highlighted as yellow dot-halos. The residues associated with H-ABC are marked with bold black lines. The residues not associated with H-ABC but associated with other diseases, such as isolated hypomyelination, hypomyelinating leukodystrophy and spastic paraplegia, are marked with gray lines. The residue p.F367 is located behind Taxol in the figure. The location of the present mutation, p.G96R, is marked with a red line. The amino acid at the position 364 is Ala(A) in human but Ser(S) in bovine. GTP, guanosine triphosphate; H-ABC, hypomyelination with atrophy of the basal ganglia and cerebellum; MRI, magnetic resonance imaging.