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

Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
Paediatrics Department, Venizelion Hospital, Knossos Ave, P.O. Box 44, Heraklion, 714 09 Crete, Greece
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, MA 02115, USA
Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK
Department of Neuroradiology, North Bristol NHS Trust, Frenchay Hospital, Bristol BS16 1LE, UK
Division of Neurogenetics, Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA
Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland, MD 21287, USA
Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, MD 21287, USA
Unité d’Embryofœtopathologie, Service d’Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75004 Paris, France
Institut Imagine, INSERM U1163, Université Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France
Institute of Life Science, Swansea University Medical School, Swansea SA2 8PP, UK
Department of Clinical Genetics, West of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Brain Sci. 2018, 8(8), 145;
Received: 30 May 2018 / Revised: 6 July 2018 / Accepted: 17 July 2018 / Published: 7 August 2018
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. View Full-Text
Keywords: TUBA1A; tubulin; p.(Arg2His), R2H; tubulinopathy; polymicrogyria; cerebellar hypoplasia TUBA1A; tubulin; p.(Arg2His), R2H; tubulinopathy; polymicrogyria; cerebellar hypoplasia
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Gardner, J.F.; Cushion, T.D.; Niotakis, G.; Olson, H.E.; Grant, P.E.; Scott, R.H.; Stoodley, N.; Cohen, J.S.; Naidu, S.; Attie-Bitach, T.; Bonnières, M.; Boutaud, L.; Encha-Razavi, F.; Palmer-Smith, S.M.; Mugalaasi, H.; Mullins, J.G.L.; Pilz, D.T.; Fry, A.E. Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation. Brain Sci. 2018, 8, 145.

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