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Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
Dodd, Daniel O; Mechaussier, Sabrina; Yeyati, Patricia L; McPhie, Fraser; Anderson, Jacob R; Khoo, Chen Jing; Shoemark, Amelia; Gupta, Deepesh K; Attard, Thomas; Zariwala, Maimoona A; Legendre, Marie; Bracht, Diana; Wallmeier, Julia; Gui, Miao; Fassad, Mahmoud R; Parry, David A; Tennant, Peter A; Meynert, Alison; Wheway, Gabrielle; Fares-Taie, Lucas; Black, Holly A; Mitri-Frangieh, Rana; Faucon, Catherine; Kaplan, Josseline; Patel, Mitali; McKie, Lisa; Megaw, Roly; Gatsogiannis, Christos; Mohamed, Mai A; Aitken, Stuart; Gautier, Philippe; Reinholt, Finn R; Hirst, Robert A; O'Callaghan, Chris; Heimdal, Ketil; Bottier, Mathieu; Escudier, Estelle; Crowley, Suzanne; Descartes, Maria; Jabs, Ethylin W; Kenia, Priti; Amiel, Jeanne; Bacci, Giacomo Maria; Calogero, Claudia; Palazzo, Viviana; Tiberi, Lucia; Blümlein, Ulrike; Rogers, Andrew; Wambach, Jennifer A; Wegner, Daniel J.
Afiliação
  • Dodd DO; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Mechaussier S; Laboratory of Genetics in Ophthalmology, INSERM UMR_1163, Institute of Genetic Diseases, Institut Imagine, Université de Paris, Paris 75015, France.
  • Yeyati PL; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • McPhie F; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Anderson JR; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Khoo CJ; School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
  • Shoemark A; Respiratory Research Group, Molecular and Cellular Medicine, University of Dundee, Dundee DD1 9SY, UK.
  • Gupta DK; Respiratory Paediatrics, Royal Brompton Hospital, London SW3 6NP, UK.
  • Attard T; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130, USA.
  • Zariwala MA; Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
  • Legendre M; Department of Pathology and Laboratory Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA.
  • Bracht D; Molecular Genetics Laboratory, Sorbonne Université, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Paris 75012, France.
  • Wallmeier J; Sorbonne Université, INSERM, Childhood Genetic Disorders, Paris 75012, France.
  • Gui M; Department of General Pediatrics, University Children's Hospital Münster, Münster 48149, Germany.
  • Fassad MR; Department of General Pediatrics, University Children's Hospital Münster, Münster 48149, Germany.
  • Parry DA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • Tennant PA; Genetics and Genomic Medicine Department, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Meynert A; Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt.
  • Wheway G; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Fares-Taie L; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Black HA; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Mitri-Frangieh R; Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
  • Faucon C; Laboratory of Genetics in Ophthalmology, INSERM UMR_1163, Institute of Genetic Diseases, Institut Imagine, Université de Paris, Paris 75015, France.
  • Kaplan J; Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Patel M; South East of Scotland Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK.
  • McKie L; Department of Anatomy, Cytology and Pathology, Hôpital Intercommuncal de Créteil, Créteil 94000, France.
  • Megaw R; Biomechanics and Respiratory Apparatus, IMRB, U955 INSERM - Université Paris Est Créteil, CNRS ERL 7000, Créteil 94000, France.
  • Gatsogiannis C; Department of Anatomy, Cytology and Pathology, Hôpital Intercommuncal de Créteil, Créteil 94000, France.
  • Mohamed MA; Laboratory of Genetics in Ophthalmology, INSERM UMR_1163, Institute of Genetic Diseases, Institut Imagine, Université de Paris, Paris 75015, France.
  • Aitken S; Genetics and Genomic Medicine Department, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Gautier P; MRC Prion Unit, Institute of Prion Diseases, University College London, London W1W 7FF, UK.
  • Reinholt FR; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Hirst RA; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • O'Callaghan C; Princess Alexandra Eye Pavilion, Edinburgh EH3 9HA, UK.
  • Heimdal K; Center for Soft Nanoscience and Institute of Medical Physics and Biophysics, Münster 48149, Germany.
  • Bottier M; Genetics and Genomic Medicine Department, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
  • Escudier E; Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Ash Sharqiyah 44519, Egypt.
  • Crowley S; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Descartes M; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • Jabs EW; Core Facility for Electron Microscopy, Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo 0372, Norway.
  • Kenia P; Centre for PCD Diagnosis and Research, Department of Respiratory Sciences, University of Leicester, Leicester LE1 9HN, UK.
  • Amiel J; Centre for PCD Diagnosis and Research, Department of Respiratory Sciences, University of Leicester, Leicester LE1 9HN, UK.
  • Bacci GM; Department of Medical Genetics, Oslo University Hospital, Oslo 0407, Norway.
  • Calogero C; Respiratory Research Group, Molecular and Cellular Medicine, University of Dundee, Dundee DD1 9SY, UK.
  • Palazzo V; Sorbonne Université, INSERM, Childhood Genetic Disorders, Paris 75012, France.
  • Tiberi L; Department of Anatomy, Cytology and Pathology, Hôpital Intercommuncal de Créteil, Créteil 94000, France.
  • Blümlein U; Paediatric Department of Allergy and Lung Diseases, Oslo University Hospital, Oslo 0407, Norway.
  • Rogers A; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
  • Wambach JA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029-6504, New York, USA.
  • Wegner DJ; Department of Clinical Genomics, Mayo Clinic, Rochester, NY 55905, USA.
Science ; 384(6694): eadf5489, 2024 Apr 26.
Article em En | MEDLINE | ID: mdl-38662826
ABSTRACT
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the TUBB4B isotype that specifically perturbed centriole and cilium biogenesis. Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tubulina (Proteína) / Centríolos / Cílios / Transtornos da Motilidade Ciliar / Axonema Limite: Animals / Female / Humans / Male Idioma: En Revista: Science Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Tubulina (Proteína) / Centríolos / Cílios / Transtornos da Motilidade Ciliar / Axonema Limite: Animals / Female / Humans / Male Idioma: En Revista: Science Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Reino Unido