TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins

Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy.
Human Molecular Genetics (Impact Factor: 6.39). 05/2010; 19(14):2817-27. DOI: 10.1093/hmg/ddq182
Source: PubMed


We previously showed that mutations in LIS1 and DCX account for approximately 85% of patients with the classic form of lissencephaly (LIS). Some rare forms of LIS are associated with a disproportionately small cerebellum, referred to as lissencephaly with cerebellar hypoplasia (LCH). Tubulin alpha1A (TUBA1A), encoding a critical structural subunit of microtubules, has recently been implicated in LIS. Here, we screen the largest cohort of unexplained LIS patients examined to date to determine: (i) the frequency of TUBA1A mutations in patients with lissencephaly, (ii) the spectrum of phenotypes associated with TUBA1A mutations and (iii) the functional consequences of different TUBA1A mutations on microtubule function. We identified novel and recurrent TUBA1A mutations in approximately 1% of children with classic LIS and in approximately 30% of children with LCH, making this the first major gene associated with the rare LCH phenotype. We also unexpectedly found a TUBA1A mutation in one child with agenesis of the corpus callosum and cerebellar hypoplasia without LIS. Thus, our data demonstrate a wider spectrum of phenotypes than previously reported and allow us to propose new recommendations for clinical testing. We also provide cellular and structural data suggesting that LIS-associated mutations of TUBA1A operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins (MAPs).

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    • "However, since TUBA4A W407X shows aggregation propensities analogous to other ALS-associated mutant proteins , its deleterious effect may be through a different mechanism , such as trapping tubulin-binding proteins into aggregates or by overburdening the ubiquitin proteasome system. Mutations in at least seven other tubulin family members (TUBA1A [Keays et al., 2007; Kumar et al., 2010; Poirier et al., 2007], TUBA8 [Abdollahi et al., 2009], TUBB2B [Jaglin et al., 2009], TUBB3 [Poirier et al., 2010; Tischfield et al., 2010], TUBB5 [Breuss et al., 2012], TUBB4A [Hersheson et al., 2013; Tian et al., 2008], and TUBG1 [Poirier et al., 2013]) have been described to cause several neurodevelopmental and neurodegenerative disorders . Moreover, the progressive motor neuronopathy (pmn) mutant mouse, a commonly used model for human motor neuron disease, bears a mutation in the Tubulin-specific Chaperone E (TBCE) gene (Bö mmel et al., 2002; Martin et al., 2002). "
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    ABSTRACT: Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
    Neuron 10/2014; 84(2):324-31. DOI:10.1016/j.neuron.2014.09.027 · 15.05 Impact Factor
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    • "Although there are at least 34 known TUBA1A mutations, and many of these mutations are located in the C-terminal half of the amino acid sequence [3,11,14-27], this report is the first to describe the E27Q mutation (Additional file 1: Figure S1). In contrast to most of the previously reported mutations, this mutation is located in the N-terminal region (Additional file 1: Figure S1). "
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    ABSTRACT: Background Owing to the number of genetic mutations that contribute to malformations of cortical development, identification of causative mutations in candidate genes is challenging. To overcome these challenges, we performed whole-exome sequencing in this study. Case presentation A Japanese patient presented with microcephaly and severe developmental delay. Brain magnetic resonance imaging showed the presence of colpocephaly associated with lateral ventricle dilatation and the presence of a simplified gyral pattern. Hypoplasia of the corpus callosum and cerebellar vermis were also noted. Because Sanger sequencing is expensive, laborious, and time-consuming, whole-exome sequencing was performed and a de novo missense mutation in TUBA1A (E27Q) was identified. Conclusion The novel mutation identified in this study was located in the genetic region that encodes the N-terminal domain of TUBA1A, a region of TUBA1A with few reported mutations. Retrospective assessment of the clinical and radiological features of this patient―i.e., microcephaly, lissencephaly (pachygyria) with cerebellar hypoplasia, and corpus callosum hypoplasia―indicated that the TUBA1A mutation did not lead to any contradictions. Because rapid and comprehensive mutation analysis by whole-exome sequencing is time- and cost-effective, it might be useful for genetic counseling of patients with sporadic malformations of cortical development.
    BMC Research Notes 07/2014; 7(1):465. DOI:10.1186/1756-0500-7-465
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    • "The N-terminal structural domain forms the GTP binding pocket required for protein folding and stability and for the correct conformation of longitudinal protofilaments . N-terminal domain interactions with the adjacent intermediate domain contribute to structural rearrangements resulting from the hydrolysis of GTP bound by b-tubulin and leading to microtubule depolymerization [6] [10] [12]. Other residues within this domain mediate longitudinal and lateral interactions, flanking the side and inner surface of heterodimers that are necessary for both heterodimer and microtubule stability . "
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    ABSTRACT: The tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this family encode dimeric proteins consisting of two closely related subunits (α and β), representing the major constituents of microtubules. Tubulin genes play a crucial role in the mechanisms of the Central Nervous System development such as neuronal migration and axonal guidance (axon outgrowth and maintenance). Different mutations in α/β-tubulin genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, and TUBB) might alter the dynamic properties and functions of microtubules in several ways, effecting a reduction in the number of functional tubulin heterodimers and causing alterations in GTP binding and disruptions of the binding of other proteins to microtubules (motor proteins and other microtubule interacting proteins).
    Brain and Development 07/2014; 37(3). DOI:10.1016/j.braindev.2014.06.002 · 1.88 Impact Factor
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