Molecular classification of nemaline myopathies: “nontyping” specimens exhibit unique patterns of gene expression

Sanoudou, Despina; Frieden, Leslie A.; Haslett, Judith N.; Kho, Alvin T.; Greenberg, Steven A.; Kohane, Isaac S.; Kunkel, Louis M.; Beggs, Alan H.

doi:10.1016/j.nbd.2003.12.013

Cited by 13 publications

(9 citation statements)

References 24 publications

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“…The large number of down‐regulated genes functioning in diverse metabolic processes reflects probably the metabolic crisis also seen in human DMD, LGMD‐2D, FSHD, and nemaline myopathy patients (16, 22, 23). From our and data of others (51, 52), we conclude that the metabolic crisis in mdx mice is less severe than in sarcoglycan‐deficient mice.…”

Section: Discussionsupporting

confidence: 64%

Common pathological mechanisms in mouse models for muscular dystrophies

et al. 2005

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Duchenne/Becker and limb-girdle muscular dystrophies share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. To get a closer view on the differentiating molecular events responsible for the muscular dystrophies, we have carried out a comparative gene expression profiling of hindlimb muscles of the following mouse models: dystrophin-deficient (mdx, mdx(3cv)), sarcoglycan-deficient (Sgca null, Sgcb null, Sgcg null, Sgcd null), dysferlin-deficient (Dysf null, SJL(Dysf)), sarcospan-deficient (Sspn null), and wild-type (C57Bl/6, C57Bl/10) mice. The expression profiles clearly discriminated between severely affected (dystrophinopathies and sarcoglycanopathies) and mildly or nonaffected models (dysferlinopathies, sarcospan-deficiency, wild-type). Dystrophin-deficient and sarcoglycan-deficient profiles were remarkably similar, sharing inflammatory and structural remodeling processes. These processes were also ongoing in dysferlin-deficient animals, albeit at lower levels, in agreement with the later age of onset of this muscular dystrophy. The inflammatory proteins Spp1 and S100a9 were up-regulated in all models, including sarcospan-deficient mice, which points, for the first time, at a subtle phenotype for Sspn null mice. In conclusion, we identified biomarker genes for which expression correlates with the severity of the disease, which can be used for monitoring disease progression. This comparative study is an integrating step toward the development of an expression profiling-based diagnostic approach for muscular dystrophies in humans.

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Section: Discussionsupporting

confidence: 64%

Common pathological mechanisms in mouse models for muscular dystrophies

et al. 2005

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“…None of the cases had the "nontyping" pattern of pathology defined by Ryan and colleagues 7 and Sanoudou and colleagues, 26 nor did any exhibit type 2 fiber predominance which has been reported in 4% of unselected NM cases. 7 Moderate to severe increases of endomysial and or perimysial connective tissues were noted in two cases (117-1 and 308-1).…”

Section: Pathological Findingsmentioning

confidence: 82%

Heterogeneity of nemaline myopathy cases with skeletal muscle α‐actin gene mutations

Agrawal

Strickland

Midgett

et al. 2004

Annals of Neurology

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133

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Nemaline myopathy (NM) is the most common of several congenital myopathies that present with skeletal muscle weakness and hypotonia. It is clinically heterogeneous and the diagnosis is confirmed by identification of nemaline bodies in affected muscles. The skeletal muscle alpha-actin gene (ACTA1) is one of five genes for thin filament proteins identified so far as responsible for different forms of NM. We have screened the ACTA1 gene in a cohort of 109 unrelated patients with NM. Here, we describe clinical and pathological features associated with 29 ACTA1 mutations found in 38 individuals from 28 families. Although ACTA1 mutations cause a remarkably heterogeneous range of phenotypes, they were preferentially associated with severe clinical presentations (p < 0.0001). Most pathogenic ACTA1 mutations were missense changes with two instances of single base pair deletions. Most patients with ACTA1 mutations had no prior family history of neuromuscular disease (24/28). One severe case, caused by compound heterozygous recessive ACTA1 mutations, demonstrated increased alpha-cardiac actin expression, suggesting that cardiac actin might partially compensate for ACTA1 abnormalities in the fetal/neonatal period. This cohort also includes the first instance of an ACTA1 mutation manifesting with adult-onset disease and two pedigrees exhibiting potential incomplete penetrance. Overall, ACTA1 mutations are a common cause of NM, accounting for more than half of severe cases and 26% of all NM cases in this series.

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“…Interestingly, very low levels or undetectable nebulin expression occurred in several patients, indicating that protein levels are not a reliable test of which gene might be mutated in NM as the whole balance may be altered. This also indicates that the phenotype of NM is likely to result not only from the expression of mutant actin, but also from alterations of the expression of several proteins, perhaps emphasizing the need for global analyses (gene chips and proteomics) such as those currently being developed by the Beggs laboratory 32, 33. The expression of mutants in C2C12 cells resulted in the formation of rods and aggregates similar to those seen in patient samples in several cases, although some of the mutants behaved similarly to the wild‐type actin 31.…”

Section: The Genetics Of CM Mutationsmentioning

confidence: 99%

“…Microarray technology is being applied to CMs to study how global gene expression patterns determine the ‘downstream’ or secondary consequences of particular genetic mutations and to identify novel muscle genes for further study. These genomic and proteomic approaches are yielding important new insights into basic muscle biology as well as the pathophysiology of inherited muscle diseases 32, 33, 56, 57, 58.…”

Section: Further Researchmentioning

confidence: 99%

Congenital myopathies: diseases of the actin cytoskeleton

Clarkson

Costa

Machesky

2004

The Journal of Pathology

101

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Congenital myopathies are clinical and genetic heterogeneous disorders characterized by skeletal muscle weakness ranging in severity. Three major forms have been identified: actin myopathy, intranuclear rod myopathy, and nemaline myopathy. Nemaline myopathy is the most common of these myopathies and is further subdivided into seven groups according to severity, progressiveness, and age of onset. At present, five genes have been linked to congenital myopathies. These include α-actin (ACTA1), α-and β-tropomyosin (TPM3 and TPM2), troponin T (TNNT1), and nebulin (NEB). Their protein products are all components of the thin filament of the sarcomere. The mutations identified within these genes have varying impacts on protein structure and give rise to different forms of congenital myopathies. Greater understanding of muscle formation and cause of disease can be established through the study of the effect of mutations on the functional proteins. However, a major limitation in the understanding of congenital myopathies is the lack of correlation between the degree of sarcomeric disruption and disease severity. Consequently, great difficulty may be encountered when diagnosing patients and predicting the progression of the disorders. There are no existing cures for congenital myopathies, although improvements can be made to both the standard of living and the life expectancy of the patient through various therapies.

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Molecular classification of nemaline myopathies: “nontyping” specimens exhibit unique patterns of gene expression

Cited by 13 publications

References 24 publications

Common pathological mechanisms in mouse models for muscular dystrophies

Common pathological mechanisms in mouse models for muscular dystrophies

Heterogeneity of nemaline myopathy cases with skeletal muscle α‐actin gene mutations

Congenital myopathies: diseases of the actin cytoskeleton

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