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.

Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia

“…This group of patients often has severe DCX mutations in boys or microdeletions of the 17p13.3 region, but our experience suggests that additional causative genes are most likely to be found, such as the new TUBA1A gene. 20 Intragenic deletions of the DCX gene were found in 33% of female patients with SBH in whom no mutations of DCX had previously been identified. The SBH phenotype in the patients with DCX deletions was similar to those with DCX mutations detected by sequencing.…”

“…A combination of DNA sequencing and deletion/duplication analysis of the LIS1 and/or DCX genes will therefore detect abnormalities in approximately 85% of patients with ILS, considering 17p13.3 microdeletions, LIS1 and DCX mutations detected by sequencing (which includes DCX deletions in males) and LIS1 intragenic deletions/duplications. Mutations in the TUBA1A gene have also been implicated in a small percentage of patients with LIS or SBH, 20,23 and result in a malformation pattern very similar to that caused by defects in the LIS1 gene, although additional features have been recognized that may distinguish a subset of these patients. Mutations in the other three known LIS genes -ARX, RELN and VLDLR -have been associated with additional abnormalities that exclude them from the ILS category, and none of these genes are associated with SBH.…”

Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria

“…1,21 In this study, we provide additional evidences showing that de novo missense mutations in the TUBA1A gene are causative for perisylvian PMG, further expanding the spectrum of TUBA1A-related cortical dysgenesis. Two of these three mutations involved in PMG are novel, and the remaining one was previously (e-h) brain MRI of patient 2 at the age of 11 years; (i-l) brain MRI of patient 3 at the age of 12 months.…”

“…Mutation analysis of the coding exons of TUBA1A were performed by direct sequencing of genomic DNA as described previously. 2,21 …”

“…18 The TUBA1A protein is formed by a core of two b-sheets surrounded by a-helices and can be divided into three functional domains: an N-terminal domain (residues 1-205) that contains the guanine nucleotide-binding region, an intermediate domain (residues 206-381) involved in interprotofilament lateral contacts and the regulation of tubulin curvature, and a C-terminal domain (residues 382-451) that constitutes the binding surface for defined microtubule-associated proteins (MAPs) and molecular motors, such as kinesins and dynein. [19][20][21] Here, we report a TUBA1A gene analysis in a large cohort of PMG patients to investigate how common TUBA1A mutations are in patients with PMG and to identify the key phenotypical features that could guide the diagnosis. We identified three TUBA1A mutations, of these two are novel, representing 3.1% of children with PMG and 10% of children with PMG with complex cerebral malformations.…”