RGD Reference Report - Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). - Rat Genome Database
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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 
Citation: Poirier K, etal., Hum Mutat. 2007 Nov;28(11):1055-64.
RGD ID: 12859083
Pubmed: (View Article at PubMed) PMID:17584854
DOI: Full-text: DOI:10.1002/humu.20572

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.


Disease Annotations    
lissencephaly  (IAGP,ISO)

Phenotype Annotations    

Human Phenotype
Pachygyria  (IAGP)
Objects Annotated

Genes (Rattus norvegicus)
Tuba1a  (tubulin, alpha 1A)

Genes (Mus musculus)
Tuba1a  (tubulin, alpha 1A)

Genes (Homo sapiens)
TUBA1A  (tubulin alpha 1a)

Additional Information