TY - JOUR
T1 - Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules
AU - Scottish Genomes Partnership
AU - Genomics England Research Consortium
AU - Undiagnosed Diseases Network
AU - Dodd, Daniel o.
AU - Mechaussier, Sabrina
AU - Yeyati, Patricia l.
AU - Mcphie, Fraser
AU - Anderson, Jacob r.
AU - Khoo, Chen jing
AU - Shoemark, Amelia
AU - Gupta, Deepesh k.
AU - Attard, Thomas
AU - Zariwala, Maimoona a.
AU - Legendre, Marie
AU - Bracht, Diana
AU - Wallmeier, Julia
AU - Gui, Miao
AU - Fassad, Mahmoud r.
AU - Parry, David a.
AU - Tennant, Peter a.
AU - Meynert, Alison
AU - Wheway, Gabrielle
AU - Fares-Taie, Lucas
AU - Black, Holly a.
AU - Mitri-Frangieh, Rana
AU - Faucon, Catherine
AU - Kaplan, Josseline
AU - Patel, Mitali
AU - Mckie, Lisa
AU - Megaw, Roly
AU - Gatsogiannis, Christos
AU - Mohamed, Mai a.
AU - Aitken, Stuart
AU - Gautier, Philippe
AU - Reinholt, Finn r.
AU - Hirst, Robert a.
AU - O’callaghan, Chris
AU - Heimdal, Ketil
AU - Bottier, Mathieu
AU - Escudier, Estelle
AU - Crowley, Suzanne
AU - Descartes, Maria
AU - Jabs, Ethylin w.
AU - Kenia, Priti
AU - Amiel, Jeanne
AU - Bacci, Giacomo maria
AU - Calogero, Claudia
AU - Palazzo, Viviana
AU - Tiberi, Lucia
AU - Blümlein, Ulrike
AU - Rogers, Andrew
AU - Wambach, Jennifer a.
AU - Wegner, Daniel j.
AU - Fulton, Anne b.
AU - Kenna, Margaret
AU - Rosenfeld, Margaret
AU - Holm, Ingrid a.
AU - Quigley, Alan
AU - Hall, Emma a.
AU - Murphy, Laura c.
AU - Cassidy, Diane m.
AU - Von kriegsheim, Alex
AU - Papon, Jean-François
AU - Pasquier, Laurent
AU - Murris, Marlène s.
AU - Chalmers, James d
AU - Hogg, Claire
AU - Macleod, Kenneth a.
AU - Urquhart, Don s.
AU - Unger, Stefan
AU - Aitman, Timothy j.
AU - Amselem, Serge
AU - Leigh, Margaret w.
AU - Knowles, Michael r.
AU - Omran, Heymut
AU - Mitchison, Hannah m.
AU - Brown, Alan
AU - Marsh, Joseph a.
AU - Welburn, Julie p. i.
AU - Ti, Shih-Chieh
AU - Horani, Amjad
AU - Rozet, Jean-Michel
AU - Perrault, Isabelle
AU - Mill, Pleasantine
PY - 2024/4/26
Y1 - 2024/4/26
N2 - 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.
AB - 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.
U2 - 10.1126/science.adf5489
DO - 10.1126/science.adf5489
M3 - Article
SN - 0036-8075
VL - 384
JO - Science
JF - Science
IS - 6694
ER -