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. 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 G.M. Van Engelen; Nicol C. Voermans; Coen A.C. 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 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 journal › Article › peer-review

33 Scopus citations

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 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 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
State	Published - Feb 3 2020

Bibliographical note

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

ASJC Scopus subject areas

General Medicine

Access to Document

10.1172/JCI124000

Cite this

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. P., Van Kleef, E. S. B., 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. C. (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{1cd6b4cde03b4053a4256ab1c4c9bd2a,

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 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.",

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 J.P.} and {Van Kleef}, {Esmee S.B.} 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 G.M.} and Voermans, {Nicol C.} and Ottenheijm, {Coen A.C.}",

note = "Publisher Copyright: {\textcopyright} 2020, American Society for Clinical Investigation.",

year = "2020",

month = feb,

day = "3",

doi = "10.1172/JCI124000",

language = "English",

volume = "130",

pages = "754--767",

number = "2",

}

De Winter, JM, Molenaar, JP, Yuen, M, Van Der Pijl, R, Shen, S, Conijn, S, Van De Locht, M, Willigenburg, M, Bogaards, SJP, Van Kleef, ESB, 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, BGM, Voermans, NC & Ottenheijm, CAC 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 J.P.

AU - Van Kleef, Esmee S.B.

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 G.M.

AU - Voermans, Nicol C.

AU - Ottenheijm, Coen A.C.

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 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=85078869872&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85078869872&partnerID=8YFLogxK

U2 - 10.1172/JCI124000

DO - 10.1172/JCI124000

M3 - Article

C2 - 31671076

AN - SCOPUS:85078869872

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

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this