Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules,Science

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Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
Science ( IF 56.9 ) Pub Date : 2024-04-26 , DOI: 10.1126/science.adf5489
Daniel O. Dodd ₁ , Sabrina Mechaussier ₂ , Patricia L. Yeyati ₁ , Fraser McPhie ₁ , Jacob R. Anderson ₃ , Chen Jing Khoo ₄ , Amelia Shoemark _{5,

6} , Deepesh K. Gupta ₇ , Thomas Attard ₈ , Maimoona A. Zariwala ₉ , Marie Legendre _{10,

11} , Diana Bracht ₁₂ , Julia Wallmeier ₁₂ , Miao Gui ₃ , Mahmoud R. Fassad _{13,

14} , David A. Parry ₁ , Peter A. Tennant ₁ , Alison Meynert ₁ , Gabrielle Wheway ₁₅ , Lucas Fares-Taie ₂ , Holly A. Black _{16,

17} , Rana Mitri-Frangieh _{18,

19} , Catherine Faucon ₁₈ , Josseline Kaplan ₂ , Mitali Patel _{13,

20} , Lisa McKie ₁ , Roly Megaw _{1,

21} , Christos Gatsogiannis ₂₂ , Mai A. Mohamed _{13,

23} , Stuart Aitken ₁ , Philippe Gautier ₁ , Finn R. Reinholt ₂₄ , Robert A. Hirst ₂₅ , Chris O’Callaghan ₂₅ , Ketil Heimdal ₂₆ , Mathieu Bottier ₅ , Estelle Escudier _{11,

18} , Suzanne Crowley ₂₇ , Maria Descartes ₂₈ , Ethylin W. Jabs _{29,

30} , Priti Kenia ₃₁ , Jeanne Amiel _{32,

33} , Giacomo Maria Bacci ₃₄ , Claudia Calogero ₃₅ , Viviana Palazzo ₃₆ , Lucia Tiberi ₃₆ , Ulrike Blümlein ₃₇ , Andrew Rogers ₆ , Jennifer A. Wambach ₇ , Daniel J. Wegner ₇ , Anne B. Fulton ₃₈ , Margaret Kenna ₃₉ , Margaret Rosenfeld ₄₀ , Ingrid A. Holm _{41,

42} , Alan Quigley ₄₃ , Emma A. Hall ₁ , Laura C. Murphy ₁ , Diane M. Cassidy ₅ , Alex von Kriegsheim ₄₄ , Jean-François Papon ₄₅ , Laurent Pasquier ₄₆ , Marlène S. Murris ₄₇ , James D Chalmers ₅ , Claire Hogg ₆ , Kenneth A. Macleod ₄₈ , Don S. Urquhart _{48,

49} , Stefan Unger _{48,

49} , Timothy J. Aitman ₁₆ , Serge Amselem _{10,

11} , Margaret W. Leigh ₅₀ , Michael R. Knowles ₅₁ , Heymut Omran ₁₂ , Hannah M. Mitchison ₁₃ , Alan Brown ₃ , Joseph A. Marsh ₁ , Julie P. I. Welburn ₈ , Shih-Chieh Ti ₄ , Amjad Horani _{7,

