Absence of β-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

Monnier, Nicole; Lunardi, Joël; Marty, Isabelle; Mézin, P.; Labarre-Vila, Annick; Dieterich, Klaus; Jouk, Pierre‐Simon

doi:10.1016/j.nmd.2008.11.009

Cited by 59 publications

(43 citation statements)

References 31 publications

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“…Other associated features are cleft palate, deafness, short stature and scoliosis [52]. Escobar syndrome is genetically heterogeneous and has been described in prenatal myasthenia associated with mutations in the gamma subunit of the nicotinergic acetylcholine receptor gene CHRNG and with mutations in TPM2 [20,53].…”

Section: Escobar Syndromementioning

confidence: 99%

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Myopathies associated with β-tropomyosin mutations

Tajsharghi

Ohlsson

Palm

et al. 2012

Neuromuscular Disorders

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Section: Escobar Syndromementioning

confidence: 99%

“…In addition, Escobar syndrome associated with nemaline myopathy has been found in association with the total absence of b-Tm [20].…”

Section: Introductionmentioning

confidence: 99%

Myopathies associated with β-tropomyosin mutations

Tajsharghi

Ohlsson

Palm

et al. 2012

Neuromuscular Disorders

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“…MH susceptibility and CCD are allelic conditions stemming from predominantly dominant mutations in the type 1 ryanodine receptor (RYR1) gene. RYR1 encodes the skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1) (12)(13)(14), and more than 178 mutations have been identified throughout the RYR1 gene to date, most of them missense mutations, with a few being deletions and splicing site mutations (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A few rare mutations conferring MH susceptibility have been associated with mutations in CaV1.1, the major subunit of the sarcolemmal slow voltage-gated Ca 2ϩ channel (CACNA1S, dihydropyridine receptor) (25,26).…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

Giulivi

Ross-Inta

Omanska-Klusek

et al. 2011

Journal of Biological Chemistry

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Malignant hyperthermia (MH) and central core disease in humans have been associated with mutations in the skeletal ryanodine receptor (RyR1). Heterozygous mice expressing the human MH/central core disease RyR1 R163C mutation exhibit MH when exposed to halothane or heat stress. Considering that many MH symptoms resemble those that could ensue from a mitochondrial dysfunction (e.g. metabolic acidosis and hyperthermia) and that MH-susceptible mice or humans have a higher than normal cytoplasmic Ca 2؉ concentration at rest, we evaluated the role of mitochondria in skeletal muscle from R163C compared with wild type mice under basal (untriggered) conditions. R163C skeletal muscle exhibited a significant increase in matrix Ca 2؉ , increased reactive oxygen species production, lower expression of mitochondrial proteins, and higher mtDNA copy number. These changes, in conjunction with lower myoglobin and glycogen contents, Myh4 and GAPDH transcript levels, GAPDH activity, and lower glucose utilization suggested a switch to a compromised bioenergetic state characterized by both low oxidative phosphorylation and glycolysis. The shift in bioenergetic state was accompanied by a dysregulation of Ca 2؉ -responsive signaling pathways regulated by calcineurin and ERK1/2. Chronically elevated resting Ca 2؉ in R163C skeletal muscle elicited the maintenance of a fast-twitch fiber program and the development of insulin resistance-like phenotype as part of a metabolic adaptation to the R163C RyR1 mutation.

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“…16 TPM2: Two heterozygous, dominant missense variants causing nemaline myopathy are known. 17 Also a homozygous null variant in a patient with nemaline and Escobar syndrome, 18 and a dominant heterozygous variant in a mother with nemaline myopathy and her daughter with cap myopathy 19 have been identified. A K7del variant was identified in a family with nemaline bodies and minicores (presenting as a distal myopathy), and also in four unrelated families with distal arthrogryposis type 7 with nemaline bodies.…”

Section: Mutational Spectrummentioning

confidence: 99%