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Case Reports
. 2012 Sep;20(9):995-8.
doi: 10.1038/ejhg.2012.21. Epub 2012 Feb 15.

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

Renzo Guerrini  1 , Davide Mei, Duccio Maria Cordelli, Daniela Pucatti, Emilio Franzoni, Elena Parrini
Affiliations
Case Reports

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

Renzo Guerrini et al. Eur J Hum Genet. 2012 Sep.

Abstract

The purpose of the study is to explore the causative role of TUBB2B gene mutations in patients with different malformations of cortical development. We collected and evaluated clinical and MRI data of a cohort of 128 consecutive patients (61 females and 67 males) in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, who were mutation-negative to other possible causative genes. Mutation analysis of the TUBB2B gene was performed. We identified three new TUBB2B mutations in three unrelated patients (3 out of 128; 2.3%) with a diffuse and rather symmetrical cortical abnormality, including diffuse polymicrogyria in two and bilateral regional pachygyria in one. One patient harbored a p.Asp417Asn amino-acid substitution in the C-terminal domain of the protein; one patient a p.Asn256Ser amino-acid substitution in the intermediate domain and one patient a p.Leu117Pro amino-acid substitution in the N-terminal domain. The localization of each mutation within the secondary structure of the β2-tubulin polypeptide suggests that these mutations might alter the proper functions of microtubules. The phenotypic spectrum associated with TUBB2B mutations is wider than previously reported and includes diffuse, symmetric malformations of cortical development.

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Figures

Figure 1
Figure 1
Brain MRI scans of the three individuals with TUBB2B mutations. (a–d): Patient 1; (e–h): patient 2; (i–l): patient 3. (a, e, i): T1-weighed sagittal sections passing through the midline show a small pons in patient 1 (a), a thin corpus callosum in patient 2 (e), and normal structures in patient 3 (i). (b, j) are T1-weighed sagittal sections passing through the sylvian cortex; (f) is a proton density (PD)-weighed axial section passing through the semiovale centers. Note the thickening of the perisylvian cortex, with abnormal orientation of the sylvian fissure in patient 1 (b) and 3 (j), and pachygyria of the post-rolandic cortex in patient 2 (f). (c, g, k) are axial T1- (c), PD (g), and T2-weighed (k) sections. In patient 1 (c), the gyral pattern is diffusely abnormal whereas there is prominent thickening in the perisylvian cortex. In patient 2 (g), there is pronounced thickening in the posterior perisylvian cortex, with abnormal folding, which is more prominent on the left. In patient 3 (k), the cortical mantle is diffusely abnormal, with prominent infoldings in the posterior aspect of the abnormally oriented sylvian fissures, more on the left (black arrowhead). This aspect is consistent with both polymicrogyria and cobblestone-type cortex. (d, h, l) are coronal T1 (d), T2 (h), and PD-weighed (l) cuts through the posterior sylvian fissures. The gyral pattern is diffusely abnormal, with prominent thickening and infolding of the sylvian fissures.
Figure 2
Figure 2
Cartoon representation of the human α-tubulin/β-tubulin dimer. In blue, the mutations identified in the present study; in green, the mutations identified by Jaglin et al. The Asn256 residue, located in the β-tubulin H8 helix, is involved in the formation of the longitudinal contacts between α and β-tubulin at both the intradimer and interdimer interface. The Asp417 residue is located in the β-tubulin H12 helix, which represents a major site for interaction with motor proteins. The H12 helix contributes to generate lateral contacts between tubulin protofilaments. The H3 helix too, in which the Leu117 residue is located, is involved in the interaction between protofilaments. The Leu117Pro mutation substitutes a leucine with a proline that may act as a structural disruptor in the middle of regular secondary structure elements, such as α-helices.
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