The most common cause of typical NM is mutations in the NEB gene that encodes the sarcomeric protein nebulin 3, 9, 10. It can clinically be divided into subtypes of which the typical subtype (congenital and static or only slowly progressive) accounts for about half of the patients 5, 6, 7, 8. Nemaline myopathy (NM) is a heterogeneous disease with varying age of onset and severity and is characterized by skeletal muscle weakness, muscle atrophy, and intracellular nemaline rod bodies 1, 2, 3, 4, 5. The unique disease mechanism of nebulin-based typical NM reveals novel therapeutic targets. 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. In contrast to nebulin-based severe NM where haplo-insufficiency is the disease driver, Compound-Het mice express normal amounts of nebulin. Muscles have a reduced myofibrillar fractional-area and sarcomeres are disorganized, contain rod bodies, and have longer thin filaments. We show that Compound-Het mice are growth-retarded and have muscle weakness. 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. Compound-heterozygous mutations in the nebulin gene ( NEB) cause typical nemaline myopathy (NM), a muscle disorder characterized by muscle weakness with limited treatment options. Nebulin is a giant protein that winds around the actin filaments in the skeletal muscle sarcomere.
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