KBTBD13 is an actin-binding protein that modulates muscle kinetics

Josine M. de Winter; Joery P. Molenaar; Michaela Yuen; Robbert van der Pijl; Shengyi Shen; Stefan Conijn; Martijn van de Locht; Menne Willigenburg; Sylvia Jp Bogaards; Esmee Sb van Kleef; Saskia Lassche; Malin Persson; Dilson E. Rassier; Tamar E. Sztal; Avnika A. Ruparelia; Viola Oorschot; Georg Ramm; Thomas E. Hall; Zherui Xiong; Christopher N. Johnson; Frank Li; Balazs Kiss; Noelia Lozano-Vidal; Reinier A. Boon; Manuela Marabita; Leonardo Nogara; Bert Blaauw; Richard J. Rodenburg; Benno Küsters; Jonne Doorduin; Alan H. Beggs; Henk Granzier; Ken Campbell; Weikang Ma; Thomas Irving; Edoardo Malfatti; Norma B. Romero; Robert J. Bryson-Richardson; Baziel Gm van Engelen; Nicol C. Voermans; Coen Ac Ottenheijm

doi:10.1172/JCI124000

KBTBD13 is an actin-binding protein that modulates muscle kinetics

Josine M. de Winter
, Joery P. Molenaar
, Michaela Yuen
, Robbert van der Pijl
, Shengyi Shen
, Stefan Conijn
, Martijn van de Locht
, Menne Willigenburg
, Sylvia Jp Bogaards
, Esmee Sb van Kleef
, Saskia Lassche
, Malin Persson
, Dilson E. Rassier
, Tamar E. Sztal
, Avnika A. Ruparelia
, Viola Oorschot
, Georg Ramm
, Thomas E. Hall
, Zherui Xiong
, Christopher N. Johnson

Frank Li, Balazs Kiss, Noelia Lozano-Vidal, Reinier A. Boon, Manuela Marabita, Leonardo Nogara, Bert Blaauw, Richard J. Rodenburg, Benno Küsters, Jonne Doorduin, Alan H. Beggs, Henk Granzier, Ken Campbell, Weikang Ma, Thomas Irving, Edoardo Malfatti, Norma B. Romero, Robert J. Bryson-Richardson, Baziel Gm van Engelen, Nicol C. Voermans, Coen Ac Ottenheijm

Department of Neurology, Rijnstate Hospital, Arnhem, The Netherlands.
Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, Australia.
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
Department of Obstetrics and Gynecology, VU University Medical Center, Amsterdam, The Netherlands; Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care Medicine, Karolinska Institutet, 171 77, Stockholm, Sweden.
Department of Kinesiology and Physical Education, McGill University, Montreal, Canada.
School of Biological Sciences, Monash University, Melbourne, Australia.
Monash Ramaciotti Centre for Structural Cryo-Electron Microscopy, Monash University, Melbourne, Australia.
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia.
Division of Clinical Pharmacology, Center for Arrhythmia Research and Therapeutics and Center for Structural Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Venetian Institute of Molecular Medicine, Department of Biomedical Sciences, University of Padova, Italy.
Department of Pediatrics, Radboud University Medical Centre, Translational Metabolic Laboratory, Nijmegen, Netherlands.
Department of Pathology, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.
Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Physiology and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky, USA.
BioCAT, Illinois Institute of Technology, Chicago, Illinois, USA.
Service Neurologie Médicale, Centre de Référence Maladies Neuromusculaire Paris-Nord CHU Raymond-Poincaré, U1179 UVSQ-INSERM Handicap Neuromusculaire: Physiologie, Biothérapie et Pharmacologie Appliquées, UFR des Sciences de la Santé Simone Veil, Université Versailles-Saint-Quentin-en-Yvelines, Garches, France.
Centre de Référence de Pathologie Neuromusculaire Paris-Est, GHU Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

Original language	English
Pages (from-to)	754-767
Number of pages	14
Journal	Journal of clinical investigation
Volume	130
Issue number	2
DOIs	https://doi.org/10.1172/JCI124000
Publication status	Published - 3 Feb 2020

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de Winter, J. M., Molenaar, J. P., Yuen, M., van der Pijl, R., Shen, S., Conijn, S., van de Locht, M., Willigenburg, M., Bogaards, S. J., van Kleef, E. S., Lassche, S., Persson, M., Rassier, D. E., Sztal, T. E., Ruparelia, A. A., Oorschot, V., Ramm, G., Hall, T. E., Xiong, Z., ... Ottenheijm, C. A. (2020). KBTBD13 is an actin-binding protein that modulates muscle kinetics. Journal of clinical investigation, 130(2), 754-767. https://doi.org/10.1172/JCI124000

