Mutations in the nebulin gene can cause severe congenital nemaline myopathy

Wallgren‐Pettersson, Carina; Donner, Kati; Sewry, Caroline A.; Bijlsma, Emilia K.; Lammens, Martin; Bushby, Kate; Uzielli, Maria Luisa Giovannucci; Lapi, Elisabetta; Odent, Sylvie; Akçören, Zühal; Topaloǧlu, Haluk; Pelin, Katarina

doi:10.1016/s0960-8966(02)00065-2

Cited by 88 publications

(62 citation statements)

References 25 publications

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“…6 Four alternative exons, 168 -171, previously named 177A -177D, 11,12 encode simple repeat domain M177/M178, and three alternative exons, 172 -174, previously named 177E, 178A and 178B, encode simple repeat M178/M179. The rat Neb gene has five exons encoding simple repeat M177/M178, and only one encoding M178/ M179.…”

Section: Discussionmentioning

confidence: 99%

“…We have reported a 2-bp deletion in exon 177 (181) in two brothers compound heterozygous for the mutation, and another 2-bp deletion in the constitutive exon 163 (previously 172). 10 Both patients had a severe form of nemaline myopathy, 12 and showed some muscle fibres negative for the nebulin SH3-domain antibody. 13 Antibodies to other domains showed the presence of nebulin.…”

Section: Discussionmentioning

confidence: 99%

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Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts

et al. 2004

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The giant nebulin protein is a fundamental structural component of the thin filaments of the striated muscle sarcomere. Nebulin binds to actin and the size of nebulin correlates with actin filament length, suggesting that nebulin may determine the length of the thin filaments during myofibrillogenesis. We have previously described the genomic organization of the 3 0 end of the nebulin gene (NEB), and identified 18 different NEB mutations in patients with autosomal recessive nemaline myopathy. Here we present the genomic organization of the entire nebulin gene, and the identification of numerous alternatively spliced mRNAs. The gene comprises 183 exons spanning 249 kb of the genomic sequence. The translation initiation codon is in exon 3, and the stop codon and the 3 0 UTR are in exon 183. There are four regions with alternatively spliced exons, that is, exons 63 -66, 82-105, 143 -144 and 166 -177, giving rise to a number of different transcripts. The alternatively spliced exons 143 -144 give rise to two different transcripts varying between muscle types and between muscles of different developmental stages. The alternatively spliced exons 166 -177 express at least 20 different transcripts in adult human tibialis anterior muscle alone. Preliminary results show several transcripts in both of the two remaining alternatively spliced regions. Extensive alternative splicing of NEB may explain why nemaline myopathy patients with homozygous truncating mutations show expression of the carboxy-terminus of the nebulin protein contrary to expectations . The use of alternative transcripts might also explain why severe phenotypes are rare among patients with two truncating mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts

et al. 2004

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“…Both milder and more severe forms have been recognized including presentations with profound muscle weakness, arthrogryposis and even neonatal death. [4][5][6] Late-onset presentations with predominantly distal involvement as well as cores and rods on muscle biopsy have been reported in rare cases. 7,8 Most NEB mutations identified to date are unique, however, a recurrent inframe deletion of NEB exon 55 has been recognized, associated with a form of NM of variable severity.…”

Section: Introductionmentioning

confidence: 99%

Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing

Scoto¹,

Cullup

Çırak³

et al. 2013

Eur J Hum Genet

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Recessive nebulin (NEB) mutations are a common cause of nemaline myopathy (NM), typically characterized by generalized weakness of early-onset and nemaline rods on muscle biopsy. Exceptional adult cases with additional cores and an isolated distal weakness have been reported. The large NEB gene with 183 exons has been an obstacle for the genetic work-up. Here we report a childhood-onset case with distal weakness and a core-rod myopathy, associated with recessive NEB mutations identified by next generation sequencing (NGS). This 6-year-old boy presented with a history of gross-motor difficulties following a normal early development. He had distal leg weakness with bilateral foot drop, as well as axial muscle weakness, scoliosis and spinal rigidity; additionally he required nocturnal respiratory support. Muscle magnetic resonance (MR) imaging showed distal involvement in the medial and anterior compartment of the lower leg. A muscle biopsy featured both rods and cores. Initial targeted testing identified a heterozygous Nebulin exon 55 deletion. Further analysis using NGS revealed a frameshifting 4 bp duplication, c.24372_24375dup (P.Val8126fs), on the opposite allele. This case illustrates that NEB mutations can cause childhood onset distal NM, with additional cores on muscle biopsy and proves the diagnostic utility of NGS for myopathies, particularly when large genes are implicated.

