基于12例原发性睫状肌运动障碍患者和小鼠突变体，研究人员鉴定并描述了TUBB4B亚型变体的特征，这些变体特别扰乱了中心粒和纤毛的生物发生。不同的TUBB4B变体以显性抑制方式对微管动力学和纤毛形成产生不同影响。
结构-功能研究显示，不同的TUBB4B变体会破坏不同的微管蛋白界面，从而将患者分为三类纤毛病理。这些发现表明，特定的微管蛋白亚型具有不同的非冗余亚细胞功能，并在微管蛋白病和纤毛病理之间建立了联系。
据悉，微管蛋白是最丰富的细胞骨架结构单元之一，在后生动物中有许多异型，由不同的保守基因编码。这些不同的异型是否会形成细胞类型和环境特异性的微管结构，目前还不甚了解。
附：英文原文
Title: Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
Author: Daniel O. Dodd, Sabrina Mechaussier, Patricia L. Yeyati, Fraser McPhie, Jacob R. Anderson, Chen Jing Khoo, Amelia Shoemark, Deepesh K. Gupta, Thomas Attard, Maimoona A. Zariwala, Marie Legendre, Diana Bracht, Julia Wallmeier, Miao Gui, Mahmoud R. Fassad, David A. Parry, Peter A. Tennant, Alison Meynert, Gabrielle Wheway, Lucas Fares-Taie, Holly A. Black, Rana Mitri-Frangieh, Catherine Faucon, Josseline Kaplan, Mitali Patel, Lisa McKie, Roly Megaw, Christos Gatsogiannis, Mai A. Mohamed, Stuart Aitken, Philippe Gautier, Finn R. Reinholt, Robert A. Hirst, Chris O’Callaghan, Ketil Heimdal, Mathieu Bottier, Estelle Escudier, Suzanne Crowley, Maria Descartes, EthylinW. Jabs, Priti Kenia, Jeanne Amiel, Giacomo Maria Bacci, Claudia Calogero, Viviana Palazzo, Lucia Tiberi, Ulrike Blümlein, Andrew Rogers, Jennifer A. Wambach, Daniel J. Wegner, Anne B. Fulton, Margaret Kenna, Margaret Rosenfeld, Ingrid A. Holm, Alan Quigley, Emma A. Hall, Laura C. Murphy, Diane M. Cassidy, Alex von Kriegsheim, Scottish Genomes Partnership, Genomics England Research Consortium, Undiagnosed Diseases Network, Jean-Franois Papon, Laurent Pasquier, Marlène S. Murris, James D Chalmers, Claire Hogg, Kenneth A. Macleod, Don S. Urquhart, Stefan Unger, Timothy J. Aitman, Serge Amselem, Margaret W. Leigh, Michael R. Knowles, Heymut Omran, Hannah M. Mitchison, Alan Brown, Joseph A. Marsh, Julie P. I. Welburn, Shih-Chieh Ti, Amjad Horani, Jean-Michel Rozet, Isabelle Perrault, Pleasantine Mill
Issue&Volume: 2024-04-26
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.
DOI: adf5489
Source: https://www.science.org/doi/10.1126/science.adf5489