Affinage

CASQ1

Calsequestrin-1 · UniProt P31415

Length
396 aa
Mass
45.2 kDa
Annotated
2026-06-09
18 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CASQ1 is the major Ca2+-storage protein of the junctional sarcoplasmic reticulum (jSR) in skeletal muscle, where it buffers luminal Ca2+ and directly shapes the structure of the terminal cisternae: reintroduction of CASQ1 into null fibers fills and widens the cisternal lumen and restores both peak Ca2+ transient amplitude and sustained Ca2+ release during tetanic stimulation (PMID:22049211). It is retained at the RyR-bearing jSR membrane through periodically spaced anchors built primarily from triadin, with junctin contributing; loss of these anchors disorganizes the jSR and depletes CASQ1, with SR Ca2+ content tracking the amount of CASQ1 retained (PMID:22768324). CASQ1 stores Ca2+ by Ca2+-dependent polymerization into elongated polymers, and it serves as a negative regulator of store-operated Ca2+ entry (SOCE) (PMID:28895244, PMID:39126637) while, together with JP45, modulating Cav1.1 (DHPR) channel activity to set muscle contraction strength (PMID:23443569). Disease-causing CASQ1 mutations converge on two coupled defects: impaired Ca2+-dependent polymerization/aggregation that degrades Ca2+ storage and SR Ca2+ release (PMID:25116801, PMID:28895244), and protein mislocalization and misfolding that produce SR/ER-derived vacuoles, aggregates colocalizing with SQSTM1/p62, and activation of ER stress and proteostasis pathways underlying a tubular aggregate myopathy (PMID:25116801, PMID:33786938, PMID:41699400).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2011 High

    Establishing whether CASQ1 is causally responsible for jSR structure and Ca2+ handling rather than merely correlated answered whether the protein has a direct structural-functional role.

    Evidence In vivo cDNA electrotransfer rescue in CASQ1-null mouse fibers with EM and Ca2+ transient readouts

    PMID:22049211

    Open questions at the time
    • Did not resolve the molecular partners anchoring CASQ1 at the jSR
    • Mechanism of Ca2+-dependent polymerization not directly measured
  2. 2012 High

    Identifying which membrane proteins anchor CASQ1 to the RyR-bearing jSR clarified how CASQ1 is positioned and retained at the Ca2+ release site.

    Evidence Triadin-null, junctin-null, and double-null mouse models with Ca2+ imaging, microelectrodes, and EM

    PMID:22768324

    Open questions at the time
    • Stoichiometry and direct biochemical interface between CASQ1 and triadin not defined
    • Does not address CASQ1 role in SOCE or DHPR modulation
  3. 2013 High

    Testing the combined loss of JP45 and CASQ1 revealed an unexpected role for CASQ1 in regulating Cav1.1 channel activity and contraction strength.

    Evidence JP45/CASQ1 double-knockout mice with Ca2+ imaging, Cav1.1 patch-clamp, and force measurements

    PMID:23443569

    Open questions at the time
    • Direct physical interaction between CASQ1 and Cav1.1 not established
    • Molecular route by which CASQ1/JP45 loss enhances Cav1.1 influx unresolved
  4. 2014 High

    A patient missense mutation in a high-affinity Ca2+-binding site connected impaired polymerization to altered Ca2+ release and SR vacuole formation, defining a disease mechanism.

    Evidence p.Asp244Gly expression in COS-7 cells and myotubes, EM, and Ca2+ release kinetics in fibers

    PMID:25116801

    Open questions at the time
    • Did not separate the polymerization defect from downstream proteostasis effects
    • In vivo consequences over time not assessed
  5. 2017 High

    Characterizing multiple mutations biochemically and functionally linked loss of Ca2+-dependent aggregation to reduced Ca2+ storage and loss of SOCE inhibition.

    Evidence Turbidity/light scattering, limited trypsin proteolysis, caffeine stimulation of fibers, and SOCE measurements in cells

    PMID:28895244

    Open questions at the time
    • Mechanism by which CASQ1 inhibits SOCE not structurally defined
    • Differential severity among mutations not fully explained
  6. 2021 High

    A knock-in model showed that the D244G mutation drives mislocalization to the ER and chronic proteostatic stress, establishing misfolding/mislocalization as a myopathy driver beyond Ca2+ buffering loss.

