Familial neuromuscular disease with tubular aggregates

Pierobon-Bormioli, Sandra; Armani, Mario; Ringel, Steven P.; Angelini, C.; Vergani, L; Betto, Romeo; Salviati, G.

doi:10.1002/mus.880080405

Cited by 43 publications

(23 citation statements)

References 26 publications

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“…However, the mechanism(s) responsible for the formation of these aggregates is unknown. A relationship between disordered Ca 2+ metabolism and tubular aggregates has been suggested as early as 1985 (51,52). We propose that disordered, sustained Ca 2+ entry through the CRAC channel over long periods of time results in an environment within the sarcoplasmic reticulum that is hostile to protein folding, thus initiating the formation of tubular aggregates.…”

Section: Discussionmentioning

confidence: 88%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

345

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Signaling through the store-operated Ca 2+ release-activated Ca 2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca 2+ homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca 2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca 2+ -dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca 2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. human genetics | calcium signaling C a 2+ influx in response to the depletion of intracellular Ca 2+ stores, or store-operated Ca 2+ entry, constitutes one of the major routes of Ca 2+ entry in all animal cells (1). Under physiological conditions, Ca 2+ influx is activated in response to numerous G protein-coupled receptors and receptor tyrosine kinases signaling via inositol-1,4,5-trisphosphate as a second messenger (2). Store-operated Ca 2+ entry is mediated primarily by the Ca 2+ release-activated Ca 2+ (CRAC) channel (3), which consists of the pore-forming subunits ORAI1-3 (or CRAC modulators 1-3) and Ca 2+ sensors, STIM1 and STIM2 (4-7). STIM proteins reside in the membrane of endoplasmic reticulum (ER), whereas ORAI proteins reside in the plasma membrane. STIM1 is a single transmembrane-spanning protein (8-12) that, in resting cells, exists as a dimer that binds Ca 2+ through two EF hand-containing domains located in the ER lumen (13). Depletion of Ca 2+ in the ER induces a series of molecular events in the conformation and localization of STIM1, initiated by the formation of higher-order oligomers, protein unfolding, and accumulation at discrete sites in the cell where the ER membrane is in close proximity to the plasma membrane (11,(13)(14)(15)(16). In these sites, STIM1 binds to the cytosolic C and N termini of ORAI1 (17, 18), resulting in channel activation and generation of a highly Ca 2+ -selective CRAC current, or I CRAC (3,19,20). I CRAC is responsible not only ...

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Section: Discussionmentioning

confidence: 88%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

216

345

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“…The diseases include periodic paralysis (9), hyperaldosteronism (10), facioscapulohumeral dystrophy with aminoaciduria (11), myasthenia gravis (12), exercise-induced cramps (13), alcohol, caffeine, or drugs such as zidovudine (14,15). However, patients with these tubular aggregates may present as a specific type of primary myopathy (1)(2)(3)(4)(5)(6)(7)(8). Primary tubular aggregate myopathy of familial occurrence was first reported by De Groot and Arts (1) in 1982.…”

Section: Discussionmentioning

confidence: 99%

“…Primary tubular aggregate myopathy of familial occurrence was first reported by De Groot and Arts (1) in 1982. To date, 24 patients from 7 families have been reported (1)(2)(3)(4)(5)(6)(7)(8). Clinically, the age of onset ranged from 6 to 45 yr (mean: 25.4 yr).…”

Section: Discussionmentioning

confidence: 99%

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Tubular Aggregate Myopathy: A Case Report

Kim

Suh

2003

J Korean Med Sci

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We report a first Korean case of presumably dominantly inherited primary tubular aggregate myopathy in a 19-yr-old man, who presented with slowly progressive proximal muscle stiffness and weakness. In hematoxylin and eosin stain, it showed subsarcolemmal, or central pale basophilic granular vacuoles, which stained red with modified Gomori' s trichrome and intensive blue with nicotinamide adenonine dinucleotide-tetrazolium reductase, respectively. Ultrastructurally, aggregates of 60 nm-sized hexagonal tubules were found in both type 1 and type 2 fibers.

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“…An unusual accumulation of elongated SR-derived tubules, defined tubular aggregates (TAs) occurs in a variety of muscle conditions. TAs were first described as proliferations of the SR in a human myopathy (Engel 1964;Engel et al 1970) and found to be a relatively nonspecific alteration in patients with various neuromuscular disorders including, but not limited to, periodic paralysis, some types of congenital myasthenic syndromes, and myotonic disorders (Rosenberg et al 1985;Pierobon-Bormioli et al 1985;Morgan-Hughes 1998). Since the human and animal diseases that present these morphological alterations are quite varied, and TAs are sometimes also found in asymptomatic probands (Niakan et al 1985;Engel et al 1970;Muller et al 2001), the relationship of TAs to disease and/or particular physiological states is still debated.…”

Section: Introductionmentioning

confidence: 99%

Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement

Boncompagni

Protasi²,

Franzini‐Armstrong

2011

AGE

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Tubular aggregates (TAs), ordered arrays of elongated sarcoplasmic reticulum (SR) tubules, are present in skeletal muscle from patients with myopathies and are also experimentally induced by extreme anoxia. In wild-type mice TAs develop in a clear age-, sex-(male), and fiber type-(fast twitch) dependence. However, the events preceding the appearance of TAs have not been explored. We investigated the sequential stages leading to the initial appearance and maturation of TAs in EDL from male mice. TAs' formation requires two temporally distinct steps that operate via different mechanisms. Initially (before 1 year of age), the SR Ca 2+ binding protein calsequestrin (CASQ) accumulates specifically at the I band level causing swelling of free SR cisternae. In the second stage, the enlarged SR sacs at the I band level extend into multiple, longitudinally oriented tubules with a full complement of sarco(endo)plasmic reticulum Ca 2+ ATPases (SERCA) in the membrane and CASQ in the lumen. Tubules gradually acquire a regular cylindrical shape and uniform size apparently in concert with partial crystallization of SERCA. Multiple, small TAs associate to form fewer mature TAs of very large size. Interestingly, in fibers from CASQ1-knockout mice abnormal aggregates of SR tubules have different conformation and never develop into ordered aggregates of straight cylinders, possibly due to lack of CASQ accumulation. We conclude that TAs do not arise abruptly but are the final result of a gradually changing SR architecture and we suggest that the crystalline ATPase within the aggregates may be inactive.

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Familial neuromuscular disease with tubular aggregates

Cited by 43 publications

References 26 publications

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Tubular Aggregate Myopathy: A Case Report

Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement

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