Triggering typical nemaline myopathy with compound heterozygous nebulin mutations reveals myofilament structural changes as pathomechanism.
Actin Cytoskeleton
/ chemistry
Animals
Heterozygote
Mice, 129 Strain
Mice, Inbred C57BL
Microscopy, Electron, Transmission
Muscle Proteins
/ chemistry
Muscle, Skeletal
/ metabolism
Mutation, Missense
Myofibrils
/ metabolism
Myopathies, Nemaline
/ genetics
Sarcomeres
/ metabolism
Tropomyosin
/ chemistry
Troponin
/ chemistry
X-Ray Diffraction
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
09
09
2019
accepted:
06
05
2020
entrez:
3
6
2020
pubmed:
3
6
2020
medline:
18
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32483185
doi: 10.1038/s41467-020-16526-9
pii: 10.1038/s41467-020-16526-9
pmc: PMC7264197
doi:
Substances chimiques
Muscle Proteins
0
Tropomyosin
0
Troponin
0
nebulin
02X6KNJ5EE
Types de publication
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.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2699Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103622
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR060697
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR053897
Pays : United States
Organisme : NIH HHS
ID : S10 OD018090
Pays : United States
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