    Evidence D244G knock-in mouse with fractionation, Ca2+ release, ER stress and mTOR markers, proteasome assays, and EM

    PMID:33786938

    Open questions at the time
    • Whether proteostatic collapse is reversible not tested
    • Trigger linking ER accumulation to mTOR activation unresolved
  7. 2024 High

    Reconstituting TAM-associated mutants in knockout fibers confirmed CASQ1 as a negative regulator of skeletal muscle SOCE.

    Evidence Expression of CASQ1 mutants in Casq1-knockout mouse fibers with intracellular Ca2+ and SOCE measurements

    PMID:39126637

    Open questions at the time
    • Molecular partners through which CASQ1 inhibits SOCE not identified
    • Does not address structural jSR consequences
  8. 2025 Medium

    A frameshift variant producing an extended, aggregation-prone protein and a variant altering triadic SR-feet architecture broadened the spectrum of CASQ1 pathogenic mechanisms.

    Evidence Genome/exome sequencing, western blot of patient muscle, cell transfection, and EM of patient biopsies

    PMID:41313434

    Open questions at the time
    • Aggregation mechanism from a single study
    • Functional Ca2+ handling consequences not measured
  9. 2026 Medium

    Co-localization of an aggregating CASQ1 mutant with SQSTM1/p62 and PERK in patient muscle directly tied CASQ1 misfolding to autophagy markers and ER stress activation.

    Evidence HeLa expression and patient muscle immunofluorescence for SQSTM1/p62 and PERK; exome sequencing

    PMID:41699400

    Open questions at the time
    • No functional rescue performed
    • Causal order between aggregation and PERK activation not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular interface by which CASQ1 inhibits store-operated Ca2+ entry and the direct structural basis of its modulation of Cav1.1 remain undefined.
  • No structural model of CASQ1-SOCE machinery interaction
  • No defined CASQ1-Cav1.1 physical interface
  • Stoichiometry of CASQ1-triadin anchoring undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-397014 Muscle contraction 2
Partners
ASPHCACNA1SJSRP1TRDN
Complex memberships
junctional SR (triadin-CASQ1 anchor complex)

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 Triadin (not junctin) is the main component of periodically located anchors connecting CASQ1 to the RyR-bearing junctional SR membrane. Both triadin and junctin are required for structural organization of jSR cisternae and retention of CASQ1 within them, but triadin disruption has the more profound effect. CASQ1 presence is responsible for the wide lumen of jSR cisternae. Changes in SR Ca2+ content and resting [Ca2+] in null muscles are directly correlated to the effect of each deletion on CASQ1 content and organization. Triadin-null, junctin-null, and triadin/junctin double-null mouse models; Ca2+ imaging; Ca2+-selective microelectrodes; electron microscopy PloS one High 22768324
2011 Exogenously reintroduced CASQ1 correctly targets to junctional SR, fills terminal cisternae lumen and increases its width, rescues peak Ca2+ transient amplitude, and allows sustained cytosolic Ca2+ during tetanic stimulation in CASQ1-null muscle fibers, establishing that CASQ1 plays a direct role in both Ca2+ homeostasis and terminal cisternae structure. In vivo cDNA electrotransfer into flexor digitorum brevis of CASQ1-null mice; immunofluorescence/confocal microscopy; electron microscopy; Ca2+ transient measurements American journal of physiology. Cell physiology High 22049211
2013 JP45 and CASQ1 together modulate Cav1.1 (DHPR) channel activity to strengthen skeletal muscle contraction. In JP45/CASQ1 double knockout mice, Ca2+ transients evoked by tetanic stimulation result from massive Ca2+ influx due to enhanced Cav1.1 channel activity, which compensatorily restores muscle strength. JP45/CASQ1 double knockout mice; muscle fiber Ca2+ transient measurements; patch-clamp of Cav1.1; force measurements Nature communications High 23443569
2014 The CASQ1 p.Asp244Gly mutation, located in a high-affinity Ca2+-binding site, markedly reduces ability of CASQ1 to form elongated polymers and alters kinetics of Ca2+ release in muscle fibers. Expression in cultured myotubes and in vivo mouse fibers induces formation of electron-dense SR vacuoles containing aggregates of mutant CASQ1 and other SR proteins. Missense mutation in patients; expression in COS-7 cells and myotubes; electron microscopy; Ca2+ release kinetics measurement in muscle fibers Human mutation High 25116801
2017 CASQ1 mutations p.Asp44Asn and p.Gly103Asp reduce Ca2+-dependent aggregation of CASQ1 protein and increase susceptibility to trypsin proteolysis in the presence of Ca2+. All three mutations (p.Asp44Asn, p.Gly103Asp, p.Ile385Thr) reduce ability to store Ca2+ in eukaryotic cells. p.Gly103Asp in patient muscle fibers significantly reduces response to caffeine stimulation. p.Ile385Thr and p.Asp44Asn reduce the inhibitory effect of CASQ1 on store-operated Ca2+ entry (SOCE). Turbidity and dynamic light scattering at increasing Ca2+ concentrations; limited trypsin proteolysis assay; single muscle fiber caffeine stimulation; eukaryotic cell expression with Ca2+ store measurements; SOCE measurements Human mutation High 28895244
2021 The D244G mutation causes CASQ1 to partially dissociate from junctional SR and accumulate in the ER, reducing SR Ca2+ release. Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate proteasomal clearance, and elevation of protein aggregates and lysosomes, indicating that CASQ1 mislocalization and misfolding drive the myopathy. D244G knock-in mouse model; subcellular fractionation; Ca2+ release measurements; ER stress markers; mTOR signaling assays; proteasome activity assays; electron microscopy FASEB journal High 33786938
2024 TAM-associated CASQ1 mutants expressed in muscle fibers from Casq1 knockout mice have impaired ability to store Ca2+ and lose their ability to inhibit skeletal muscle SOCE, confirming that CASQ1 functions as a negative regulator of store-operated Ca2+ entry in skeletal muscle. Expression of CASQ1 mutants in Casq1 knockout mouse muscle fibers; intracellular Ca2+ measurements; SOCE measurements Journal of muscle research and cell motility High 39126637
2025 A CASQ1 frameshift variant p.(Gly383Alafs*39) results in protein extension (confirmed by western blotting) and the extended protein forms aggregates in cell-transfection studies. Morphological changes in SR-feet (triadic junctions) are observed in patients carrying the p.(Glu89Lys) variant, indicating a novel pathogenetic mechanism involving disruption of junctional SR architecture. Genome/exome sequencing; western blotting of patient muscle; cell-transfection studies; electron microscopy of patient biopsies Journal of neurology Medium 41313434
2026 CASQ1 p.Asp244His mutant expressed in HeLa cells shows aggregation tendency. In patient muscle, the mutant CASQ1 protein aggregates around vacuole edges and co-localizes with SQSTM1/p62 and the ER stress marker PERK, linking CASQ1 misfolding to ER stress activation. In vitro expression in HeLa cells; immunofluorescence with SQSTM1/p62 and PERK co-localization; whole-exome sequencing; muscle biopsy Journal of human genetics Medium 41699400

