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In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [miRNA]

ABSTRACT: In the present study, we used a multimodal approach including protein and gene expression analysis and combined in vivo and in vitro measurements of force production. Overall, we aimed at investigating the functional impact of the expression of a single nebulin allele. Comparison of the miRNA expression profile of quadriceps in 3 nebulin wild type mice with 3 nebulin heterozygous mice.

ORGANISM(S): Mus musculus

SUBMITTER: Carsten Sticht

PROVIDER: E-GEOD-36741 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy

Project description:This SuperSeries is composed of the following subset Series: GSE36741: In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [miRNA] GSE36743: In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [mRNA] Refer to individual Series

2012-09-01 | E-GEOD-36745 | biostudies-arrayexpress

In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [mRNA]

Project description:In the present study, we used a multimodal approach including protein and gene expression analysis and combined in vivo and in vitro measurements of force production. Overall, we aimed at investigating the functional impact of the expression of a single nebulin allele. Comparison of the mRNA expression profile of quadriceps in 3 nebulin wild type mice with 3 nebulin heterozygous mice.

2012-09-01 | E-GEOD-36743 | biostudies-arrayexpress

In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [mRNA]

2012-09-01 | GSE36743 | GEO

In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy [miRNA]

2012-09-01 | GSE36741 | GEO

In vivo and in vitro investigations of heterozygous nebulin knock-out mice reveal similarities with mild human form of nemaline myopathy

Project description:This SuperSeries is composed of the SubSeries listed below.

2012-09-01 | GSE36745 | GEO

NRAP reduction rescues sarcomere defects in nebulin-related nemaline myopathy.

Project description:Nemaline myopathy (NM) is a rare neuromuscular disorder associated with congenital or childhood-onset of skeletal muscle weakness and hypotonia, which results in limited motor function. NM is a genetic disorder and mutations in 12 genes are known to contribute to autosomal dominant or recessive forms of the disease. Recessive mutations in nebulin (NEB) are the most common cause of NM affecting about 50% of patients. Because of the large size of the NEB gene and lack of mutational hot spots, developing therapies that can benefit a wide group of patients is challenging. Although there are several promising therapies under investigation, there is no cure for NM. Therefore, targeting disease modifiers that can stabilize or improve skeletal muscle function may represent alternative therapeutic strategies. Our studies have identified Nrap upregulation in nebulin deficiency that contributes to structural and functional deficits in NM. We show that genetic ablation of nrap in nebulin deficiency restored sarcomeric disorganization, reduced protein aggregates and improved skeletal muscle function in zebrafish. Our findings suggest that Nrap is a disease modifier that affects skeletal muscle structure and function in NM; thus, therapeutic targeting of Nrap in nebulin-related NM and related diseases may be beneficial for patients.

| S-EPMC10162428 | biostudies-literature

Neb: a zebrafish model of nemaline myopathy due to nebulin mutation.

Project description:Nemaline myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with nemaline myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of nemaline myopathy. This model, termed neb, harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human nemaline myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of nemaline myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder.

| S-EPMC3339832 | biostudies-other

Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy.

Project description:The congenital nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of nemaline myopathy, the disease is caused by a mutation in the alpha-tropomyosin gene TPM3. The typical form of nemaline myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that mutations in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in the thin filaments of striated muscle. A variety of nebulin isoforms are thought to contribute to the molecular diversity of Z discs. We have studied the 3' end of the 20. 8-kb cDNA encoding the Z disc part of the 800-kDa protein and describe six disease-associated mutations in patients from five families of different ethnic origins. In two families with consanguineous parents, the patients were homozygous for point mutations. In one family with nonconsanguineous parents, the affected siblings were compound heterozygotes for two different mutations, and in two further families with one detected mutation each, haplotypes are compatible with compound heterozygosity. Immunofluorescence studies with antibodies specific to the C-terminal region of nebulin indicate that the mutations may cause protein truncation possibly associated with loss of fiber-type diversity, which may be relevant to disease pathogenesis.

| S-EPMC26779 | biostudies-literature

Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.

Project description:Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations.Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 ?M CK-2066260 on force production was assessed.Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation-without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle.Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.

| S-EPMC3865762 | biostudies-literature

The effect of Nebulin-Deficiency on Skeletal Muscle

Project description:Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical NEM adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin’s functional roles in adult muscle we performed studies on a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscle but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survives to adulthood with low nebulin levels (<5% of control), contain nemaline rods, and undergo fiber-type switching towards oxidative types. These microarrays investigate the changes in gene expression when nebulin is deficient.

2015-06-25 | GSE70213 | GEO

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