@article{3f33a0db598d473c9ca62cee624d4dcc,

title = "KBTBD13 is an actin-binding protein that modulates muscle kinetics",

abstract = "The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.",

author = "\{de Winter\}, \{Josine M.\} and Molenaar, \{Joery P.\} and Michaela Yuen and \{van der Pijl\}, Robbert and Shengyi Shen and Stefan Conijn and \{van de Locht\}, Martijn and Menne Willigenburg and Bogaards, \{Sylvia Jp\} and \{van Kleef\}, \{Esmee Sb\} and Saskia Lassche and Malin Persson and Rassier, \{Dilson E.\} and Sztal, \{Tamar E.\} and Ruparelia, \{Avnika A.\} and Viola Oorschot and Georg Ramm and Hall, \{Thomas E.\} and Zherui Xiong and Johnson, \{Christopher N.\} and Frank Li and Balazs Kiss and Noelia Lozano-Vidal and Boon, \{Reinier A.\} and Manuela Marabita and Leonardo Nogara and Bert Blaauw and Rodenburg, \{Richard J.\} and Benno K{\"u}sters and Jonne Doorduin and Beggs, \{Alan H.\} and Henk Granzier and Ken Campbell and Weikang Ma and Thomas Irving and Edoardo Malfatti and Romero, \{Norma B.\} and Bryson-Richardson, \{Robert J.\} and \{van Engelen\}, \{Baziel Gm\} and Voermans, \{Nicol C.\} and Ottenheijm, \{Coen Ac\}",

year = "2020",

month = feb,

day = "3",

doi = "10.1172/JCI124000",

language = "English",

volume = "130",

pages = "754--767",

journal = "Journal of clinical investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "2",

}

de Winter, JM, Molenaar, JP, Yuen, M, van der Pijl, R, Shen, S, Conijn, S, van de Locht, M, Willigenburg, M, Bogaards, SJ, van Kleef, ES, Lassche, S, Persson, M, Rassier, DE, Sztal, TE, Ruparelia, AA, Oorschot, V, Ramm, G, Hall, TE, Xiong, Z, Johnson, CN, Li, F, Kiss, B, Lozano-Vidal, N, Boon, RA, Marabita, M, Nogara, L, Blaauw, B, Rodenburg, RJ, Küsters, B, Doorduin, J, Beggs, AH, Granzier, H, Campbell, K, Ma, W, Irving, T, Malfatti, E, Romero, NB, Bryson-Richardson, RJ, van Engelen, BG, Voermans, NC & Ottenheijm, CA 2020, 'KBTBD13 is an actin-binding protein that modulates muscle kinetics', Journal of clinical investigation, vol. 130, no. 2, pp. 754-767. https://doi.org/10.1172/JCI124000

TY - JOUR

T1 - KBTBD13 is an actin-binding protein that modulates muscle kinetics

AU - de Winter, Josine M.

AU - Molenaar, Joery P.

AU - Yuen, Michaela

AU - van der Pijl, Robbert

AU - Shen, Shengyi

AU - Conijn, Stefan

AU - van de Locht, Martijn

AU - Willigenburg, Menne

AU - Bogaards, Sylvia Jp

AU - van Kleef, Esmee Sb

AU - Lassche, Saskia

AU - Persson, Malin

AU - Rassier, Dilson E.

AU - Sztal, Tamar E.

AU - Ruparelia, Avnika A.

AU - Oorschot, Viola

AU - Ramm, Georg

AU - Hall, Thomas E.

AU - Xiong, Zherui

AU - Johnson, Christopher N.

AU - Li, Frank

AU - Kiss, Balazs

AU - Lozano-Vidal, Noelia

AU - Boon, Reinier A.

AU - Marabita, Manuela

AU - Nogara, Leonardo

AU - Blaauw, Bert

AU - Rodenburg, Richard J.

AU - Küsters, Benno

AU - Doorduin, Jonne

AU - Beggs, Alan H.

AU - Granzier, Henk

AU - Campbell, Ken

AU - Ma, Weikang

AU - Irving, Thomas

AU - Malfatti, Edoardo

AU - Romero, Norma B.

AU - Bryson-Richardson, Robert J.

AU - van Engelen, Baziel Gm

AU - Voermans, Nicol C.

AU - Ottenheijm, Coen Ac

PY - 2020/2/3

Y1 - 2020/2/3

N2 - The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

AB - The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

UR - https://www.scopus.com/pages/publications/85078869872

U2 - 10.1172/JCI124000

DO - 10.1172/JCI124000

M3 - Article

C2 - 31671076

SN - 0021-9738

VL - 130

SP - 754

EP - 767

JO - Journal of clinical investigation

JF - Journal of clinical investigation

IS - 2

ER -

KBTBD13 is an actin-binding protein that modulates muscle kinetics

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