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“…In addition, NEB is required for normal muscle contractility, which has been demonstrated by altered Ca 2ϩ sensitivity (55) and inferior isometric stress production (3) in NEB-deficient muscle. NEB is of clinical interest because 50% or more of nemaline myopathy cases are caused by mutations in its gene (21,35,48,49).To assess the role of NEB, NEB knockout (NEB-KO) mice were compared with wild-type (WT) mice. NEB deficiency is a neonatal lethal mutation; NEB-KO mice have abnormally short thin filaments, exhibit rapid postnatal myofibrillar disorganization and muscle degeneration, and die after ϳ1-2 postnatal weeks (3, 55).…”

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Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

Gokhin

Bang

Zhang

et al. 2009

American Journal of Physiology-Cell Physiology

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Gokhin DS, Bang ML, Zhang J, Chen J, Lieber RL. Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties. Am J Physiol Cell Physiol 296: C1123-C1132, 2009. First published March 18, 2009 doi:10.1152/ajpcell.00503.2008 is a large, rod-like protein believed to dictate actin thin filament length in skeletal muscle. NEB gene defects are associated with congenital nemaline myopathy. The functional role of NEB was investigated in gastrocnemius muscles from neonatal wild-type (WT) and NEB knockout (NEB-KO) mice, whose thin filaments have uniformly shorter lengths compared with WT mice. Isometric stress production in NEB-KO skeletal muscle was reduced by 27% compared with WT skeletal muscle on postnatal day 1 and by 92% on postnatal day 7, consistent with functionally severe myopathy. NEB-KO muscle was also more susceptible to a decline in stress production during a bout of 10 cyclic isometric tetani. Length-tension properties in NEB-KO muscle were altered in a manner consistent with reduced thin filament length, with length-tension curves from NEB-KO muscle demonstrating a 7.4% narrower functional range and an optimal length reduced by 0.13 muscle lengths. Expression patterns of myosin heavy chain isoforms and total myosin content did not account for the functional differences between WT and NEB-KO muscle. These data indicate that NEB is essential for active stress production, maintenance of functional integrity during cyclic activation, and lengthtension properties consistent with a role in specifying normal thin filament length. Continued analysis of NEB's functional properties will strengthen the understanding of force transmission and thin filament length regulation in skeletal muscle and may provide insights into the molecular processes that give rise to nemaline myopathy. neonatal mouse; isometric stress; myosin heavy chain; length-tension curve FORCE GENERATION in skeletal muscle results from the interdigitation of actin (thin) filaments and myosin (thick) filaments in the sarcomeres of the myofibrillar lattice. The magnitude of active force production is predicted by the sliding filament model, which states that active muscle force is proportional to the degree of thin and thick filament overlap (15, 16). The length-tension relationship quantifies the relationship between myofilament overlap and force production and is determined by eliciting isometric tetani at a discrete series of lengths (7,9,10,14). Myofilaments are polymeric, but their lengths are controlled precisely during sarcomere assembly and are highly uniform within a fiber (6, 24). Myofilament length varies across muscle type and species (11,13,43,44,47), with resultant functional consequences on the shape of the lengthtension curve (11). Therefore, the molecular basis of myofilament length regulation has substantial physiological implications.Previous studies have demonstrated that thin filament length is partly controlled by the action of "capping" proteins. At the thin filament barbed end (anchore...

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Mutations in the nebulin gene can cause severe congenital nemaline myopathy

Cited by 88 publications

References 25 publications

Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts

Complete genomic structure of the human nebulin gene and identification of alternatively spliced transcripts

Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing

Reduced thin filament length in nebulin-knockout skeletal muscle alters isometric contractile properties

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