Title: Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A)
Authors: Poirier, Karine ×
Keays, David A
Francis, Fiona
Saillour, Yoann
Bahi, Nadia
Manouvrier, Sylvie
Fallet-Bianco, Catherine
Pasquier, Laurent
Toutain, Annick
Tuy, Françoise Phan Dinh
Bienvenu, Thierry
Joriot, Sylvie
Odent, Sylvie
Ville, Dorothée
Desguerre, Isabelle
Goldenberg, Alice
Moutard, Marie-Laure
Fryns, Jean-Pierre
Van Esch, Hilde
Harvey, Robert J
Siebold, Christian
Flint, Jonathan
Beldjord, Chérif
Chelly, Jamel #
Issue Date: Nov-2007
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:28 issue:11 pages:1055-1064
Abstract: We have recently reported a missense mutation in exon 4 of the tubulin alpha 1A (Tuba1a) gene in a hyperactive N-ethyl-N-nitrosourea (ENU) induced mouse mutant with abnormal lamination of the hippocampus. Neuroanatomical similarities between the Tuba1a mutant mouse and mice deficient for Doublecortin (Dcx) and Lis1 genes, and the well-established functional interaction between DCX and microtubules (MTs), led us to hypothesize that mutations in TUBA1A (TUBA3, previous symbol), the human homolog of Tuba1a, might give rise to cortical malformations. This hypothesis was subsequently confirmed by the identification of TUBA1A mutations in two patients with lissencephaly and pachygyria, respectively. Here we report additional TUBA1A mutations identified in six unrelated patients with a large spectrum of brain dysgeneses. The de novo occurrence was shown for all mutations, including one recurrent mutation (c.790C>T, p.R264C) detected in two patients, and two mutations that affect the same amino acid (c.1205G>A, p.R402H; c.1204C>T, p.R402C) detected in two other patients. Retrospective examination of MR images suggests that patients with TUBA1A mutations share not only cortical dysgenesis, but also cerebellar, hippocampal, corpus callosum, and brainstem abnormalities. Interestingly, the specific high level of Tuba1a expression throughout the period of central nervous system (CNS) development, shown by in situ hybridization using mouse embryos, is in accordance with the brain-restricted developmental phenotype caused by TUBA1A mutations. All together, these results, in combination with previously reported data, strengthen the relevance of the known interaction between MTs and DCX, and highlight the importance of the MTs/DCX complex in the neuronal migration process. Hum Mutat 0, 1-10, 2007. (c) 2007 Wiley-Liss, Inc.
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical Genetics Section (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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