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy. Human mutation 60 28895244
2014 A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates. Human mutation 52 25116801
2012 Triadin/Junctin double null mouse reveals a differential role for Triadin and Junctin in anchoring CASQ to the jSR and regulating Ca(2+) homeostasis. PloS one 50 22768324
2004 Polymorphism in the calsequestrin 1 (CASQ1) gene on chromosome 1q21 is associated with type 2 diabetes in the old order Amish. Diabetes 36 15561962
2013 Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice. Nature communications 33 23443569
2011 Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice. American journal of physiology. Cell physiology 29 22049211
2004 Calsquestrin 1 (CASQ1) gene polymorphisms under chromosome 1q21 linkage peak are associated with type 2 diabetes in Northern European Caucasians. Diabetes 27 15561963
2013 CASQ1 gene is an unlikely candidate for malignant hyperthermia susceptibility in the North American population. Anesthesiology 22 23460944
2018 The clinical spectrum of CASQ1-related myopathy. Neurology 21 30258016
2015 A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia. Journal of medical genetics 13 26136523
2022 CASQ1-related myopathy: The first report from China and the literature review. Clinical case reports 9 36514469
2021 Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7 33786938
2014 An association study of CASQ1 gene polymorphisms and heat stroke. Genomics, proteomics & bioinformatics 7 24887214
2024 TAM-associated CASQ1 mutants diminish intracellular Ca2+ content and interfere with regulation of SOCE. Journal of muscle research and cell motility 4 39126637
2023 Acute aerobic exercise regulation of myocardial calcium homeostasis involves CASQ1, CASQ2, and TRDN. Journal of applied physiology (Bethesda, Md. : 1985) 3 37589058
2025 Characterization of novel CASQ1 variants in two families with unusual phenotypic features. Journal of neurology 2 41313434
2007 Studies of association of the CASQ1 rs2275703 polymorphism in relation to type 2 diabetes and related quantitative metabolic traits among 7,088 Danish whites. Molecular genetics and metabolism 2 17681849
2026 Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families. Journal of human genetics 0 41699400

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