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Title: 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:
 [1]; ORCiD logo [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1];  [1]; ORCiD logo [1];  [1];  [2]; ORCiD logo [1]
  1. Univ. of Arizona, Tucson, AZ (United States)
  2. Illinois Inst. of Technology, Chicago, IL (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
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)
OSTI Identifier:
1631850
Grant/Contract Number:  
R01AR053897; AC02-06CH11357; 9 P41 GM103622; 1S10OD018090-01
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cytoskeleton; Muscle; Neuromuscular disease

Citation Formats

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, and Granzier, Henk. Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-16526-9.
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. Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism. United States. https://doi.org/10.1038/s41467-020-16526-9
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, and Granzier, Henk. Mon . "Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism". United States. https://doi.org/10.1038/s41467-020-16526-9. https://www.osti.gov/servlets/purl/1631850.
@article{osti_1631850,
title = {Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism},
author = {Lindqvist, Johan and Ma, Weikang and Li, Frank and Hernandez, Yaeren and Kolb, Justin and Kiss, Balazs and Tonino, Paola and van der Pijl, Robbert and Karimi, Esmat and Gong, Henry and Strom, Josh and Hourani, Zaynab and Smith III, John E. and Ottenheijm, Coen and Irving, Thomas and Granzier, Henk},
abstractNote = {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.},
doi = {10.1038/s41467-020-16526-9},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {6}
}

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