title: Mutation-specific effects on thin filament length in thin filament myopathy.
abstract: Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation.
  
  
  
  We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41.
  
  
  
  Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force-sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin-thick filament overlap.
  
  
  
  These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths. Ann Neurol 2016;79:959-969.
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Josine M de
authors.initials: JM
authors.lastname: Winter
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Barbara
authors.initials: B
authors.lastname: Joureau
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Eun-Jeong
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Balázs
authors.initials: B
authors.lastname: Kiss
authors.affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia.|Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Michaela
authors.initials: M
authors.lastname: Yuen
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Vandana A
authors.initials: VA
authors.lastname: Gupta
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Pappas
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Physics and Astronomy, VU University, Amsterdam, the Netherlands.
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.affiliation: Pediatric Neurology Unit, Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.|Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.affiliation: Department of Medical and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.|Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.affiliation: Folkhaelsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland.|Division of Genetics, Department of Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Katarina
authors.initials: K
authors.lastname: Pelin
authors.affiliation: Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Malfatti
authors.affiliation: Center for Research in Myology, Pitié-Salpêtrière Hospital Group, Paris, France.
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Baziel G van
authors.initials: BG
authors.lastname: Engelen
authors.affiliation: Department of Neurology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicol C
authors.initials: NC
authors.lastname: Voermans
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD.
authors.forename: Sandra
authors.initials: S
authors.lastname: Donkervoort
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institutes of Health, Bethesda, MD.
authors.forename: C G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, New South Wales, Australia.|Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Henk
authors.initials: H
authors.lastname: Granzier
authors.affiliation: Department of Physiology, VU University Medical Center, Amsterdam, the Netherlands.|Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ.
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D016022:Case-Control Studies; D003599:Cytoskeleton / Q000235:genetics* / Q000502:physiology; D006801:Humans; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D012518:Sarcomeres / Q000235:genetics* / Q000502:physiology
chemical_list: D000199:Actins; D009124:Muscle Proteins; C035620:nebulin