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

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 c...

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Autores principales: Gardner, Jennifer F., Cushion, Thomas D., Niotakis, Georgios, Olson, Heather E., Grant, P. Ellen, Scott, Richard H., Stoodley, Neil, Cohen, Julie S., Naidu, Sakkubai, Attie-Bitach, Tania, Bonnières, Maryse, Boutaud, Lucile, Encha-Razavi, Férechté, Palmer-Smith, Sheila M., Mugalaasi, Hood, Mullins, Jonathan G. L., Pilz, Daniela T., Fry, Andrew E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119949/
https://www.ncbi.nlm.nih.gov/pubmed/30087272
http://dx.doi.org/10.3390/brainsci8080145
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author Gardner, Jennifer F.
Cushion, Thomas D.
Niotakis, Georgios
Olson, Heather E.
Grant, P. Ellen
Scott, Richard H.
Stoodley, Neil
Cohen, Julie S.
Naidu, Sakkubai
Attie-Bitach, Tania
Bonnières, Maryse
Boutaud, Lucile
Encha-Razavi, Férechté
Palmer-Smith, Sheila M.
Mugalaasi, Hood
Mullins, Jonathan G. L.
Pilz, Daniela T.
Fry, Andrew E.
author_facet Gardner, Jennifer F.
Cushion, Thomas D.
Niotakis, Georgios
Olson, Heather E.
Grant, P. Ellen
Scott, Richard H.
Stoodley, Neil
Cohen, Julie S.
Naidu, Sakkubai
Attie-Bitach, Tania
Bonnières, Maryse
Boutaud, Lucile
Encha-Razavi, Férechté
Palmer-Smith, Sheila M.
Mugalaasi, Hood
Mullins, Jonathan G. L.
Pilz, Daniela T.
Fry, Andrew E.
author_sort Gardner, Jennifer F.
collection PubMed
description 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.
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spelling pubmed-61199492018-09-06 Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation Gardner, Jennifer F. Cushion, Thomas D. Niotakis, Georgios Olson, Heather E. Grant, P. Ellen Scott, Richard H. Stoodley, Neil Cohen, Julie S. Naidu, Sakkubai Attie-Bitach, Tania Bonnières, Maryse Boutaud, Lucile Encha-Razavi, Férechté Palmer-Smith, Sheila M. Mugalaasi, Hood Mullins, Jonathan G. L. Pilz, Daniela T. Fry, Andrew E. Brain Sci Article 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. MDPI 2018-08-07 /pmc/articles/PMC6119949/ /pubmed/30087272 http://dx.doi.org/10.3390/brainsci8080145 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gardner, Jennifer F.
Cushion, Thomas D.
Niotakis, Georgios
Olson, Heather E.
Grant, P. Ellen
Scott, Richard H.
Stoodley, Neil
Cohen, Julie S.
Naidu, Sakkubai
Attie-Bitach, Tania
Bonnières, Maryse
Boutaud, Lucile
Encha-Razavi, Férechté
Palmer-Smith, Sheila M.
Mugalaasi, Hood
Mullins, Jonathan G. L.
Pilz, Daniela T.
Fry, Andrew E.
Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title_full Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title_fullStr Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title_full_unstemmed Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title_short Clinical and Functional Characterization of the Recurrent TUBA1A p.(Arg2His) Mutation
title_sort clinical and functional characterization of the recurrent tuba1a p.(arg2his) mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119949/
https://www.ncbi.nlm.nih.gov/pubmed/30087272
http://dx.doi.org/10.3390/brainsci8080145
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