Congenital Myopathies: An Update

Nance, Jessica; Dowling, James J.; Gibbs, Elizabeth M.; Bönnemann, Carsten G.

doi:10.1007/s11910-012-0255-x

Cited by 109 publications

(105 citation statements)

References 102 publications

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“…A previous study noted that the presence of nemaline bodies does not correlate with the severity of the disease (2). Instead, it is believed that decreased contractility due to primary defects in the sarcomere thin filament is the underlying cause for symptoms in NM (10). This hypothesis is supported by studies with P1 NEB-deficient mice, which have a dramatic loss in muscle contractility, with no visible sarcomere defects (36,45).…”

Section: Discussionmentioning

confidence: 97%

“…Tropomyosin and the troponin complex regulate myosin-actin crossbridges in a calcium-dependent manner. In NM, it is believed that mutations disrupting thin filament proteins result in reduced force generation and subsequent myopathy (10). However, mutations in 3 proteins with no established association with the sarcomere thin filament, kelch repeat and BTB (POZ) domain containing 13 (KBTBD13), kelch-like family member 40 (KLHL40), and KLHL41, have been shown recently to cause NM in patients by an unknown mechanism (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

Garg¹,

ORourke

Long³

et al. 2014

J. Clin. Invest.

109

126

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Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klhl40 -/-mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

Garg¹,

ORourke

Long³

et al. 2014

J. Clin. Invest.

109

126

View full text Add to dashboard Cite

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“…CNMs are a subset of the broader category of muscle diseases called congenital myopathies [4]. CNMs are unified by common histopathologic features on muscle biopsy, most notably the presence of large, centrally located nuclei in at least 10% (and often in excess of 25%) of muscle fibers [41].…”

Section: Cnmsmentioning

confidence: 99%

“…Recently, defects in triad structure and function have emerged as important underlying causes and/or contributors to a wide range of human muscle diseases [4]. Broadly speaking, alterations in the triad can be grouped into primary "triadopathes"-genetic myopathies where the primary pathogenic mechanism involves an alteration in triad functionand diseases with secondary triad defects.…”

Section: Introductionmentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

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“…These myopathies have characteristic histological hallmarks in muscle biopsy allowing the differential classification in distinct entities: centronuclear myopathy (CNM), core myopathy (centralcore and minicore diseases) and nemaline rod myopathy. 1,2 In CNM, the most prominent histopathological features include hypotrophy of type 1 fibers and a high frequency of centrally located nuclei with perinuclear halos lacking myofilaments and occupied by mitochondrial and glycogen aggregates. 1 Several genes are reported to be associated with CNM; these include MTM1 in the X-linked form, 3,4 DNM2 and MTMR14 in the autosomal dominant forms, [4][5][6] BIN1 and RYR1 associated with the autosomal recessive forms.…”

Section: Introductionmentioning

confidence: 99%

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

Oliveira

Kreß

et al. 2012

Eur J Hum Genet

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Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin -a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligationdependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343_444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

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Congenital Myopathies: An Update

Cited by 109 publications

References 102 publications

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

KLHL40 deficiency destabilizes thin filament proteins and promotes nemaline myopathy

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

Expanding the MTM1 mutational spectrum: novel variants including the first multi-exonic duplication and development of a locus-specific database

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