52} , Jean-Michel Rozet ₂ , Isabelle Perrault ₂ , Pleasantine Mill ₁ , , ,

Affiliation

MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
Laboratory of Genetics in Ophthalmology, INSERM UMR_1163, Institute of Genetic Diseases, Institut Imagine, Université de Paris, Paris 75015, France.
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
Respiratory Research Group, Molecular and Cellular Medicine, University of Dundee, Dundee DD1 9SY, UK.
Respiratory Paediatrics, Royal Brompton Hospital, London SW3 6NP, UK.
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63130, USA.
Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
Department of Pathology and Laboratory Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA.
Molecular Genetics Laboratory, Sorbonne Université, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Armand Trousseau, Paris 75012, France.
Sorbonne Université, INSERM, Childhood Genetic Disorders, Paris 75012, France.
Department of General Pediatrics, University Children’s Hospital Münster, Münster 48149, Germany.
Genetics and Genomic Medicine Department, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt.
Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
South East of Scotland Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK.
Department of Anatomy, Cytology and Pathology, Hôpital Intercommuncal de Créteil, Créteil 94000, France.
Biomechanics and Respiratory Apparatus, IMRB, U955 INSERM – Université Paris Est Créteil, CNRS ERL 7000, Créteil 94000, France.
MRC Prion Unit, Institute of Prion Diseases, University College London, London W1W 7FF, UK.
Princess Alexandra Eye Pavilion, Edinburgh EH3 9HA, UK.
Center for Soft Nanoscience and Institute of Medical Physics and Biophysics, Münster 48149, Germany.
Biochemistry Division, Chemistry Department, Faculty of Science, Zagazig University, Ash Sharqiyah 44519, Egypt.
Core Facility for Electron Microscopy, Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo 0372, Norway.
Centre for PCD Diagnosis and Research, Department of Respiratory Sciences, University of Leicester, Leicester LE1 9HN, UK.
Department of Medical Genetics, Oslo University Hospital, Oslo 0407, Norway.
Paediatric Department of Allergy and Lung Diseases, Oslo University Hospital, Oslo 0407, Norway.
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294-0024, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029-6504, New York, USA.
Department of Clinical Genomics, Mayo Clinic, Rochester, NY 55905, USA.
Department of Paediatric Respiratory Medicine, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham B15 2TG, UK.
Département de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris 75015, France.
Laboratory of Embryology and Genetics of Human Malformations, INSERM UMR 1163, Institut Imagine, Université de Paris, Paris 75015, France.
Pediatric Ophthalmology Unit, Meyer Children’s Hospital IRCCS, Florence 50139, Italy.
Pediatric Pulmonary Unit, Meyer Children’s Hospital IRCCS, Florence 50139, Italy.
Medical Genetics Unit, Meyer Children’s Hospital IRCCS, Florence 50139, Italy.
Carl-Thiem-Klinikum Cottbus, Cottbus 03048, Germany.
Department of Ophthalmology, Boston Children’s Hospital, Boston, MA 02115, USA.
Department of Otolaryngology, Boston Children’s Hospital, Boston, MA 02115, USA.
Department of Pediatrics, University of Washington School of Medicine and Seattle Children’s Research Institute, Seattle, WA 98015, USA.
Division of Genetics and Genomics and the Manton Center for Orphan Diseases Research, Boston Children’s Hospital, Boston, MA 02115, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA 02115 USA.
Department of Paediatric Radiology, Royal Hospital for Children and Young People, Edinburgh EH16 4TJ, UK.
Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
ENT Department, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris-Saclay University, Le Kremlin-Bicêtre 94270, France.
Medical Genetics Department, CHU Pontchaillou, Rennes 35033, France.
Department of Pulmonology, Transplantation, and Cystic Fibrosis Centre, Larrey Hospital, Toulouse 31400, France.
Department of Paediatric Respiratory and Sleep Medicine, Royal Hospital for Children and Young People, Edinburgh EH16 4TJ, UK.
Department of Child Life and Health, University of Edinburgh, Edinburgh EH16 4TJ, UK.
Department of Pediatrics, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA.
Department of Medicine, Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248, USA.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

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.

中文翻译：

纤毛病患者变异揭示了轴丝微管中 TUBB4B 的细胞器特异性功能

微管蛋白是最丰富的细胞骨架构件之一，在后生动物中具有由不同保守基因编码的多种同种型。这些不同的同种型是否形成细胞类型和特定环境的微管结构尚不清楚。基于 12 名原发性纤毛运动障碍患者和小鼠突变体的队列，我们鉴定并表征了TUBB4B同种型中特异性干扰中心粒和纤毛生物发生的变异。不同的TUBB4B变异以显性负向方式对微管动力学和纤毛形成产生不同的影响。结构功能研究表明，不同的 TUBB4B 变体破坏了不同的微管蛋白界面，从而将患者分为三类纤毛病。这些发现表明，特定的微管蛋白同种型具有独特且非冗余的亚细胞功能，并在微管蛋白病和纤毛病之间建立了联系。

更新日期：2024-04-27

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