纤毛病患者的变异揭示了TUBB4B在轴丝微管中的细胞器特异性功能。
Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
作者信息
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, Fulton Anne B, Kenna Margaret, Rosenfeld Margaret, Holm Ingrid A, Quigley Alan, Hall Emma A, Murphy Laura C, Cassidy Diane M, von Kriegsheim Alex, Papon Jean-François, Pasquier Laurent, Murris Marlène S, Chalmers James D, Hogg Claire, Macleod Kenneth A, Urquhart Don S, Unger Stefan, Aitman Timothy J, Amselem Serge, Leigh Margaret W, Knowles Michael R, Omran Heymut, Mitchison Hannah M, Brown Alan, Marsh Joseph A, Welburn Julie P I, Ti Shih-Chieh, Horani Amjad, Rozet Jean-Michel, Perrault Isabelle, Mill Pleasantine
机构信息
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.
出版信息
Science. 2024 Apr 26;384(6694):eadf5489. doi: 10.1126/science.adf5489.
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 isotype that specifically perturbed centriole and cilium biogenesis. Distinct 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.
微管蛋白是细胞骨架中最丰富的组成成分之一，在后生动物中有多种由不同保守基因编码的同种型。这些不同的同种型是否形成细胞类型和环境特异性的微管结构，目前了解甚少。基于一组12名原发性纤毛运动障碍患者以及小鼠突变体，我们鉴定并表征了同种型中的变异体，这些变异体特异性地干扰了中心粒和纤毛的生物发生。不同的变异体以显性负性方式差异性地影响微管动力学和纤毛形成。结构-功能研究表明，不同的TUBB4B变异体破坏了不同的微管蛋白界面，从而能够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。
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