Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism

Journal Article · · Nature Communications
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1];  [1];  [1];  [2];  [1]
  1. Univ. of Arizona, Tucson, AZ (United States)
  2. Illinois Inst. of Technology, Chicago, IL (United States)
+ Show Author Affiliations
Nebulin is a giant protein that winds around the actin filaments in the skeletal muscle sarcomere. Compound-heterozygous mutations in the nebulin gene (NEB) cause typical nemaline myopathy (NM), a muscle disorder characterized by muscle weakness with limited treatment options. We created a mouse model with a missense mutation p.Ser6366Ile and a deletion of NEB exon 55, the Compound-Het model that resembles typical NM. We show that Compound-Het mice are growth-retarded and have muscle weakness. Muscles have a reduced myofibrillar fractional-area and sarcomeres are disorganized, contain rod bodies, and have longer thin filaments. In contrast to nebulin-based severe NM where haplo-insufficiency is the disease driver, Compound-Het mice express normal amounts of nebulin. X-ray diffraction revealed that the actin filament is twisted with a larger radius, that tropomyosin and troponin behavior is altered, and that the myofilament spacing is increased. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
A Foundation Building Strength; National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1631850
Journal Information:
Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (68)

Nemaline myopathy: A clinical study of 143 cases journal January 2001
Mutation-specific effects on thin filament length in thin filament myopathy: Thin Filament Myopathy journal April 2016
Vertical agarose gel electrophoresis and electroblotting of high-molecular-weight proteins journal June 2003
Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy journal January 2006
Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies journal November 2014
Nebulin, a helical actin binding protein. journal April 1994
Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb journal August 1994
A nebulin super-repeat panel reveals stronger actin binding toward the ends of the super-repeat region: Nebulin Binding of Actin journal November 2018
Nemaline myopathy in the Ashkenazi Jewish population is caused by a deletion in the nebulin gene journal June 2004
Titin/connectin-based modulation of the Frank-Starling mechanism of the heart journal February 2006
Nemaline myopathies: a current view journal June 2019
Nebulin as a giant actin-binding template protein in skeletal muscle sarcomere Interaction of actin and cloned human nebulin fragments journal April 1991
Evidence that nebulin is a protein-ruler in muscle thin filaments journal May 1991
Ultrastructure of skeletal muscle fibers studied by a plunge quick freezing method: myofilament lengths journal July 1994
X-ray diffraction evidence for the extensibility of actin and myosin filaments during muscle contraction journal December 1994
Extensibility and Symmetry of Actin Filaments in Contracting Muscles journal December 1999
The Complete Mouse Nebulin Gene Sequence and the Identification of Cardiac Nebulin journal May 2003
Nebulin mutations in autosomal recessive nemaline myopathy: an update journal October 2002
Genetics of the nemaline myopathies and the myotubular myopathies journal August 1998
Each Actin Subunit Has Three Nebulin Binding Sites journal March 2002
Tropomodulins and Leiomodins: Actin Pointed End Caps and Nucleators in Muscles journal May 2017
Thick-Filament Extensibility in Intact Skeletal Muscle journal October 2018
Expression of Distinct Classes of Titin Isoforms in Striated and Smooth Muscles by Alternative Splicing, and Their Conserved Interaction with Filamins journal September 2006
Altered Contractility of Skeletal Muscle in Mice Deficient in Titin’s M-Band Region journal October 2009
Altered myofilament function depresses force generation in patients with nebulin-based nemaline myopathy (NEM2) journal May 2010
The exon 55 deletion in the nebulin gene – One single founder mutation with world-wide occurrence journal March 2009
Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene journal February 2019
Congenital myopathies: disorders of excitation–contraction coupling and muscle contraction journal February 2018
The giant protein titin regulates the length of the striated muscle thick filament journal October 2017
Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts journal July 2004
Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo journal August 2006
Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle journal September 2018
Rate of force generation in muscle: correlation with actomyosin ATPase activity in solution. journal May 1986
Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy journal March 1999
