Abstract
BackgroundNemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases.ResultsWe describe two siblings with severe NM, arthrogryposis and neonatal death caused by two novel NEB mutations: a point mutation in intron 13 and a frameshift mutation in exon 81. Levels of detectable nebulin protein were significantly lower than those in normal control muscle biopsies or those from patients with less severe NM due to deletion of NEB exon 55. Mechanical studies of skinned myofibers revealed marked impairment of force development, with an increase in tension cost.ConclusionsOur findings demonstrate that the mechanical phenotype of severe NM is the consequence of mutations that severely reduce nebulin protein levels and suggest that the level of nebulin expression may correlate with the severity of disease.
Highlights
Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies in muscle fibers
A biopsy of the right rectus femoris muscle obtained at eight days of life revealed myopathic muscle with numerous nemaline bodies and/or rods, which are diagnostic for NM
The compound heterozygous mutations described in this report represent another scenario in which NEB mutations can cause severe NM that is associated with an even shorter life expectancy than that of the most severely affected patients with exon 55 mutations
Summary
Nemaline myopathy (NM) is a congenital muscle disease associated with weakness and the presence of nemaline bodies (rods) in muscle fibers. Mutations in seven genes have been associated with NM, but the most commonly mutated gene is nebulin (NEB), which is thought to account for roughly 50% of cases. A diagnosis of NM requires symptoms of skeletal muscle weakness and the presence of nemaline rods in muscle fibers, in the absence of findings diagnostic of other unrelated conditions [1]. The skeletal muscle-specific NEB gene is large, with a total of 183 exons spanning 249 kb of genomic sequence and a theoretical full-length transcript of 26 kb, and is predicted to encode an approximately 800-kDa protein [10]. Studies of two nebulin-knockout mouse models, both of which exhibit severe, early, lethal phenotypes, have shown that nebulin absence is associated with shorter thin filaments [18,20,21] and altered cross-bridge cycling [22]
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