Clinical utility gene card for: Nemaline myopathy – update 2015

Nowak, Kristen J.; Davis, Mark; Wallgren‐Pettersson, Carina; Lamont, Phillipa; Laing, Nigel G.

doi:10.1038/ejhg.2015.12

Cited by 11 publications

(11 citation statements)

References 57 publications

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“…22 Consequently, shortened thin filaments are likely to be a phenotype that contributes to lower force generation in a large number of patients with thin filament myopathy. The effect of shorter thin filaments on force development is sarcomere- and muscle length–dependent, with a more pronounced effect at greater lengths.…”

Section: Discussionmentioning

confidence: 99%

Mutation‐specific effects on thin filament length in thin filament myopathy

Winter

Joureau

Lee

et al. 2016

Annals of Neurology

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Objective Thin filament myopathies are among the most common nondystrophic congenital muscular disorders, and are caused by mutations in genes encoding proteins that are associated with the skeletal muscle thin filament. Mechanisms underlying muscle weakness are poorly understood, but might involve the length of the thin filament, an important determinant of force generation. Methods We investigated the sarcomere length-dependence of force, a functional assay that provides insights into the contractile strength of muscle fibers as well as the length of the thin filaments, in muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. Results Lower force generation was observed in muscle fibers from patients of all genotypes. In a subset of patients who harbor mutations in NEB and ACTA1, the lower force was associated with downward shifted force–sarcomere length relations, indicative of shorter thin filaments. Confocal microscopy confirmed shorter thin filaments in muscle fibers of these patients. A conditional Neb knockout mouse model, which recapitulates thin filament myopathy, revealed a compensatory mechanism; the lower force generation that was associated with shorter thin filaments was compensated for by increasing the number of sarcomeres in series. This allowed muscle fibers to operate at a shorter sarcomere length and maintain optimal thin–thick filament overlap. Interpretation These findings might provide a novel direction for the development of therapeutic strategies for thin filament myopathy patients with shortened thin filament lengths.

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Section: Discussionmentioning

confidence: 99%

Mutation‐specific effects on thin filament length in thin filament myopathy

Winter

Joureau

Lee

et al. 2016

Annals of Neurology

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“…Over 140 recessive variants have been identified in nebulin (499). Due to the heterogeneity of nemaline myopathy pathology and the large size of nebulin, it has been difficult to study the role of this protein in disease development.…”

Section: Sarcomere—the Basic Contractile Unit Of Striated Musclementioning

confidence: 99%

“…The most common is Duchenne muscular dystrophy (DMD), which is an X-linked recessive disease that affects 1 in 3500 to 5000 males [reviewed in (438)]. Another example is nemaline myopathy, which affects 1 in 50,000 births [reviewed in (499)]. Advances in next generation sequencing have identified numerous mutations in humans.…”

Section: Introductionmentioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

234

193

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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“…In contrast to the phenotypic variability caused by NEB or ACTA1 mutations, KLHL40 mutations are always associated with a poor prognosis (average age of death is 5 months), and prenatal presentations have been documented in greater than 80% of cases . Seven other genetic loci and additional cases of NM not linked to any of the known loci have been identified, with variable clinical presentations .…”

Section: Nemaline Myopathymentioning

confidence: 99%

Prenatal diagnosis of congenital myopathies and muscular dystrophies

et al. 2016

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Congenital myopathies and muscular dystrophies constitute a genetically and phenotypically heterogeneous group of rare inherited diseases characterized by muscle weakness and atrophy, motor delay and respiratory insufficiency. To date, curative care is not available for these diseases, which may severely affect both life-span and quality of life. We discuss prenatal diagnosis and genetic counseling for families at risk, as well as diagnostic possibilities in sporadic cases.

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Clinical utility gene card for: Nemaline myopathy – update 2015

Cited by 11 publications

References 57 publications

Mutation‐specific effects on thin filament length in thin filament myopathy

Mutation‐specific effects on thin filament length in thin filament myopathy

Overview of the Muscle Cytoskeleton

Prenatal diagnosis of congenital myopathies and muscular dystrophies

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