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

Nat Commun. 2020 Jun 1;11(1):2699. doi: 10.1038/s41467-020-16526-9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / chemistry
  • Actin Cytoskeleton / metabolism
  • Animals
  • Heterozygote
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Muscle Proteins / chemistry
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / ultrastructure
  • Mutation, Missense*
  • Myofibrils / metabolism*
  • Myofibrils / pathology
  • Myofibrils / ultrastructure
  • Myopathies, Nemaline / genetics*
  • Myopathies, Nemaline / metabolism
  • Sarcomeres / metabolism
  • Sarcomeres / pathology
  • Sarcomeres / ultrastructure
  • Tropomyosin / chemistry
  • Tropomyosin / metabolism
  • Troponin / chemistry
  • Troponin / metabolism
  • X-Ray Diffraction

Substances

  • Muscle Proteins
  • Tropomyosin
  • Troponin
  • nebulin