Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

Böhm, Johann; Chevessier, Frédéric; Paula, André Maues De; Koch, Catherine; Attarian, Shahram; Feger, Claire; Hantaı̈, Daniel; Laforêt, Pascal; Ghorab, Karima; Vallat, Jean‐Michel; Fardeau, Michel; Figarella‐Branger, Dominique; Pouget, Jean; Romero, Norma B.; Koch, Marc; Ebel, Claudine; Levy, Nicolas; Krahn, Martin; Eymard, B.; Bartoli, Marc; Laporte, Jocelyn

doi:10.1016/j.ajhg.2012.12.007

Cited by 169 publications

(316 citation statements)

References 31 publications

(49 reference statements)

Supporting

Mentioning

282

Contrasting

Unclassified

Order By: Relevance

“…However, evidence that gain-of-function mutations in STIM1 and ORAI1 can affect human health is only recently starting to emerge. It was shown that mutations in the domain of STIM1 that binds Ca 2+ (EF hand domain) in resting conditions are associated with nonsyndromic myopathy with tubular aggregates (24). Functional studies demonstrated that these mutations cause hyperactivation of the CRAC channel (24).…”

mentioning

confidence: 99%

“…It was shown that mutations in the domain of STIM1 that binds Ca 2+ (EF hand domain) in resting conditions are associated with nonsyndromic myopathy with tubular aggregates (24). Functional studies demonstrated that these mutations cause hyperactivation of the CRAC channel (24). However, it remains unknown whether myopathy with tubular aggregates is caused by the increased activity of the CRAC channel, increased activity of another Ca 2+ channel using STIM1 as a sensor (25), or a function of STIM1 that is unrelated to Ca 2+ signaling, as STIM1 can function independently of ORAI1 (26)(27)(28).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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.

212

331

View full text Add to dashboard Cite

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 ...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

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.

212

331

View full text Add to dashboard Cite

show abstract

“…Interestingly, most STIM1 mutations identified in patients are located within the NH 2 terminal EF hand Ca 2+ binding domain of Stim1, leading to a constitutively active molecule that oligomerizes and clusters at ER/PM junctions independently of Ca 2+ store depletion. Theoretically, such Stim1 molecules should activate Ca 2+ influx independently of how full the intracellular Ca 2+ stores are, a hypothesis confirmed in cells carrying STIM1 mutations, which exhibit dysregulation of Ca 2+ homeostasis characterized by a high resting [Ca 2+ ] and Ca 2+ entry independent of store depletion [84,93,94,96].…”

Section: Disorders Of Soce: Tubular Aggregate Myopathymentioning

confidence: 91%

“…Specifically, they have been identified in several patients with childhood or adult onset tubular aggregate myopathy [82][83][84]93,94] as well as patients with Stormorken syndrome [95,96] a rare disorder characterized by prolonged bleeding, thrombocytopenia/thrombocytopathy, asplenia, intellectual disability, mild hypocalcemia, muscle fatigue and tubular aggregate myopathy. Muscle weakness is generally only mild in the adultonset cases and some of the patients with an ORAI1 mutation presented only with exertional cramps [97].…”

Section: Disorders Of Soce: Tubular Aggregate Myopathymentioning

confidence: 99%

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

View full text Add to dashboard Cite

a b s t r a c tThe physiological process by which Ca 2+ is released from the sarcoplasmic reticulum is called excitationcontraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca 2+ channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca 2+ release channel of the sarcoplasmic reticulum. The released Ca 2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca 2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca 2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca 2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca 2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca 2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca 2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca 2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca 2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca 2+ homeostasis.

show abstract

“…These include autosomal recessive (AR) mutations in GFPT1 and DPAGT1 which encode enzymes in the protein glycosylation pathway and cause CMS (9,10) and mutations in genes encoding proteins involved in calcium homeostasis, STIM1 and ORAI1 in TAM with miosis. (11,12) Although the staining characteristics of TA are relatively uniform, differences have been reported. This variation could be accounted for by different genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

Tubular Aggregates and Cylindrical Spirals Have Distinct Immunohistochemical Signatures

Brady

Healy

Gang

et al. 2016

J Neuropathol Exp Neurol

View full text Add to dashboard Cite

Tubular aggregates and cylindrical spirals are two distinct ultrastructural abnormalities, observed on muscle biopsy, with similar histochemical staining characteristics on light microscopy. Both are found in a wide range of disorders. Recently a number of genetic mutations have been reported in conditions with tubular aggregates in skeletal muscle. It is widely accepted that TA arise from the sarcoplasmic reticulum, but the origin of cylindrical spirals has been less clearly defined. We describe the histopathological features of myopathies with tubular aggregates, including a detailed immunohistochemical analysis of congenital myasthenic syndromes with tubular aggregates due to mutations in GFPT1 and DPAGT1 and myopathies with cylindrical spirals. Our findings support the notion that cylindrical spirals, like tubular aggregates, derive primarily from the sarcoplasmic 3 reticulum, however, immunohistochemistry indicates that different molecular components of the sarcoplasmic reticulum may be involved and can be used to distinguish between these different inclusions. The immunohistochemical differences may also help to guide genetic testing.

show abstract

Constitutive Activation of the Calcium Sensor STIM1 Causes Tubular-Aggregate Myopathy

Cited by 169 publications

References 31 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

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Tubular Aggregates and Cylindrical Spirals Have Distinct Immunohistochemical Signatures

Contact Info

Product

Resources

About