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

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.

• Authors: Johan Lindqvist, Weikang Ma, Frank Li, Yaeren Hernandez, Justin Kolb, Balazs Kiss, Paola Tonino, Robbert van der Pijl, Esmat Karimi, Henry Gong, Josh Strom, Zaynab Hourani, John E Smith 3rd, Coen Ottenheijm, Thomas Irving, Henk Granzier
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 2699 (06 01 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32483185 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Muscle Proteins
• Tropomyosin
• Troponin
• nebulin

Topics

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