Nebulin Alters Cross-bridge Cycling Kinetics and Increases Thin Filament Activation: A NOVEL MECHANISM FOR INCREASING TENSION AND REDUCING TENSION COST journal September 2009
Interactions between Nebulin-like Motifs and Thin Filament Regulatory Proteins journal November 2002
Architecture of the sarcomere matrix of skeletal muscle: immunoelectron microscopic evidence that suggests a set of parallel inextensible nebulin filaments anchored at the Z line journal December 1988
Nebulin as a length regulator of thin filaments of vertebrate skeletal muscles: correlation of thin filament length, nebulin size, and epitope profile journal October 1991
An Atomic Model of Actin Filaments Cross-Linked by Fimbrin and Its Implications for Bundle Assembly and Function journal May 2001
Nebulin-deficient mice exhibit shorter thin filament lengths and reduced contractile function in skeletal muscle journal June 2006
Nebulin increases thin filament stiffness and force per cross-bridge in slow-twitch soleus muscle fibers journal October 2018
Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity journal April 2019
Nemaline Myopathy: a new Congenital Myopathy journal January 1963
Distal myopathy caused by homozygous missense mutations in the nebulin gene journal April 2007
Deleting exon 55 from the nebulin gene induces severe muscle weakness in a mouse model for nemaline myopathy journal May 2013
Thin filament length dysregulation contributes to muscle weakness in nemaline myopathy patients with nebulin deficiency journal April 2009
Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy journal June 2015
Deleting nebulin's C-terminus reveals its importance to sarcomeric structure and function and is sufficient to invoke nemaline myopathy journal January 2019
Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle journal August 2008
Nebulin plays a direct role in promoting strong actin-myosin interactions journal December 2009
The BioCAT undulator beamline 18ID: a facility for biological non-crystalline diffraction and X-ray absorption spectroscopy at the Advanced Photon Source journal August 2004
Myopathology in congenital myopathies journal February 2017
The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres. journal June 1979
Nemaline myopathy: current concepts. The ENMC International Consortium and Nemaline Myopathy. journal September 1997
The Filament Lattice of Striated Muscle journal April 1998
Modulation of Muscle Atrophy, Fatigue and MLC Phosphorylation by MuRF1 as Indicated by Hindlimb Suspension Studies on MuRF1-KO Mice journal January 2010
New Insights into the Structural Roles of Nebulin in Skeletal Muscle journal January 2010
Developmental Control of Titin Isoform Expression and Passive Stiffness in Fetal and Neonatal Myocardium journal March 2004
Novel mutations in NEB cause abnormal nebulin expression and markedly impaired muscle force generation in severe nemaline myopathy journal January 2011
Nebulin interactions with actin and tropomyosin are altered by disease-causing mutations journal January 2014
SMASH – semi-automatic muscle analysis using segmentation of histology: a MATLAB application journal January 2014
Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype journal April 2014
Reduced myofibrillar connectivity and increased Z-disk width in nebulin-deficient skeletal muscle journal January 2010
The nebulin SH3 domain is dispensable for normal skeletal muscle structure but is required for effective active load bearing in mouse journal September 2013
Sarcomere Dysfunction in Nemaline Myopathy journal May 2017
Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle journal September 2018
Tissue Triage and Freezing for Models of Skeletal Muscle Disease journal January 2014
SMASH – semi-automatic muscle analysis using segmentation of histology: a MATLAB application dataset January 2014

Figures / Tables (8)

Fig. 1(p. 3)figure Fig. 1
Fig. 2(p. 4)figure Fig. 2
Fig. 3(p. 5)figure Fig. 3
Fig. 4(p. 6)figure Fig. 4
Fig. 5(p. 7)figure Fig. 5
Fig. 6(p. 8)figure Fig. 6
Fig. 7(p. 9)figure Fig. 7
Fig. 8(p. 11)figure Fig. 8

Similar Records

Nebulin stiffens the thin filament and augments cross-bridge interaction in skeletal muscle
Journal Article · Sun Sep 23 20:00:00 EDT 2018 · Proceedings of the National Academy of Sciences of the United States of America · OSTI ID:1478092
Comparative decline of the protein profiles of nebulin in response to denervation in skeletal muscle
Journal Article · Fri Oct 09 00:00:00 EDT 2015 · Biochemical and Biophysical Research Communications · OSTI ID:22592748
Nebulin and titin modulate cross-bridge cycling and length-dependent calcium sensitivity
Journal Article · Wed Apr 03 20:00:00 EDT 2019 · Journal of General Physiology · OSTI ID:1558308

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Cytoskeleton
Muscle
Neuromuscular disease