Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation.

P Grant,Tania Attie-Bitach,Heather Olson,Thomas Cushion,Férechté Encha-Razavi,Hood Mugalaasi,Maryse Bonnières,Neil Stoodley,Sakkubai Naidu,Jonathan Mullins,Julie Cohen,Andrew Fry,Jennifer Gardner,Daniela Pilz,Georgios Niotakis,Sheila Palmer-Smith,Lucile Boutaud,Richard Scott

doi:10.3390/brainsci8080145

Abstract

The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.

Highlights

TUBA1A is a highly-conserved gene with few changes among eukaryotes and few polymorphic variants in human populations
We identified two unrelated patients (Patients 1 and 2) with the same TUBA1A missense mutation, c.5G>A, p.(Arg2His)
The p.(Arg2His) mutation was the second highest in the group (Table S2). These results suggest p.(Arg2His) has a mutation rate that is similar to other recurrent TUBA1A mutations

Summary

Introduction

TUBA1A is a highly-conserved gene with few changes among eukaryotes and few polymorphic variants in human populations. TUBA1A encodes the tubulin alpha-1A chain, a protein that is highly-expressed in the cerebral cortex, hippocampus, cerebellum, and brainstem of the developing fetal brain, with a decrease in postnatal and adult stages [1,2]. Alpha- and beta-tubulin subunits form dimers that coassemble into microtubules. As major components of the mitotic spindle, microtubules control division of neuronal progenitors to produce neurons. They generate the push-and-pull forces that are required for the migration of primitive neurons, from deep proliferative areas to the cortical plate. Bundles of stable and polarised microtubule polymers generate long axons facilitating cortical organisation and synaptic connectivity

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Conclusion