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

Lindqvist, Johan; Ma, Weikang; Li, Frank; Hernandez, Yaeren; Kolb, Justin; Kiss, Balazs; Tonino, Paola; van der Pijl, Robbert; Karimi, Esmat; Gong, Henry; Strom, Josh; Hourani, Zaynab; Smith III, John E.; Ottenheijm, Coen; Irving, Thomas; Granzier, Henk

doi:10.1038/s41467-020-16526-9

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

Journal Article · 01 June 2020 · Nature Communications

DOI: https://doi.org/10.1038/s41467-020-16526-9 · OSTI ID:1631850

Lindqvist, Johan ^[1];

^[2]; Li, Frank ^[1]; Hernandez, Yaeren ^[1]; Kolb, Justin ^[1]; Kiss, Balazs ^[1]; Tonino, Paola ^[1]; van der Pijl, Robbert ^[1]; Karimi, Esmat ^[1]; Gong, Henry ^[2]; Strom, Josh ^[1]; Hourani, Zaynab ^[1];

^[1]; Ottenheijm, Coen ^[1]; Irving, Thomas ^[2];

^[1]

Univ. of Arizona, Tucson, AZ (United States)
Illinois Inst. of Technology, Chicago, IL (United States)

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.

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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:: R01AR053897; AC02-06CH11357; 9 P41 GM103622; 1S10OD018090-01

OSTI ID:: 1631850

Journal Information:: Nature Communications, Vol. 11, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 8 works

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