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 J.P. Bogaards, Esmee S.B. 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. JohnsonFrank 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 G.M. Van Engelen, Nicol C. Voermans, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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 GFPlabeled 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 languageEnglish
Pages (from-to)754-767
Number of pages14
JournalJournal of Clinical Investigation
Issue number2
StatePublished - Feb 3 2020

Bibliographical note

Funding Information:
This work was supported by the Dutch Foundation for Scientific Research (VIDI 016.126.319 to CACO); the Princess Beatrix Muscle Foundation (W.OR17-08 to CACO, NCV, and BGMVE); H2020-MSCA-RISE-2014 (645648 Muscle Stress Relief to CACO); the Advanced Photon Source (DE-AC02-06CH11357); A Foundation Building Strength for Nemaline Myopathy (to CACO); the National Health and Medical Research Council (NHMRC) Early Career Fellowship (APP1121651 to MY); the National Institute of Child Health and Human Development (NIH R01 HD075802 to AHB); the Muscular Dystrophy Association (USA) (MDA602235 to AHB); the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH R01 AR053897 to HG), the NIH (HL133359 to KC). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This project was supported by grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the NIH. Use of the Pilatus 3 1M detector was provided by grant 1S10OD018090-01 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of General Medical Sciences or the NIH. MP was funded by a postdoctoral grant from the Swedish Research Council (2015-00385).

Publisher Copyright:
© 2020, American Society for Clinical Investigation.

ASJC Scopus subject areas

  • Medicine (all)


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