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

Journal Article · · Nature Communications
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  1. Univ. of Arizona, Tucson, AZ (United States)
  2. Illinois Inst. of Technology, Chicago, IL (United States)
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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); USDOE Office of Science (SC); National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH)
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

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Figures / Tables (8)

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Cytoskeleton
Muscle
Neuromuscular disease