CASQ1

CASQ1 is the principal luminal Ca²⁺-buffering protein of the junctional sarcoplasmic reticulum (jSR) in fast-twitch skeletal muscle, where it undergoes Ca²⁺-dependent polymerization to store Ca²⁺, maintains jSR cisternae structural integrity, and regulates both ryanodine receptor–mediated Ca²⁺ release and store-operated Ca²⁺ entry (SOCE) (PMID:22049211, PMID:39126637). CASQ1 is anchored to the jSR membrane through Triadin and Junctin, which are required for its retention and for normal jSR architecture, with Triadin playing the dominant structural role (PMID:22768324). CASQ1 additionally modulates Cav1.1 (DHPR) channel activity in concert with JP45, providing an alternative pathway for Ca²⁺ influx when SR stores are depleted (PMID:23443569). Disease-causing mutations that impair Ca²⁺-dependent polymerization lead to CASQ1 mislocalization to the ER, aggregate formation, ER stress with PERK activation, and vacuolar myopathy characteristic of tubular aggregate myopathy (TAM) (PMID:25116801, PMID:33786938, PMID:41699400).

1. 2011 High

   Whether CASQ1 is required for both Ca²⁺ homeostasis and jSR structural integrity was unresolved; rescue of CASQ1-null fibers with CASQ1 cDNA restored terminal cisternae width, peak Ca²⁺ transient amplitude, and sustained Ca²⁺ during tetanus, establishing that CASQ1 is essential for both luminal Ca²⁺ storage and jSR architecture.

   Evidence In vivo cDNA electrotransfer rescue in CASQ1-null mouse FDB fibers with confocal, EM, and Ca²⁺ transient measurements

   PMID:22049211

   Open questions at the time

   • How CASQ1 polymerization directly determines cisternae lumen width is not structurally resolved
   • Whether CASQ2 can substitute for CASQ1 in fast-twitch fibers is not tested
2. 2012 High

   How CASQ1 is physically anchored within the jSR was unclear; knockout studies showed Triadin forms periodic anchors connecting CASQ1 to RyR-bearing membranes, with both Triadin and Junctin required for CASQ1 retention, establishing the molecular tethering mechanism.

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

   PMID:22768324

   Open questions at the time

   • Direct binding stoichiometry between Triadin, Junctin, and CASQ1 polymers is not defined
   • Whether additional luminal anchoring partners exist is untested
3. 2013 High

   Whether CASQ1 influences sarcolemmal Ca²⁺ channel activity was unknown; double knockout of JP45 and CASQ1 revealed compensatory enhancement of Cav1.1 channel activity providing massive Ca²⁺ influx that rescued tetanic force, establishing a functional link between CASQ1/JP45 and DHPR gating.

   Evidence JP45/CASQ1 double-KO mouse; electrophysiology of Cav1.1, Ca²⁺ transients, and force measurements in isolated fibers

   PMID:23443569

   Open questions at the time

   • Whether CASQ1 and JP45 interact directly or signal indirectly via luminal Ca²⁺ is unresolved
   • The molecular mechanism by which CASQ1/JP45 loss upregulates Cav1.1 activity is not identified
4. 2014 High

   How disease-associated CASQ1 mutations cause myopathy was unknown; the p.Asp244Gly mutation was shown to impair Ca²⁺-dependent polymerization, form electron-dense aggregates in SR vacuoles, and alter Ca²⁺ release kinetics, establishing defective polymerization as a pathogenic mechanism.

   Evidence Mutant expression in COS-7 cells, myotubes, and in vivo mouse fibers; EM and Ca²⁺ release measurements

   PMID:25116801

   Open questions at the time

   • Atomic-resolution structure of wild-type versus D244G polymer is lacking
   • Whether aggregates are cytotoxic independently of Ca²⁺ dysregulation is untested
5. 2017 High

   Whether multiple TAM mutations share a common biochemical defect was unclear; three novel mutations all reduced Ca²⁺ storage capacity, with two also impairing SOCE inhibition, consolidating the view that loss of Ca²⁺-dependent polymerization and loss of SOCE regulation are convergent disease mechanisms.

   Evidence Turbidity, DLS, limited proteolysis, single-fiber caffeine stimulation, and cell-based Ca²⁺/SOCE assays

   PMID:28895244

   Open questions at the time

   • How CASQ1 polymerization state is communicated across the jSR membrane to inhibit SOCE is mechanistically undefined
   • Genotype–phenotype correlation across the full spectrum of TAM mutations is incomplete
6. 2021 High

   The downstream cellular consequences of CASQ1 mislocalization were unexplored; a D244G knock-in mouse showed that mutant CASQ1 accumulates in the ER, triggering ER stress, mTOR activation, inadequate proteasomal clearance, and lysosome/aggregate accumulation, placing CASQ1 mutations upstream of proteostasis failure in aged muscle.

   Evidence Knock-in mouse model with subcellular fractionation, Ca²⁺ measurements, ER stress and mTOR markers, proteasome activity assays, and EM

   PMID:33786938

   Open questions at the time

   • Whether ER stress is a primary driver of myopathy or secondary to Ca²⁺ dysregulation is not dissected
   • Therapeutic targeting of mTOR or proteasome in this model has not been reported
7. 2024 High

   Whether CASQ1 is a direct negative regulator of SOCE in intact skeletal muscle fibers was not definitively shown; expression of TAM-associated mutants in CASQ1-null fibers confirmed that wild-type CASQ1 inhibits SOCE and that disease mutations abolish this inhibition, establishing CASQ1 as a native SOCE regulator.

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

   PMID:39126637

   Open questions at the time

   • The SOCE channel target (STIM1/Orai1 axis components) through which CASQ1 acts is not identified
   • Whether CASQ1-mediated SOCE inhibition is relevant in slow-twitch or cardiac muscle is untested
8. 2025 Medium

   Whether C-terminal CASQ1 alterations represent a distinct pathomechanism was unknown; a frameshift variant producing a protein extension formed aggregates and disrupted triad/SR-feet morphology, suggesting that aberrant C-terminal extension is a novel pathogenetic mechanism.

   Evidence Western blot of patient muscle, cell-transfection aggregation assay, and EM of patient biopsies

   PMID:41313434

   Open questions at the time

   • Functional Ca²⁺ measurements with the frameshift variant are lacking
   • Single patient/lab study, not independently replicated
   • Whether the extended protein enters normal polymerization is untested

• The molecular mechanism by which CASQ1 polymerization state signals across the jSR membrane to regulate SOCE and Cav1.1 remains undefined, and whether ER stress or Ca²⁺ dysregulation is the primary driver of vacuolar myopathy has not been dissected.
• No structural model of CASQ1 polymer in complex with Triadin/Junctin/RyR exists
• The signaling relay from luminal CASQ1 to plasma membrane SOCE channels is unknown
• Whether therapeutic correction of polymerization can reverse myopathy is untested