Myopathy Due To Calsequestrin And SERCA1 Protein Overload

Mendelian MONDO:0014546 Pathograph 34 Show in embeddings browser Protein aggregate myopathy Hereditary skeletal muscle disorder

An autosomal dominant skeletal-muscle disorder caused by heterozygous CASQ1 variants that disturb the calcium-dependent polymerisation of calsequestrin-1, the main calcium buffer of the sarcoplasmic reticulum in fast-twitch fibres. Most patients carry the Italian founder allele p.Asp244Gly and show optically empty vacuoles in type II fibres that contain aggregated calsequestrin, SERCA1 and other sarcoplasmic reticulum proteins. A smaller group of alleles instead produces tubular aggregates. Presentation is usually in adulthood with exercise intolerance, myalgia, cramps, fatigue and raised creatine kinase, sometimes with no symptoms beyond hyperCKaemia, followed in some patients by slowly progressive proximal weakness with quadriceps atrophy and scapular winging.

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1
Inheritance
12
Pathophys.
13
Phenotypes
2
Gaps
34
Pathograph
1
Genes
8
Variants
2
Subtypes
1
Differentials
1
Models
3
References
1
Deep Research
👪

Inheritance

1
Autosomal dominant HP:0000006
Heterozygous CASQ1 variants segregate as an autosomal dominant trait in families. De novo occurrence has been reported.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:26136523 SUPPORT Human Clinical
"In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia"
Dominant segregation in three families.
PMID:41313434 SUPPORT BACKGROUND Human Clinical
"To date, seven pathogenic variants have been described, all dominant missense variants."
Summarises the dominant inheritance of known alleles.
PMID:38818562 SUPPORT Human Clinical
"The same variant was not found in his unaffected parents."
A de novo occurrence.
◆

Subtypes

2
Vacuolar aggregate myopathy (CASQ1 p.Asp244Gly / p.Asp244His)
CASQ1 hgnc:1512 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CASQ1 (hgnc:1512). hgnc:1512 is a gene from the HUGO Gene Nomenclature Committee.
The common presentation, caused by the Italian founder allele p.Asp244Gly and by p.Asp244His at the same residue. Muscle biopsy shows vacuoles in type II fibres that appear empty on routine stains but contain aggregated calsequestrin, SERCA1, RyR1 and other sarcoplasmic reticulum proteins. Store-operated calcium entry is not increased in knock-in mice carrying p.Asp244Gly. Histology overlaps between alleles: a de novo p.Asp244His patient had both vacuoles and tubular aggregates.
Show evidence (4 references)
PMID:30258016 SUPPORT Human Clinical
"Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
Defines the vacuolar histopathology of the founder allele in the largest cohort.
PMID:41699400 SUPPORT Human Clinical
"Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers."
The p.Asp244His allele produces the same vacuolar picture.
PMID:33786938 SUPPORT Model Organism
"SR Ca2+ stores are not significantly depleted and SOCE is not increased in fibers of DG compared to WT mice"
The vacuolar founder allele does not engage the store-operated calcium entry mechanism of the tubular aggregate alleles.
+ 1 more reference
CASQ1 tubular aggregate myopathy
CASQ1 hgnc:1512 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CASQ1 (hgnc:1512). hgnc:1512 is a gene from the HUGO Gene Nomenclature Committee.
Caused by other CASQ1 missense alleles, including p.Asp44Asn, p.Gly103Asp and p.Ile385Thr. Muscle biopsy shows tubular aggregates, sometimes alongside vacuoles. These alleles reduce calcium storage by calsequestrin and, in mouse muscle fibres, all three lose its inhibition of store-operated calcium entry, a mechanism shared with the STIM1 and ORAI1 tubular aggregate myopathies.
Show evidence (2 references)
PMID:28895244 SUPPORT Human Clinical
"Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy."
Establishes CASQ1 tubular aggregate myopathy as an allelic presentation.
PMID:30258016 SUPPORT Human Clinical
"The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
Contrasts the tubular aggregate histopathology of p.Gly103Asp with the vacuoles of p.Asp244Gly.
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Discussions and Knowledge Gaps

2
Are the subclinical cardiac abnormalities seen in some CASQ1 myopathy patients part of the disease, given that the heart expresses CASQ2 rather than CASQ1?
KNOWLEDGE GAP OPEN casq1_cardiac_involvement
Attached to
disease#Myopathy Due To Calsequestrin And SERCA1 Protein Overload
Three of 22 patients in the largest cohort had subclinical cardiac findings, but the report gives no mechanism, and a later literature review notes that cardiac insufficiency is rarely seen. No cardiac phenotype is recorded in this entry.
Show evidence (2 references)
PMID:30258016 SUPPORT Human Clinical
"Three patients presented subclinical cardiac abnormalities."
The cohort report of cardiac findings.
PMID:36514469 SUPPORT REVIEW SYNTHESIS Human Clinical
"Despite experimental evidence suggesting that CASQ1 deficiency is causally related to malignant hyperthermia-like arrhythmia, respiratory and cardiac insufficiency have rarely appeared in CASQ1-related cases."
Literature review finding cardiac involvement uncommon.
How much of the vacuolar myopathy is driven by reduced sarcoplasmic reticulum calcium release, and how much by ER stress and failed clearance of aggregated protein?
KNOWLEDGE GAP OPEN casq1_calcium_versus_proteotoxic_drivers
Attached to
pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Release pathophysiology#Endoplasmic Reticulum Stress and Unfolded Protein Response pathophysiology#Impaired Clearance of Aggregated Proteins
In the knock-in mouse both processes are present and appear to act through largely separate pathways, but their relative weight has not been tested, for example by relieving ER stress without changing calcium handling.
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"Differentiating between the contributions to the disease process of altered Ca2+ signaling and changes driven by ER stress and uncleared protein aggregates requires further study."
The model's authors state the question as open.
⚙

Pathophysiology

12
Heterozygous CASQ1 Variant
A heterozygous germline CASQ1 variant alters calsequestrin-1. Reported alleles are almost all missense, at conserved residues; p.Asp244Gly sits in a high-affinity calcium-binding site. A C-terminal frameshift that extends the protein has also been reported. The disease alleles reduce the calcium binding and storage of calsequestrin-1, its molecular function.
CASQ1 hgnc:1512 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CASQ1 (hgnc:1512). hgnc:1512 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS
calcium ion binding GO:0005509 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased calcium ion binding (GO:0005509). GO:0005509 is a molecular function from the Gene Ontology.
Downstream
Loss of CASQ1 Inhibition of Store-Operated Calcium Entry Applies to the tubular aggregate alleles. The source treats this as an effect of the variant in parallel with the calcium-binding defect, not as a consequence of it.
Impaired Calcium-Dependent CASQ1 Polymerisation
Show evidence (4 references)
PMID:25116801 SUPPORT Human Clinical
"The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+) -binding sites of CASQ1"
Identifies the founder missense variant and its location in a calcium-binding site.
PMID:41313434 SUPPORT Human Clinical
"In silico analysis indicated that the variant results in protein extension, which was confirmed by western blotting of patient muscle."
Shows a non-missense C-terminal extension allele in a second family.
PMID:26416891 SUPPORT In Vitro
"Equilibrium dialysis and turbidity measurements showed that D244G and, to a lesser extent, M87T partially lose Ca(2+) binding exhibited by wild type calsequestrin 1 at high Ca(2+) concentrations."
The founder allele reduces calcium binding by calsequestrin-1.
+ 1 more reference
Impaired Calcium-Dependent CASQ1 Polymerisation
Calsequestrin-1 normally binds calcium and assembles into polymers that buffer calcium in the terminal cisternae next to RyR1. Disease alleles change this behaviour in two directions. p.Asp244Gly partially loses calcium binding at high calcium concentrations and aggregates abruptly instead of forming ordered polymers, while p.Asp44Asn and p.Gly103Asp show reduced calcium-dependent aggregation.
calcium-dependent calsequestrin polymerisation GO:0051258 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal calcium-dependent calsequestrin polymerisation, annotated with protein polymerization (GO:0051258). GO:0051258 is a biological process from the Gene Ontology.
calcium ion binding GO:0005509 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased calcium ion binding (GO:0005509). GO:0005509 is a molecular function from the Gene Ontology.
sarcoplasmic reticulum lumen GO:0033018 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sarcoplasmic reticulum lumen (GO:0033018). GO:0033018 is a cellular component from the Gene Ontology.
Downstream
Aberrant CASQ1 Aggregation with SERCA1 and RyR1 Applies to the vacuolar alleles.
Reduced Junctional CASQ1 Localisation Applies to p.Asp244Gly in the knock-in mouse.
Reduced Sarcoplasmic Reticulum Calcium Storage Applies to the tubular aggregate alleles.
Show evidence (2 references)
PMID:26416891 SUPPORT In Vitro
"Equilibrium dialysis and turbidity measurements showed that D244G and, to a lesser extent, M87T partially lose Ca(2+) binding exhibited by wild type calsequestrin 1 at high Ca(2+) concentrations."
Purified human p.Asp244Gly protein loses calcium binding.
PMID:28895244 SUPPORT In Vitro
"showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca2+ -dependent aggregation for the p.Ile385Thr"
Tubular aggregate alleles also alter calcium-dependent polymerisation, in differing directions.
Aberrant CASQ1 Aggregation with SERCA1 and RyR1
Mutant calsequestrin-1 forms aggregates within the sarcoplasmic reticulum that also contain non-mutant proteins of the terminal cisternae, including SERCA1 and RyR1. Immunoblot shows increased SERCA1 and calsequestrin in patient muscle, which gives the disease its MONDO name. The aggregates co-localise with SQSTM1/p62.
type II (fast-twitch) muscle fibre CL:0000190 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type II (fast-twitch) muscle fibre, annotated with fast muscle cell (CL:0000190). CL:0000190 is a cell type from the Cell Ontology.
inclusion body assembly GO:0070841 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inclusion body assembly (GO:0070841). GO:0070841 is a biological process from the Gene Ontology.
terminal cisterna lumen GO:0014804 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves terminal cisterna lumen (GO:0014804). GO:0014804 is a cellular component from the Gene Ontology.
Downstream
Sarcoplasmic Reticulum Vacuole Formation
Endoplasmic Reticulum Stress and Unfolded Protein Response
Show evidence (4 references)
PMID:16714317 SUPPORT Human Clinical
"The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present..."
The founding description of SERCA1 and calsequestrin overload in patient inclusions.
PMID:27196359 SUPPORT Human Clinical
"A strong co-immuno staining of both RYR1 and CASQ1 was also noted in the vacuoles of muscle biopsies derived from patients"
RyR1 co-accumulates with CASQ1 in patient vacuoles.
PMID:41699400 SUPPORT Human Clinical
"Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK."
The p.Asp244His allele produces CASQ1 aggregates with p62 in patient muscle.
+ 1 more reference
Sarcoplasmic Reticulum Vacuole Formation
Large vacuoles derived from the sarcoplasmic reticulum form mainly in type II fibres. They look empty on haematoxylin-eosin, Gomori trichrome and NADH stains but contain electron-dense material and stain strongly for sarcoplasmic reticulum proteins.
type II (fast-twitch) muscle fibre CL:0000190 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type II (fast-twitch) muscle fibre, annotated with fast muscle cell (CL:0000190). CL:0000190 is a cell type from the Cell Ontology.
Downstream
Nonrimmed vacuoles in type II fibres
Sarcoplasmic reticulum protein inclusions in vacuoles
Show evidence (1 reference)
PMID:25116801 SUPPORT Human Clinical
"Light microscopy of muscle biopsies of all probands revealed, as a distinctive feature, the presence, mainly in type II fibers, of vacuoles that did not stain by routine histochemical analysis"
Describes the vacuoles in patient biopsies and their type II predominance.
Reduced Junctional CASQ1 Localisation
In heterozygous p.Asp244Gly knock-in mice, part of the mutant calsequestrin-1 leaves the junctional sarcoplasmic reticulum next to RyR1 and accumulates in the endoplasmic reticulum. Less calsequestrin is then available at the release site.
terminal cisterna lumen GO:0014804 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves terminal cisterna lumen (GO:0014804). GO:0014804 is a cellular component from the Gene Ontology.
Animal models
Casq1 p.Asp244Gly knock-in mouse Mouse recapitulates Mutant CASQ1 partly leaves the junctional sarcoplasmic reticulum.
Downstream
Reduced Sarcoplasmic Reticulum Calcium Release
Endoplasmic Reticulum Stress and Unfolded Protein Response
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)."
Direct observation of mislocalisation in the knock-in mouse.
Reduced Sarcoplasmic Reticulum Calcium Storage
Tubular aggregate alleles lower the amount of calcium that calsequestrin-1 can hold in the sarcoplasmic reticulum, measured both in non-muscle cells and in Casq1-knockout mouse fibres re-expressing the mutant proteins.
sarcoplasmic reticulum calcium ion homeostasis GO:0032469 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal sarcoplasmic reticulum calcium ion homeostasis, annotated with endoplasmic reticulum calcium ion homeostasis (GO:0032469). GO:0032469 is a biological process from the Gene Ontology.
Downstream
Reduced Sarcoplasmic Reticulum Calcium Release
Show evidence (2 references)
PMID:28895244 SUPPORT In Vitro
"Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca2+"
All three tubular aggregate alleles store less calcium.
PMID:39126637 SUPPORT Model Organism
"Analysis of intracellular Ca2+ confirmed that CASQ1 mutants have impaired ability to store Ca2+and lose their ability to inhibit skeletal muscle SOCE"
Confirms the storage defect in skeletal muscle fibres.
Loss of CASQ1 Inhibition of Store-Operated Calcium Entry
Calsequestrin-1 binds STIM1 and STIM2 and restrains store-operated calcium entry. Tubular aggregate alleles lose this restraint. The vacuolar p.Asp244Gly allele does not: knock-in mice carrying it show no increase in store-operated calcium entry, which is one reason the two presentations are modelled as separate branches.
negative regulation of store-operated calcium entry GO:0106128 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of store-operated calcium entry (GO:0106128). GO:0106128 is a biological process from the Gene Ontology.
Downstream
Tubular Aggregate Formation
Show evidence (3 references)
PMID:28895244 SUPPORT In Vitro
"a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
Two tubular aggregate alleles weaken SOCE inhibition in cells.
PMID:39126637 SUPPORT Model Organism
"Conversely, neither one of the CASQ1 mutants induced a significant SOCE inhibition, suggesting that, beyond altering Ca2+ binding, CASQ1 mutations also influence SOCE regulation"
In mouse muscle fibres the tubular aggregate mutants fail to inhibit SOCE.
PMID:39126637 SUPPORT Model Organism
"This indicates that the ability to affect SOCE is a distinctive trait of CASQ1 mutations associated with TAM."
Scopes the SOCE defect to the tubular aggregate alleles.
Tubular Aggregate Formation
Densely packed membrane tubules derived from the sarcoplasmic reticulum accumulate in muscle fibres and react for NADH tetrazolium reductase.
skeletal muscle fibre CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fibre, annotated with skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Tubular aggregates in muscle fibres
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
Tubular aggregates in a patient with a tubular aggregate allele.
Endoplasmic Reticulum Stress and Unfolded Protein Response
Accumulating mutant calsequestrin-1 activates the unfolded protein response. In knock-in mice the markers sXbp1, BiP and CHOP rise in fast-twitch muscle by eight months of age, and patient muscle with p.Asp244His stains for the ER stress marker PERK around the vacuoles.
type II (fast-twitch) muscle fibre CL:0000190 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves type II (fast-twitch) muscle fibre, annotated with fast muscle cell (CL:0000190). CL:0000190 is a cell type from the Cell Ontology.
endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased endoplasmic reticulum unfolded protein response (GO:0030968). GO:0030968 is a biological process from the Gene Ontology.
Animal models
Casq1 p.Asp244Gly knock-in mouse Mouse recapitulates ER stress markers rise in fast-twitch muscle of older mice.
Downstream
Fast-Twitch Muscle Fibre Dysfunction
Show evidence (2 references)
PMID:33786938 SUPPORT Model Organism
"However, ER stress markers sXbp1, BiP, and CHOP were significantly elevated in the EDL muscle of 8-month-old DG compared to WT mice"
Measured ER stress in fast-twitch muscle of knock-in mice.
PMID:41699400 SUPPORT Human Clinical
"Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK."
An ER stress marker is present at the aggregates in patient muscle.
Impaired Clearance of Aggregated Proteins
In older knock-in mice, mTORC1 signalling increases, autophagic flux falls and proteasomal clearance of aggregated proteins is inadequate, so insoluble ubiquitinated proteins and lysosomes accumulate. Younger mice clear the misfolded protein, and the authors attribute the late onset to this age-dependent decline in proteolytic capacity, which in turn sustains ER stress.
TORC1 signaling GO:0038202 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TORC1 signaling (GO:0038202). GO:0038202 is a biological process from the Gene Ontology. autophagy GO:0006914 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
Downstream
Endoplasmic Reticulum Stress and Unfolded Protein Response
Fast-Twitch Muscle Fibre Dysfunction
Show evidence (3 references)
PMID:33786938 SUPPORT Model Organism
"Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate clearance of aggregated proteins by the proteasomes, and elevation of protein aggregates and lysosomes."
Summarises the age-dependent clearance failure in knock-in mice.
PMID:33786938 SUPPORT Model Organism
"Activation of mTOR is also consistent with the decreased autophagic flux detected in 8-month-old mice."
Reports the fall in autophagic flux.
PMID:33786938 SUPPORT Model Organism
"We also show that the late onset of the disease is likely due to the age-dependent decrease in the capacity of the proteolytic systems to adequately clear the misfolded proteins, leading to the formation of protein aggregates and persistent and maladaptive ER stress"
Links the late onset to age-dependent proteolytic decline.
Reduced Sarcoplasmic Reticulum Calcium Release
Less calcium is released from the sarcoplasmic reticulum on stimulation. This is shown in patient-derived p.Asp244Gly myotubes and fibres, in a p.Gly103Asp patient fibre and in knock-in mice.
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum GO:0014808 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808). GO:0014808 is a biological process from the Gene Ontology.
Animal models
Casq1 p.Asp244Gly knock-in mouse Mouse recapitulates Junctional CASQ1 loss reduces calcium release in mouse fibres.
Downstream
Fast-Twitch Muscle Fibre Dysfunction
Show evidence (2 references)
PMID:27196359 SUPPORT In Vitro
"Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls."
Patient-derived myotubes release less calcium.
PMID:28895244 SUPPORT In Vitro
"Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in response to caffeine stimulation, compared with normal control fibers."
Reduced caffeine-induced release in isolated fibres from a tubular aggregate patient, measured ex vivo.
Fast-Twitch Muscle Fibre Dysfunction
Fast-twitch muscles generate less force. Knock-in mice develop a progressive myopathy after one year, and in patients the vacuolar pathology mainly involves type II fibres.
fast-twitch muscle fibre CL:0000190 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fast-twitch muscle fibre, annotated with fast muscle cell (CL:0000190). CL:0000190 is a cell type from the Cell Ontology.
Animal models
Casq1 p.Asp244Gly knock-in mouse Mouse recapitulates Late, progressive loss of fast-twitch force.
Downstream
Proximal muscle weakness
Exercise intolerance
Fatigue
Myalgia
Muscle cramps
Elevated serum creatine kinase
Quadriceps atrophy
Scapular winging
Fibrofatty replacement of muscle on MRI
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age"
Knock-in mice reproduce a late fast-twitch force deficit.
⬡

Pathograph

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Pathograph: causal mechanism network for Myopathy Due To Calsequestrin And SERCA1 Protein Overload Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Limbs 3
Quadriceps atrophy Quadriceps muscle atrophy HP:0009050 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Quadriceps muscle atrophy (HP:0009050). HP:0009050 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
Quadriceps atrophy accompanies the proximal weakness.
Scapular winging HP:0003691 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scapular winging (HP:0003691). HP:0003691 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
Scapular winging is part of the later phenotype.
Distal upper limb weakness Distal upper limb muscle weakness HP:0008959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal upper limb muscle weakness (HP:0008959). HP:0008959 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36514469 SUPPORT Human Clinical
"presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1-related patients"
Single case report of a distal-predominant presentation.
Metabolism 1
Elevated serum creatine kinase VERY_FREQUENT Elevated circulating creatine kinase activity HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase, annotated with Elevated circulating creatine kinase activity (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:26136523 SUPPORT Human Clinical
"HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation."
Family series showing frequent and sometimes isolated hyperCKaemia.
PMID:41699400 SUPPORT Human Clinical
"Both had mildly to moderately elevated serum creatine kinase levels."
Supports the mild to moderate degree of elevation.
ORPHA:88635 SUPPORT Other
"HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
Orphanet annotates raised creatine kinase as very frequent.
Musculoskeletal 4
Muscle cramps Muscle spasm HP:0003394 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle cramps, annotated with Muscle spasm (HP:0003394). HP:0003394 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25116801 SUPPORT Human Clinical
"affected by a mild myopathy accompanied by one or more symptoms, including episodes of muscle cramping, reduced muscle strength, fatigue and elevated plasma creatine kinase (CK) levels"
Cramping episodes are among the symptoms in the first genetically defined cohort.
Proximal muscle weakness HP:0003701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proximal muscle weakness (HP:0003701), qualified as course progressive. HP:0003701 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
Describes the later weakness in the cohort.
Fibrofatty replacement of muscle on MRI Fatty replacement of skeletal muscle HP:0012548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatty replacement of skeletal muscle (HP:0012548). HP:0012548 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern."
Muscle imaging finding in the cohort.
Nonrimmed vacuoles in type II fibres Nonrimmed muscle vacuoles HP:6000978 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonrimmed muscle vacuoles (HP:6000978). HP:6000978 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30258016 SUPPORT Human Clinical
"Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
Optically empty vacuoles in type II fibres in the founder-allele cohort.
PMID:41699400 SUPPORT Human Clinical
"Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers."
The same finding with p.Asp244His.
Cellular 2
Sarcoplasmic reticulum protein inclusions in vacuoles Muscle fiber cytoplasmatic inclusion bodies HP:0100303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle fiber cytoplasmatic inclusion bodies (HP:0100303). HP:0100303 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16714317 SUPPORT Human Clinical
"The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present..."
Immunohistochemistry and immunoblot of patient inclusions.
PMID:30258016 SUPPORT Human Clinical
"Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
Vacuoles stain for sarcoplasmic reticulum proteins despite appearing empty.
Tubular aggregates in muscle fibres Muscle fiber tubular inclusions HP:0100301 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle fiber tubular inclusions (HP:0100301). HP:0100301 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30258016 SUPPORT Human Clinical
"The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
Tubular aggregates in the p.Gly103Asp patient.
PMID:28895244 SUPPORT Human Clinical
"Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy."
Patients with other CASQ1 alleles have tubular aggregate myopathy.
Constitutional 3
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"Patients usually presented in the sixth decade with exercise intolerance and myalgias"
Presenting symptoms in the 22-patient cohort.
Myalgia HP:0003326 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myalgia (HP:0003326). HP:0003326 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30258016 SUPPORT Human Clinical
"Patients usually presented in the sixth decade with exercise intolerance and myalgias"
Myalgia is a presenting symptom.
PMID:41699400 SUPPORT Human Clinical
"we report two unrelated Chinese patients presenting with late-onset, slowly progressive muscle weakness, fatigue, and myalgia."
Myalgia also accompanies the p.Asp244His allele.
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25116801 SUPPORT Human Clinical
"A missense mutation in the calsequestrin-1 gene (CASQ1) was found in a group of patients with a myopathy characterized by weakness, fatigue, and the presence of large vacuoles"
Fatigue is part of the defining clinical picture.
🧬

Genetic Associations

1
CASQ1
Gene: CASQ1 hgnc:1512 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CASQ1 (hgnc:1512). hgnc:1512 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant
Show evidence (2 references)
PMID:26136523 SUPPORT Human Clinical
"is due to the D244G heterozygous missense mutation in the CASQ1 gene"
Linkage and exome sequencing in three families identify the causal CASQ1 variant.
ORPHA:88635 SUPPORT Other
"CASQ1 | calsequestrin 1 | hgnc:1512 | Disease-causing germline mutation(s) in"
Orphanet lists CASQ1 as the disease-causing gene.
Variants (8)
p.Asp244Gly
Italian founder allele in a high-affinity calcium-binding site; causes the vacuolar aggregate presentation and accounted for 21 of 22 patients in the largest cohort.
Show evidence (2 references)
PMID:26136523 SUPPORT Human Clinical
"Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect."
Shared haplotype indicates a founder allele.
PMID:30258016 SUPPORT Human Clinical
"Twenty-two CASQ1-mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation."
Shows how dominant the founder allele is in the Italian cohort.
p.Asp244His
A second substitution at the same residue, reported in Chinese patients. Two unrelated families had the vacuolar presentation; a de novo patient had both tubular aggregates and vacuoles.
Show evidence (3 references)
PMID:41699400 SUPPORT Human Clinical
"Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue."
Identifies p.Asp244His in two unrelated families.
PMID:38818562 SUPPORT Human Clinical
"The same variant was not found in his unaffected parents."
The variant arose de novo in this patient.
PMID:38818562 SUPPORT Human Clinical
"To explore the genetic basis of a myopathic patient with pathological characteristics including tubular aggregates and vacuoles."
The de novo p.Asp244His patient had mixed histology.
p.Gly103Asp
Tubular aggregate allele with reduced calcium-dependent polymerisation.
Show evidence (1 reference)
PMID:28895244 SUPPORT In Vitro
"showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations"
Functional defect of the allele.
p.Asp44Asn
Tubular aggregate allele with reduced calcium-dependent polymerisation and weakened SOCE inhibition.
Show evidence (1 reference)
PMID:28895244 SUPPORT In Vitro
"a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
Functional defect of the allele.
p.Ile385Thr
Tubular aggregate allele with slightly increased calcium-dependent aggregation and weakened SOCE inhibition.
Show evidence (1 reference)
PMID:28895244 SUPPORT In Vitro
"a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
Functional defect of the allele.
p.Glu89Lys
Found in a family with exercise intolerance, cramps and myalgia, whose biopsies showed altered triads and SR-feet rather than vacuoles or tubular aggregates. The proband also carried biallelic NEB variants, which may explain her nemaline bodies.
Show evidence (2 references)
PMID:41313434 SUPPORT Human Clinical
"A variant in CASQ1, p.(Glu89Lys), was found in all patients, whereas the proband had also two compound heterozygous variants in NEB."
Segregation of the variant and the confounding NEB genotype.
PMID:41313434 SUPPORT Human Clinical
"In electron microscopy, there were morphological changes in the triads and the SR-feet in all patients."
Ultrastructural finding in this family.
p.Val256Met
Reported in one patient with distal-predominant upper limb weakness and rare vacuoles.
Show evidence (1 reference)
PMID:36514469 SUPPORT Human Clinical
"Next-generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1."
Case report identifying the allele.
p.Gly383Alafs*39
C-terminal frameshift that extends the protein; the extended protein aggregates in transfected cells.
Show evidence (1 reference)
PMID:41313434 SUPPORT In Vitro
"Cell-transfection studies showed that the variant protein forms aggregates."
Functional evidence for the frameshift allele.
🔬

Diagnosis

2
Muscle biopsy
The vacuoles look empty on routine stains but stain for sarcoplasmic reticulum proteins, so immunostaining or electron microscopy of biopsy tissue helps recognise them. Patients whose only sign is hyperCKaemia may go undiagnosed without a biopsy.
muscle biopsy NCIT:C51895 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26136523 SUPPORT Human Clinical
"It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed."
Authors stress the role of biopsy in recognising the disease.
Genetic testing
Exome or targeted sequencing identifies the heterozygous CASQ1 variant.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:41699400 SUPPORT Human Clinical
"Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue."
Exome sequencing established the diagnosis.
📈

Progression

1
Adult onset and slow progression
Symptoms usually begin in adulthood, often in the sixth decade, with exercise intolerance and myalgia. Weakness, when it develops, is mild to moderate and slowly progressive; some patients have only hyperCKaemia.
Show evidence (1 reference)
PMID:30258016 SUPPORT Human Clinical
"Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging."
Natural history in the largest cohort.
📊

Prevalence

1
Worldwide
Point Prevalence <1 in 1,000,000
Orphanet worldwide point-prevalence class below 1 in 1,000,000.
Show evidence (1 reference)
ORPHA:88635 SUPPORT Other
"<1 / 1 000 000 | Worldwide | Point prevalence | PMID:16714317"
Orphanet epidemiology table.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Myopathy Due To Calsequestrin And SERCA1 Protein Overload:

🐁

Animal Models

1
Casq1 p.Asp244Gly knock-in mouse
Heterozygous knock-in mice develop a late, progressive fast-twitch myopathy with CASQ1 mislocalisation, reduced calcium release, ER stress and impaired clearance of aggregated proteins.
Species
Mouse
Genotype
Casq1 D244G heterozygous knock-in
Publication
PMID:33786938
Pathograph links
Endoplasmic Reticulum Stress and Unfolded Protein Response recapitulates fidelity: moderate ER stress markers rise in fast-twitch muscle of older mice.
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"However, ER stress markers sXbp1, BiP, and CHOP were significantly elevated in the EDL muscle of 8-month-old DG compared to WT mice"
Direct measurement in the model.
Reduced Sarcoplasmic Reticulum Calcium Release recapitulates fidelity: moderate Junctional CASQ1 loss reduces calcium release in mouse fibres.
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"Decreased junctional CASQ1 reduces SR Ca2+ release."
Direct measurement in the model.
Reduced Junctional CASQ1 Localisation recapitulates fidelity: moderate Mutant CASQ1 partly leaves the junctional sarcoplasmic reticulum.
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)."
Direct observation in the model.
Fast-Twitch Muscle Fibre Dysfunction recapitulates fidelity: moderate Late, progressive loss of fast-twitch force.
Limitations: Onset is after one year in mice; the human disease typically presents in the sixth decade, so the time course is compressed.
Show evidence (1 reference)
PMID:33786938 SUPPORT Model Organism
"display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age"
Direct measurement in the model.
{ }

Source YAML

click to show 
name: Myopathy Due To Calsequestrin And SERCA1 Protein Overload
creation_date: "2026-10-15T17:45:00Z"
description: >-
  An autosomal dominant skeletal-muscle disorder caused by heterozygous CASQ1 variants
  that disturb the calcium-dependent polymerisation of calsequestrin-1, the main
  calcium buffer of the sarcoplasmic reticulum in fast-twitch fibres. Most patients
  carry the Italian founder allele p.Asp244Gly and show optically empty vacuoles in
  type II fibres that contain aggregated calsequestrin, SERCA1 and other sarcoplasmic
  reticulum proteins. A smaller group of alleles instead produces tubular aggregates.
  Presentation is usually in adulthood with exercise intolerance, myalgia, cramps,
  fatigue and raised creatine kinase, sometimes with no symptoms beyond hyperCKaemia,
  followed in some patients by slowly progressive proximal weakness with quadriceps
  atrophy and scapular winging.
category: Mendelian
synonyms:
- Vacuolar myopathy with CASQ1 aggregates
- VMCQA
- Vacuolar aggregate myopathy
- Vacuolar myopathy with sarcoplasmic reticulum protein aggregates
- CASQ1-related myopathy
- SERCA1 and calsequestrin storage myopathy
disease_term:
  preferred_term: myopathy due to calsequestrin and SERCA1 protein overload
  term:
    id: MONDO:0014546
    label: myopathy due to calsequestrin and SERCA1 protein overload
parents:
- Protein aggregate myopathy
- Hereditary skeletal muscle disorder
notes: >-
  MONDO:0014546 is the only MONDO concept for CASQ1-related muscle disease, so this
  entry covers both the vacuolar aggregate presentation and the CASQ1 tubular aggregate
  presentation, which are recorded as allelic subtypes. The two share a defect in
  calcium-dependent CASQ1 polymerisation but diverge downstream: the vacuolar alleles
  act through protein aggregation and ER stress, while the tubular aggregate alleles
  reduce calcium storage and weaken CASQ1 inhibition of store-operated calcium entry.
  No GeneReviews chapter exists for this disease. No disease-specific or supportive
  treatment has been evaluated in patients, so the entry has no treatments section.
  The vacuoles are bound to HP:6000978 Nonrimmed muscle vacuoles and their
  sarcoplasmic reticulum protein contents to HP:0100303 Muscle fiber cytoplasmatic
  inclusion bodies.
  The CASQ1 p.Met87Thr variant, weakly associated with malignant hyperthermia
  (PMID:26416891), and the malignant-hyperthermia-like episodes of Casq1-knockout mice
  reflect loss of CASQ1 function and are outside the scope of this dominant
  aggregation disease. Whether patients carry an anaesthetic or heat risk has not been
  studied, so the entry records no such precaution.
has_subtypes:
- name: Vacuolar aggregate type
  display_name: Vacuolar aggregate myopathy (CASQ1 p.Asp244Gly / p.Asp244His)
  description: >-
    The common presentation, caused by the Italian founder allele p.Asp244Gly and by
    p.Asp244His at the same residue. Muscle biopsy shows vacuoles in type II fibres
    that appear empty on routine stains but contain aggregated calsequestrin, SERCA1,
    RyR1 and other sarcoplasmic reticulum proteins. Store-operated calcium entry is
    not increased in knock-in mice carrying p.Asp244Gly. Histology overlaps between
    alleles: a de novo p.Asp244His patient had both vacuoles and tubular aggregates.
  genes:
  - preferred_term: CASQ1
    term:
      id: hgnc:1512
      label: CASQ1
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
    explanation: Defines the vacuolar histopathology of the founder allele in the largest cohort.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers."
    explanation: The p.Asp244His allele produces the same vacuolar picture.
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SR Ca2+ stores are not significantly depleted and SOCE is not increased in fibers of DG compared to WT mice"
    explanation: The vacuolar founder allele does not engage the store-operated calcium entry mechanism of the tubular aggregate alleles.
  - reference: PMID:41313434
    reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "cause sarcoplasmic reticulum aberrations such as large vacuoles with CASQ1 inclusions or, less commonly, tubular aggregates"
    explanation: Vacuoles are the more common of the two histological presentations.
- name: Tubular aggregate type
  display_name: CASQ1 tubular aggregate myopathy
  description: >-
    Caused by other CASQ1 missense alleles, including p.Asp44Asn, p.Gly103Asp and
    p.Ile385Thr. Muscle biopsy shows tubular aggregates, sometimes alongside vacuoles.
    These alleles reduce calcium storage by calsequestrin and, in mouse muscle fibres,
    all three lose its inhibition of store-operated calcium entry, a mechanism shared
    with the STIM1 and ORAI1 tubular aggregate myopathies.
  genes:
  - preferred_term: CASQ1
    term:
      id: hgnc:1512
      label: CASQ1
  evidence:
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy."
    explanation: Establishes CASQ1 tubular aggregate myopathy as an allelic presentation.
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
    explanation: Contrasts the tubular aggregate histopathology of p.Gly103Asp with the vacuoles of p.Asp244Gly.
pathophysiology:
- name: Heterozygous CASQ1 Variant
  biological_scale: MOLECULAR
  description: >-
    A heterozygous germline CASQ1 variant alters calsequestrin-1. Reported alleles are
    almost all missense, at conserved residues; p.Asp244Gly sits in a high-affinity
    calcium-binding site. A C-terminal frameshift that extends the protein has also been
    reported. The disease alleles reduce the calcium binding and storage of
    calsequestrin-1, its molecular function.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  gene:
    preferred_term: CASQ1
    term:
      id: hgnc:1512
      label: CASQ1
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  evidence:
  - reference: PMID:25116801
    reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+) -binding sites of CASQ1"
    explanation: Identifies the founder missense variant and its location in a calcium-binding site.
  - reference: PMID:41313434
    reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In silico analysis indicated that the variant results in protein extension, which was confirmed by western blotting of patient muscle."
    explanation: Shows a non-missense C-terminal extension allele in a second family.
  - reference: PMID:26416891
    reference_title: "Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Equilibrium dialysis and turbidity measurements showed that D244G and, to a lesser extent, M87T partially lose Ca(2+) binding exhibited by wild type calsequestrin 1 at high Ca(2+) concentrations."
    explanation: The founder allele reduces calcium binding by calsequestrin-1.
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca2+"
    explanation: The tubular aggregate alleles also reduce calcium storage.
  downstream:
  - target: Loss of CASQ1 Inhibition of Store-Operated Calcium Entry
    causal_link_type: DIRECT
    description: >-
      Applies to the tubular aggregate alleles. The source treats this as an effect of
      the variant in parallel with the calcium-binding defect, not as a consequence of it.
    evidence:
    - reference: PMID:39126637
      reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Conversely, neither one of the CASQ1 mutants induced a significant SOCE inhibition, suggesting that, beyond altering Ca2+ binding, CASQ1 mutations also influence SOCE regulation"
      explanation: Tubular aggregate mutants expressed in mouse fibres fail to inhibit SOCE, separately from their calcium-binding defect.
  - target: Impaired Calcium-Dependent CASQ1 Polymerisation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25116801
      reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of the mutated CASQ1 protein in COS-7 cells showed a markedly reduced ability in forming elongated polymers"
      explanation: The p.Asp244Gly allele directly impairs polymer formation.
- name: Impaired Calcium-Dependent CASQ1 Polymerisation
  biological_scale: MOLECULAR
  description: >-
    Calsequestrin-1 normally binds calcium and assembles into polymers that buffer
    calcium in the terminal cisternae next to RyR1. Disease alleles change this
    behaviour in two directions. p.Asp244Gly partially loses calcium binding at high
    calcium concentrations and aggregates
    abruptly instead of forming ordered polymers, while p.Asp44Asn and p.Gly103Asp show
    reduced calcium-dependent aggregation.
  molecular_functions:
  - preferred_term: calcium ion binding
    term:
      id: GO:0005509
      label: calcium ion binding
    modifier: DECREASED
  biological_processes:
  - preferred_term: calcium-dependent calsequestrin polymerisation
    term:
      id: GO:0051258
      label: protein polymerization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: sarcoplasmic reticulum lumen
    term:
      id: GO:0033018
      label: sarcoplasmic reticulum lumen
  evidence:
  - reference: PMID:26416891
    reference_title: "Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Equilibrium dialysis and turbidity measurements showed that D244G and, to a lesser extent, M87T partially lose Ca(2+) binding exhibited by wild type calsequestrin 1 at high Ca(2+) concentrations."
    explanation: Purified human p.Asp244Gly protein loses calcium binding.
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca2+ -dependent aggregation for the p.Ile385Thr"
    explanation: Tubular aggregate alleles also alter calcium-dependent polymerisation, in differing directions.
  downstream:
  - target: Aberrant CASQ1 Aggregation with SERCA1 and RyR1
    causal_link_type: DIRECT
    description: Applies to the vacuolar alleles.
    evidence:
    - reference: PMID:26416891
      reference_title: "Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "D244G aggregates abruptly and abnormally, a property that fully explains the protein inclusions that characterize its phenotype."
      explanation: Links the biophysical defect of the mutant protein to the inclusions seen in patients.
  - target: Reduced Junctional CASQ1 Localisation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Applies to p.Asp244Gly in the knock-in mouse.
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "The D244G mutation in CASQ1 decreases its ability to undergo back-to-back dimerization, a critical step in CASQ1 polymerization and retention at the junctional SR."
      explanation: Ties the polymerisation defect to retention at the junctional sarcoplasmic reticulum.
  - target: Reduced Sarcoplasmic Reticulum Calcium Storage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Applies to the tubular aggregate alleles.
    evidence:
    - reference: PMID:39126637
      reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: REVIEW_SYNTHESIS
      snippet: "Characterization of CASQ1 mutants demonstrated that they all display a significant alteration in Ca2+ dependent polymerization that, at the functional level, results in a reduction in Ca2+ storage capacity"
      explanation: Summarises earlier cell studies linking the polymerisation defect to reduced storage.
- name: Aberrant CASQ1 Aggregation with SERCA1 and RyR1
  biological_scale: CELLULAR
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  subtypes:
  - Vacuolar aggregate type
  description: >-
    Mutant calsequestrin-1 forms aggregates within the sarcoplasmic reticulum that
    also contain non-mutant proteins of the terminal cisternae, including SERCA1 and
    RyR1. Immunoblot shows increased SERCA1 and calsequestrin in patient muscle, which
    gives the disease its MONDO name. The aggregates co-localise with SQSTM1/p62.
  cell_types:
  - preferred_term: type II (fast-twitch) muscle fibre
    term:
      id: CL:0000190
      label: fast muscle cell
  biological_processes:
  - preferred_term: inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
    modifier: INCREASED
  cellular_components:
  - preferred_term: terminal cisterna lumen
    term:
      id: GO:0014804
      label: terminal cisterna lumen
  evidence:
  - reference: PMID:16714317
    reference_title: "SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present in the terminal cisternae of sarcoplasmic reticulum."
    explanation: The founding description of SERCA1 and calsequestrin overload in patient inclusions.
  - reference: PMID:27196359
    reference_title: "A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A strong co-immuno staining of both RYR1 and CASQ1 was also noted in the vacuoles of muscle biopsies derived from patients"
    explanation: RyR1 co-accumulates with CASQ1 in patient vacuoles.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK."
    explanation: The p.Asp244His allele produces CASQ1 aggregates with p62 in patient muscle.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro expression of the mutant CASQ1 in HeLa cells confirmed its aggregation tendency"
    explanation: Mutant protein aggregates when expressed in cells.
  downstream:
  - target: Sarcoplasmic Reticulum Vacuole Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25116801
      reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "both in cultured myotubes and in in vivo mouse fibers induced the formation of electron-dense SR vacuoles containing aggregates of the mutant CASQ1 protein that resemble those observed in muscle biopsies of patients"
      explanation: >-
        Expressing the mutant protein is sufficient to form aggregate-filled SR vacuoles.
        The sentence covers both cultured myotubes and in vivo mouse fibres; it is graded
        MODEL_ORGANISM for the in vivo part.
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41699400
      reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK."
      explanation: Co-localisation of the aggregates with an ER stress marker in patient muscle; this shows association, not causation.
- name: Sarcoplasmic Reticulum Vacuole Formation
  biological_scale: CELLULAR
  subtypes:
  - Vacuolar aggregate type
  description: >-
    Large vacuoles derived from the sarcoplasmic reticulum form mainly in type II
    fibres. They look empty on haematoxylin-eosin, Gomori trichrome and NADH stains but
    contain electron-dense material and stain strongly for sarcoplasmic reticulum
    proteins.
  cell_types:
  - preferred_term: type II (fast-twitch) muscle fibre
    term:
      id: CL:0000190
      label: fast muscle cell
  evidence:
  - reference: PMID:25116801
    reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Light microscopy of muscle biopsies of all probands revealed, as a distinctive feature, the presence, mainly in type II fibers, of vacuoles that did not stain by routine histochemical analysis"
    explanation: Describes the vacuoles in patient biopsies and their type II predominance.
  downstream:
  - target: Nonrimmed vacuoles in type II fibres
  - target: Sarcoplasmic reticulum protein inclusions in vacuoles
- name: Reduced Junctional CASQ1 Localisation
  biological_scale: CELLULAR
  subtypes:
  - Vacuolar aggregate type
  description: >-
    In heterozygous p.Asp244Gly knock-in mice, part of the mutant calsequestrin-1 leaves
    the junctional sarcoplasmic reticulum next to RyR1 and accumulates in the
    endoplasmic reticulum. Less calsequestrin is then available at the release site.
  cellular_components:
  - preferred_term: terminal cisterna lumen
    term:
      id: GO:0014804
      label: terminal cisterna lumen
  evidence:
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)."
    explanation: Direct observation of mislocalisation in the knock-in mouse.
  downstream:
  - target: Reduced Sarcoplasmic Reticulum Calcium Release
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Decreased junctional CASQ1 reduces SR Ca2+ release."
      explanation: States the causal link between mislocalisation and reduced release.
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our data suggest that the mutant CASQ1 accumulates in the perinuclear ER, leading to UPR, ER stress, and eventually accumulation of aggregated proteins."
      explanation: Mutant CASQ1 retained in the ER drives the unfolded protein response in knock-in mice.
- name: Reduced Sarcoplasmic Reticulum Calcium Storage
  biological_scale: CELLULAR
  subtypes:
  - Tubular aggregate type
  description: >-
    Tubular aggregate alleles lower the amount of calcium that calsequestrin-1 can hold
    in the sarcoplasmic reticulum, measured both in non-muscle cells and in
    Casq1-knockout mouse fibres re-expressing the mutant proteins.
  biological_processes:
  - preferred_term: sarcoplasmic reticulum calcium ion homeostasis
    term:
      id: GO:0032469
      label: endoplasmic reticulum calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca2+"
    explanation: All three tubular aggregate alleles store less calcium.
  - reference: PMID:39126637
    reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of intracellular Ca2+ confirmed that CASQ1 mutants have impaired ability to store Ca2+and lose their ability to inhibit skeletal muscle SOCE"
    explanation: Confirms the storage defect in skeletal muscle fibres.
  downstream:
  - target: Reduced Sarcoplasmic Reticulum Calcium Release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Loss of CASQ1 Inhibition of Store-Operated Calcium Entry
  biological_scale: CELLULAR
  subtypes:
  - Tubular aggregate type
  description: >-
    Calsequestrin-1 binds STIM1 and STIM2 and restrains store-operated calcium entry.
    Tubular aggregate alleles lose this restraint. The vacuolar p.Asp244Gly allele does
    not: knock-in mice carrying it show no increase in store-operated calcium entry,
    which is one reason the two presentations are modelled as separate branches.
  biological_processes:
  - preferred_term: negative regulation of store-operated calcium entry
    term:
      id: GO:0106128
      label: negative regulation of store-operated calcium entry
    modifier: DECREASED
  evidence:
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
    explanation: Two tubular aggregate alleles weaken SOCE inhibition in cells.
  - reference: PMID:39126637
    reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conversely, neither one of the CASQ1 mutants induced a significant SOCE inhibition, suggesting that, beyond altering Ca2+ binding, CASQ1 mutations also influence SOCE regulation"
    explanation: In mouse muscle fibres the tubular aggregate mutants fail to inhibit SOCE.
  - reference: PMID:39126637
    reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This indicates that the ability to affect SOCE is a distinctive trait of CASQ1 mutations associated with TAM."
    explanation: Scopes the SOCE defect to the tubular aggregate alleles.
  downstream:
  - target: Tubular Aggregate Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39126637
      reference_title: "TAM-associated CASQ1 mutants diminish intracellular Ca(2+) content and interfere with regulation of SOCE."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "this is in agreement with the evidence that alterations in Ca2+entry due to mutations in either STIM1, ORAI1 or CASQ1 represents a hallmark of TAM"
      explanation: Places altered calcium entry as the common feature of tubular aggregate myopathy genes; the causal step to aggregate formation is inferred.
- name: Tubular Aggregate Formation
  biological_scale: CELLULAR
  subtypes:
  - Tubular aggregate type
  description: >-
    Densely packed membrane tubules derived from the sarcoplasmic reticulum accumulate
    in muscle fibres and react for NADH tetrazolium reductase.
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
    explanation: Tubular aggregates in a patient with a tubular aggregate allele.
  downstream:
  - target: Tubular aggregates in muscle fibres
- name: Endoplasmic Reticulum Stress and Unfolded Protein Response
  biological_scale: CELLULAR
  subtypes:
  - Vacuolar aggregate type
  description: >-
    Accumulating mutant calsequestrin-1 activates the unfolded protein response. In
    knock-in mice the markers sXbp1, BiP and CHOP rise in fast-twitch muscle by eight
    months of age, and patient muscle with p.Asp244His stains for the ER stress marker
    PERK around the vacuoles.
  cell_types:
  - preferred_term: type II (fast-twitch) muscle fibre
    term:
      id: CL:0000190
      label: fast muscle cell
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  evidence:
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, ER stress markers sXbp1, BiP, and CHOP were significantly elevated in the EDL muscle of 8-month-old DG compared to WT mice"
    explanation: Measured ER stress in fast-twitch muscle of knock-in mice.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence revealed abnormal aggregation of CASQ1 protein around the edge of vacuoles, co-localized with SQSTM1/p62, and the endoplasmic reticulum (ER) stress marker PERK."
    explanation: An ER stress marker is present at the aggregates in patient muscle.
  downstream:
  - target: Fast-Twitch Muscle Fibre Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "It is likely that both changes in Ca2+ release and DG-CASQ1 driven UPR/ER stress/aggregation are contributing to the pathology of the disease but are doing so via relatively independent pathways."
      explanation: The authors propose ER stress as a contributor to the myopathy, separate from the calcium-release defect.
- name: Impaired Clearance of Aggregated Proteins
  biological_scale: CELLULAR
  subtypes:
  - Vacuolar aggregate type
  description: >-
    In older knock-in mice, mTORC1 signalling increases, autophagic flux falls and
    proteasomal clearance of aggregated proteins is inadequate, so insoluble
    ubiquitinated proteins and lysosomes accumulate. Younger mice clear the misfolded
    protein, and the authors attribute the late onset to this age-dependent decline in
    proteolytic capacity, which in turn sustains ER stress.
  biological_processes:
  - preferred_term: TORC1 signaling
    term:
      id: GO:0038202
      label: TORC1 signaling
    modifier: INCREASED
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Muscles from older DG mice display ER stress, ER expansion, increased mTOR signaling, inadequate clearance of aggregated proteins by the proteasomes, and elevation of protein aggregates and lysosomes."
    explanation: Summarises the age-dependent clearance failure in knock-in mice.
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Activation of mTOR is also consistent with the decreased autophagic flux detected in 8-month-old mice."
    explanation: Reports the fall in autophagic flux.
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We also show that the late onset of the disease is likely due to the age-dependent decrease in the capacity of the proteolytic systems to adequately clear the misfolded proteins, leading to the formation of protein aggregates and persistent and maladaptive ER stress"
    explanation: Links the late onset to age-dependent proteolytic decline.
  downstream:
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We also show that the late onset of the disease is likely due to the age-dependent decrease in the capacity of the proteolytic systems to adequately clear the misfolded proteins, leading to the formation of protein aggregates and persistent and maladaptive ER stress"
      explanation: Places failing clearance upstream of persistent ER stress.
  - target: Fast-Twitch Muscle Fibre Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "The subsequent maladaptive increase in protein synthesis and decreased protein aggregate clearance are likely to contribute to disease progression."
      explanation: The authors propose, rather than demonstrate, that clearance failure drives progression.
- name: Reduced Sarcoplasmic Reticulum Calcium Release
  biological_scale: CELLULAR
  description: >-
    Less calcium is released from the sarcoplasmic reticulum on stimulation. This is
    shown in patient-derived p.Asp244Gly myotubes and fibres, in a p.Gly103Asp patient
    fibre and in knock-in mice.
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: DECREASED
  evidence:
  - reference: PMID:27196359
    reference_title: "A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls."
    explanation: Patient-derived myotubes release less calcium.
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analysis of single muscle fibers of a patient carrying the p.Gly103Asp mutation showed a significant reduction in response to caffeine stimulation, compared with normal control fibers."
    explanation: Reduced caffeine-induced release in isolated fibres from a tubular aggregate patient, measured ex vivo.
  downstream:
  - target: Fast-Twitch Muscle Fibre Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27196359
      reference_title: "A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release."
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: INDIRECT
      snippet: "points out defects in Ca2+ homeostasis within muscle fibers as a possible mechanism underlying muscle cramping, weakness and fatigue"
      explanation: The authors propose the calcium-release defect as a cause of the symptoms.
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Decreased Ca2+ release is probably not directly responsible for the decrease in force generation since force is not altered in young mice."
      explanation: Young knock-in mice already release less calcium but generate normal force, which argues against a direct link.
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "However, the decreased Ca2+ release could lead to decreased activation of Ca2+ regulated pathways, which could impact muscle function."
      explanation: The same authors allow an indirect route through calcium-regulated pathways.
- name: Fast-Twitch Muscle Fibre Dysfunction
  biological_scale: TISSUE
  description: >-
    Fast-twitch muscles generate less force. Knock-in mice develop a progressive myopathy
    after one year, and in patients the vacuolar pathology mainly involves type II
    fibres.
  cell_types:
  - preferred_term: fast-twitch muscle fibre
    term:
      id: CL:0000190
      label: fast muscle cell
  evidence:
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age"
    explanation: Knock-in mice reproduce a late fast-twitch force deficit.
  downstream:
  - target: Proximal muscle weakness
  - target: Exercise intolerance
  - target: Fatigue
  - target: Myalgia
  - target: Muscle cramps
  - target: Elevated serum creatine kinase
  - target: Quadriceps atrophy
  - target: Scapular winging
  - target: Fibrofatty replacement of muscle on MRI
phenotypes:
- category: Musculoskeletal
  name: Elevated serum creatine kinase
  description: >-
    Mild to moderate hyperCKaemia is common and is sometimes the only sign of the
    disease.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  evidence:
  - reference: PMID:26136523
    reference_title: "A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation."
    explanation: Family series showing frequent and sometimes isolated hyperCKaemia.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both had mildly to moderately elevated serum creatine kinase levels."
    explanation: Supports the mild to moderate degree of elevation.
  - reference: ORPHA:88635
    reference_title: "Vacuolar myopathy with sarcoplasmic reticulum protein aggregates"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003236 | Elevated circulating creatine kinase concentration | Very frequent (99-80%)"
    explanation: Orphanet annotates raised creatine kinase as very frequent.
- category: Musculoskeletal
  name: Exercise intolerance
  description: A common presenting complaint, usually in the sixth decade.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients usually presented in the sixth decade with exercise intolerance and myalgias"
    explanation: Presenting symptoms in the 22-patient cohort.
- category: Musculoskeletal
  name: Myalgia
  phenotype_term:
    preferred_term: Myalgia
    term:
      id: HP:0003326
      label: Myalgia
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients usually presented in the sixth decade with exercise intolerance and myalgias"
    explanation: Myalgia is a presenting symptom.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report two unrelated Chinese patients presenting with late-onset, slowly progressive muscle weakness, fatigue, and myalgia."
    explanation: Myalgia also accompanies the p.Asp244His allele.
- category: Musculoskeletal
  name: Muscle cramps
  phenotype_term:
    preferred_term: Muscle cramps
    term:
      id: HP:0003394
      label: Muscle spasm
  evidence:
  - reference: PMID:25116801
    reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "affected by a mild myopathy accompanied by one or more symptoms, including episodes of muscle cramping, reduced muscle strength, fatigue and elevated plasma creatine kinase (CK) levels"
