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

Johan Lindqvist, Weikang Ma, Frank Li, Yaeren Hernandez, Justin Kolb, Balazs Kiss, Paola Tonino, Robbert Pijl, Esmat Karimi, Henry Gong, Josh Strom, Zaynab Hourani, John E. Smith, Coen Ottenheijm, Thomas Irving and Henk Granzier ()
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Johan Lindqvist: University of Arizona
Weikang Ma: Department of Biology, Illinois Institute of Technology
Frank Li: University of Arizona
Yaeren Hernandez: University of Arizona
Justin Kolb: University of Arizona
Balazs Kiss: University of Arizona
Paola Tonino: University of Arizona
Robbert Pijl: University of Arizona
Esmat Karimi: University of Arizona
Henry Gong: Department of Biology, Illinois Institute of Technology
Josh Strom: University of Arizona
Zaynab Hourani: University of Arizona
John E. Smith: University of Arizona
Coen Ottenheijm: University of Arizona
Thomas Irving: Department of Biology, Illinois Institute of Technology
Henk Granzier: University of Arizona

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16526-9

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