KBTBD13 is an actin-binding protein that modulates muscle kinetics

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., Johnson, C.N., Li, F., Kiss, B., Lozano-Vidal, N., Boon, R.A., Marabita, M., Nogara, L., Blaauw, B., Rodenburg, R.J., Kϋsters, B., Doorduin, J., Beggs, A.H., Granzier, H., Campbell, K., Ma, W., Irving, T., Malfatti, E., Romero, N.B., Bryson-Richardson, R.J., van Engelen, B.G., Voermans, N.C., Ottenheijm, C.A.
The Journal of Clinical Investigation   130(2): 754-767 (Journal)
Registered Authors
Beggs, Alan H., Bryson-Richardson, Robert, Hall, Thomas, Johnson, Christopher, Li, Frank, Ruparelia, Avnika, Sztal, Tamar Esther
Genetic diseases, Muscle Biology, Neuromuscular disease, Skeletal muscle
MeSH Terms
  • Animals
  • Humans
  • Mice
  • Mice, Knockout
  • Muscle Proteins/genetics
  • Muscle Proteins/metabolism*
  • Muscle Relaxation*
  • Myopathies, Nemaline/genetics
  • Myopathies, Nemaline/metabolism*
  • Myopathies, Nemaline/pathology
  • Sarcomeres/metabolism*
  • Sarcomeres/pathology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
31671076 Full text @ Journal of Clin. Invest.
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 super-resolution 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, binding- and contractility assays with recombinant KBTBD13, novel 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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes