title: Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).
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.
authors.affiliation: Institut Cochin, Université Paris Descartes, Centre national de la recherche scientifique Unité Mixte de Recherche 8104, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: David A
authors.initials: DA
authors.lastname: Keays
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
authors.forename: Yoann
authors.initials: Y
authors.lastname: Saillour
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier
authors.forename: Catherine
authors.initials: C
authors.lastname: Fallet-Bianco
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Françoise Phan Dinh
authors.initials: FP
authors.lastname: Tuy
authors.forename: Thierry
authors.initials: T
authors.lastname: Bienvenu
authors.forename: Sylvie
authors.initials: S
authors.lastname: Joriot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Dorothée
authors.initials: D
authors.lastname: Ville
authors.forename: Isabelle
authors.initials: I
authors.lastname: Desguerre
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Hilde
authors.initials: H
authors.lastname: van Esch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.forename: Jonathan
authors.initials: J
authors.lastname: Flint
authors.forename: Chérif
authors.initials: C
authors.lastname: Beldjord
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
mesh_terms: D001921:Brain / Q000002:abnormalities* / Q000196:embryology; D001927:Brain Diseases / Q000235:genetics*; D004247:DNA / Q000235:genetics; D000089662:Doublecortin Protein; D006801:Humans; D017403:In Situ Hybridization; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D014404:Tubulin / Q000235:genetics*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D012333:RNA, Messenger; D014404:Tubulin; D004247:DNA