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

Genomics England Research Consortium; 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; Ethylin W. 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; Undiagnosed Diseases Network; Jean François 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

doi:10.1126/science.adf5489

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

Genomics England Research Consortium, 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 WhewayLucas 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, Ethylin W. 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, Undiagnosed Diseases Network, Jean François 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

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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.

Original language	English
Article number	eadf5489
Journal	Science
Volume	384
Issue number	6694
DOIs	https://doi.org/10.1126/science.adf5489
State	Published - Apr 26 2024

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10.1126/science.adf5489

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Genomics England Research Consortium, Dodd, D. O., Mechaussier, S., Yeyati, P. L., McPhie, F., Anderson, J. R., Khoo, C. J., Shoemark, A., Gupta, D. K., Attard, T., Zariwala, M. A., Legendre, M., Bracht, D., Wallmeier, J., Gui, M., Fassad, M. R., Parry, D. A., Tennant, P. A., Meynert, A., ... Mill, P. (2024). Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules. Science, 384(6694), Article eadf5489. https://doi.org/10.1126/science.adf5489

@article{b03d2f8221734822b5b871212a2c1bd4,

title = "Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules",

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.",

author = "{Genomics England Research Consortium} and Dodd, {Daniel O.} and Sabrina Mechaussier and Yeyati, {Patricia L.} and Fraser McPhie and Anderson, {Jacob R.} and Khoo, {Chen Jing} and Amelia Shoemark and Gupta, {Deepesh K.} and Thomas Attard and Zariwala, {Maimoona A.} and Marie Legendre and Diana Bracht and Julia Wallmeier and Miao Gui and Fassad, {Mahmoud R.} and Parry, {David A.} and Tennant, {Peter A.} and Alison Meynert and Gabrielle Wheway and Lucas Fares-Taie and Black, {Holly A.} and Rana Mitri-Frangieh and Catherine Faucon and Josseline Kaplan and Mitali Patel and Lisa McKie and Roly Megaw and Christos Gatsogiannis and Mohamed, {Mai A.} and Stuart Aitken and Philippe Gautier and Reinholt, {Finn R.} and Hirst, {Robert A.} and Chris O{\textquoteright}Callaghan and Ketil Heimdal and Mathieu Bottier and Estelle Escudier and Suzanne Crowley and Maria Descartes and Jabs, {Ethylin W.} and Priti Kenia and Jeanne Amiel and Bacci, {Giacomo Maria} and Claudia Calogero and Viviana Palazzo and Lucia Tiberi and Ulrike Bl{\"u}mlein and Andrew Rogers and Wambach, {Jennifer A.} and Wegner, {Daniel J.} and Fulton, {Anne B.} and Margaret Kenna and Margaret Rosenfeld and Holm, {Ingrid A.} and Alan Quigley and Hall, {Emma A.} and Murphy, {Laura C.} and Cassidy, {Diane M.} and {von Kriegsheim}, Alex and Partnership, {Scottish Genomes} and Network, {Undiagnosed Diseases} and Papon, {Jean Fran{\c c}ois} and Laurent Pasquier and Murris, {Marl{\`e}ne S.} and Chalmers, {James D.} and Claire Hogg and Macleod, {Kenneth A.} and Urquhart, {Don S.} and Stefan Unger and Aitman, {Timothy J.} and Serge Amselem and Leigh, {Margaret W.} and Knowles, {Michael R.} and Heymut Omran and Mitchison, {Hannah M.} and Alan Brown and Marsh, {Joseph A.} and Welburn, {Julie P.I.} and Ti, {Shih Chieh} and Amjad Horani and Rozet, {Jean Michel} and Isabelle Perrault and Pleasantine Mill",

year = "2024",

month = apr,

day = "26",

doi = "10.1126/science.adf5489",

language = "English",

volume = "384",

journal = "Science",

issn = "0036-8075",

number = "6694",

}

Genomics England Research Consortium, Dodd, DO, Mechaussier, S, Yeyati, PL, McPhie, F, Anderson, JR, Khoo, CJ, Shoemark, A, Gupta, DK, Attard, T, Zariwala, MA, Legendre, M, Bracht, D, Wallmeier, J, Gui, M, Fassad, MR, Parry, DA, Tennant, PA, Meynert, A, Wheway, G, Fares-Taie, L, Black, HA, Mitri-Frangieh, R, Faucon, C, Kaplan, J, Patel, M, McKie, L, Megaw, R, Gatsogiannis, C, Mohamed, MA, Aitken, S, Gautier, P, Reinholt, FR, Hirst, RA, O’Callaghan, C, Heimdal, K, Bottier, M, Escudier, E, Crowley, S, Descartes, M, Jabs, EW, Kenia, P, Amiel, J, Bacci, GM, Calogero, C, Palazzo, V, Tiberi, L, Blümlein, U, Rogers, A, Wambach, JA, Wegner, DJ, Fulton, AB, Kenna, M, Rosenfeld, M, Holm, IA, Quigley, A, Hall, EA, Murphy, LC, Cassidy, DM, von Kriegsheim, A, Partnership, SG, Network, UD, Papon, JF, Pasquier, L, Murris, MS, Chalmers, JD, Hogg, C, Macleod, KA, Urquhart, DS, Unger, S, Aitman, TJ, Amselem, S, Leigh, MW, Knowles, MR, Omran, H, Mitchison, HM, Brown, A, Marsh, JA, Welburn, JPI, Ti, SC, Horani, A, Rozet, JM, Perrault, I & Mill, P 2024, 'Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules', Science, vol. 384, no. 6694, eadf5489. https://doi.org/10.1126/science.adf5489

TY - JOUR

T1 - Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules

AU - Genomics England Research Consortium

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 - Partnership, Scottish Genomes

AU - Network, Undiagnosed Diseases

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.

UR - http://www.scopus.com/inward/record.url?scp=85191476815&partnerID=8YFLogxK

U2 - 10.1126/science.adf5489

DO - 10.1126/science.adf5489

M3 - Article

C2 - 38662826

AN - SCOPUS:85191476815

SN - 0036-8075

VL - 384

JO - Science

JF - Science

IS - 6694

M1 - eadf5489

ER -

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

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