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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.
Afiliação
  • Gardner JF; Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK. jennifer.gardner@wales.nhs.uk.
  • Cushion TD; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. cushiont@cardiff.ac.uk.
  • Niotakis G; Paediatrics Department, Venizelion Hospital, Knossos Ave, P.O. Box 44, Heraklion, 714 09 Crete, Greece. niotakisg@yahoo.gr.
  • Olson HE; Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA 02115, USA. heather.olson@childrens.harvard.edu.
  • Grant PE; Fetal-Neonatal Neuroimaging and Developmental Science Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. ellen.grant@childrens.harvard.edu.
  • Scott RH; Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, UK. richard.scott@genomicsengland.co.uk.
  • Stoodley N; Department of Neuroradiology, North Bristol NHS Trust, Frenchay Hospital, Bristol BS16 1LE, UK. neilstoodley@doctors.org.uk.
  • Cohen JS; Division of Neurogenetics, Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA. cohenju@kennedykrieger.org.
  • Naidu S; Division of Neurogenetics, Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA. naidu@kennedykrieger.org.
  • Attie-Bitach T; Department of Neurology, The Johns Hopkins Hospital, Baltimore, Maryland, MD 21287, USA. naidu@kennedykrieger.org.
  • Bonnières M; Department of Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, MD 21287, USA. naidu@kennedykrieger.org.
  • Boutaud L; Unité d'Embryofœtopathologie, Service d'Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75004 Paris, France. tania.attie@inserm.fr.
  • Encha-Razavi F; Institut Imagine, INSERM U1163, Université Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France. tania.attie@inserm.fr.
  • Palmer-Smith SM; Unité d'Embryofœtopathologie, Service d'Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75004 Paris, France. maryse.bonniere-darcy@aphp.fr.
  • Mugalaasi H; Unité d'Embryofœtopathologie, Service d'Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75004 Paris, France. lucile.boutaud@gmail.com.
  • Mullins JGL; Institut Imagine, INSERM U1163, Université Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France. lucile.boutaud@gmail.com.
  • Pilz DT; Unité d'Embryofœtopathologie, Service d'Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), 75004 Paris, France. ferechte.razavi@aphp.fr.
  • Fry AE; Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK. sheila.palmer-smith@wales.nhs.uk.
Brain Sci ; 8(8)2018 Aug 07.
Article em En | MEDLINE | ID: mdl-30087272
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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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2018 Tipo de documento: Article