    explanation: Cramping episodes are among the symptoms in the first genetically defined cohort.
- category: Musculoskeletal
  name: Fatigue
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:25116801
    reference_title: "A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation in the calsequestrin-1 gene (CASQ1) was found in a group of patients with a myopathy characterized by weakness, fatigue, and the presence of large vacuoles"
    explanation: Fatigue is part of the defining clinical picture.
- category: Musculoskeletal
  name: Proximal muscle weakness
  description: >-
    Mild to moderate, slowly progressive proximal weakness develops after the initial
    exercise-related symptoms in some patients.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
    explanation: Describes the later weakness in the cohort.
- category: Musculoskeletal
  name: Quadriceps atrophy
  phenotype_term:
    preferred_term: Quadriceps muscle atrophy
    term:
      id: HP:0009050
      label: Quadriceps muscle atrophy
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
    explanation: Quadriceps atrophy accompanies the proximal weakness.
- category: Musculoskeletal
  name: Scapular winging
  phenotype_term:
    preferred_term: Scapular winging
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging"
    explanation: Scapular winging is part of the later phenotype.
- category: Musculoskeletal
  name: Distal upper limb weakness
  description: >-
    Reported in a single patient with the p.Val256Met allele, in whom weakness began in
    the distal upper limbs; this distribution is unusual for the disease.
  phenotype_term:
    preferred_term: Distal upper limb muscle weakness
    term:
      id: HP:0008959
      label: Distal upper limb muscle weakness
  evidence:
  - reference: PMID:36514469
    reference_title: "CASQ1-related myopathy: The first report from China and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1-related patients"
    explanation: Single case report of a distal-predominant presentation.
- category: Musculoskeletal
  name: Fibrofatty replacement of muscle on MRI
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle MRI (n = 11) showed a recurrent fibrofatty substitution pattern."
    explanation: Muscle imaging finding in the cohort.
- category: Musculoskeletal
  name: Nonrimmed vacuoles in type II fibres
  description: >-
    Vacuoles mainly in type II fibres that lack a rim and look empty on
    haematoxylin-eosin, Gomori trichrome and NADH stains.
  subtype: Vacuolar aggregate type
  diagnostic: true
  phenotype_term:
    preferred_term: Nonrimmed muscle vacuoles
    term:
      id: HP:6000978
      label: Nonrimmed muscle vacuoles
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
    explanation: Optically empty vacuoles in type II fibres in the founder-allele cohort.
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsies revealed typical optically empty vacuoles primarily in type II fibers."
    explanation: The same finding with p.Asp244His.
- category: Musculoskeletal
  name: Sarcoplasmic reticulum protein inclusions in vacuoles
  description: >-
    Vacuoles in type II fibres contain inclusions of calsequestrin, SERCA1, RyR1 and
    other sarcoplasmic reticulum proteins. The vacuoles are empty on routine stains,
    so diagnosis needs a muscle biopsy with immunostaining or electron microscopy.
  subtype: Vacuolar aggregate type
  diagnostic: true
  phenotype_term:
    preferred_term: Muscle fiber cytoplasmatic inclusion bodies
    term:
      id: HP:0100303
      label: Muscle fiber cytoplasmatic inclusion bodies
  evidence:
  - reference: PMID:16714317
    reference_title: "SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The sarcoplasmic or endoplasmic reticulum calcium 1 (SERCA1) ATPase and/or calsequestrin reactivity of inclusions, by immunohistochemistry, and the SERCA1- and calsequestrin-increased expression, by immunoblot, suggested that inclusions were constituted by an excess of proteins normally present in the terminal cisternae of sarcoplasmic reticulum."
    explanation: Immunohistochemistry and immunoblot of patient inclusions.
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle histopathology in patients with p.Asp244Gly showed vacuoles in type II fibers appearing empty in hematoxylin-eosin, Gomori, and nicotinamide adenine dinucleotide (NADH) tetrazolium reductase stains but strongly positive for sarcoplasmic reticulum proteins."
    explanation: Vacuoles stain for sarcoplasmic reticulum proteins despite appearing empty.
- category: Musculoskeletal
  name: Tubular aggregates in muscle fibres
  subtype: Tubular aggregate type
  diagnostic: true
  phenotype_term:
    preferred_term: Muscle fiber tubular inclusions
    term:
      id: HP:0100301
      label: Muscle fiber tubular inclusions
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The muscle histopathology of p.Gly103Asp mutation was different, showing also NADH-positive accumulation consistent with tubular aggregates."
    explanation: Tubular aggregates in the p.Gly103Asp patient.
  - reference: PMID:28895244
    reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy."
    explanation: Patients with other CASQ1 alleles have tubular aggregate myopathy.
genetic:
- name: CASQ1
  gene_term:
    preferred_term: CASQ1
    term:
      id: hgnc:1512
      label: CASQ1
  relationship_type: CAUSATIVE
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    CASQ1 encodes calsequestrin-1, the main calcium-binding protein of the skeletal
    muscle sarcoplasmic reticulum, expressed mainly in fast-twitch fibres. Reported
    pathogenic alleles are heterozygous and nearly all missense. No ClinGen
    gene-disease validity assertion for CASQ1 is cached in this repository.
  evidence:
  - reference: PMID:26136523
    reference_title: "A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is due to the D244G heterozygous missense mutation in the CASQ1 gene"
    explanation: Linkage and exome sequencing in three families identify the causal CASQ1 variant.
  - reference: ORPHA:88635
    reference_title: "Vacuolar myopathy with sarcoplasmic reticulum protein aggregates"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CASQ1 | calsequestrin 1 | hgnc:1512 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CASQ1 as the disease-causing gene.
  variants:
  - name: p.Asp244Gly
    description: >-
      Italian founder allele in a high-affinity calcium-binding site; causes the
      vacuolar aggregate presentation and accounted for 21 of 22 patients in the
      largest cohort.
    evidence:
    - reference: PMID:26136523
      reference_title: "A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect."
      explanation: Shared haplotype indicates a founder allele.
    - reference: PMID:30258016
      reference_title: "The clinical spectrum of CASQ1-related myopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Twenty-two CASQ1-mutated patients (12 families) were identified, 21 sharing the previously described founder mutation (p.Asp244Gly) and 1 with the p.Gly103Asp mutation."
      explanation: Shows how dominant the founder allele is in the Italian cohort.
  - name: p.Asp244His
    description: >-
      A second substitution at the same residue, reported in Chinese patients. Two
      unrelated families had the vacuolar presentation; a de novo patient had both
      tubular aggregates and vacuoles.
    evidence:
    - reference: PMID:41699400
      reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue."
      explanation: Identifies p.Asp244His in two unrelated families.
    - reference: PMID:38818562
      reference_title: "[Identification of a novel variant in a patient with Calsequestrin 1 related myopathy]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The same variant was not found in his unaffected parents."
      explanation: The variant arose de novo in this patient.
    - reference: PMID:38818562
      reference_title: "[Identification of a novel variant in a patient with Calsequestrin 1 related myopathy]."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To explore the genetic basis of a myopathic patient with pathological characteristics including tubular aggregates and vacuoles."
      explanation: The de novo p.Asp244His patient had mixed histology.
  - name: p.Gly103Asp
    description: Tubular aggregate allele with reduced calcium-dependent polymerisation.
    evidence:
    - reference: PMID:28895244
      reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "showed a reduced Ca2+ -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations"
      explanation: Functional defect of the allele.
  - name: p.Asp44Asn
    description: Tubular aggregate allele with reduced calcium-dependent polymerisation and weakened SOCE inhibition.
    evidence:
    - reference: PMID:28895244
      reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
      explanation: Functional defect of the allele.
  - name: p.Ile385Thr
    description: Tubular aggregate allele with slightly increased calcium-dependent aggregation and weakened SOCE inhibition.
    evidence:
    - reference: PMID:28895244
      reference_title: "Identification and characterization of three novel mutations in the CASQ1 gene in four patients with tubular aggregate myopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca2+ entry"
      explanation: Functional defect of the allele.
  - name: p.Glu89Lys
    description: >-
      Found in a family with exercise intolerance, cramps and myalgia, whose biopsies
      showed altered triads and SR-feet rather than vacuoles or tubular aggregates. The
      proband also carried biallelic NEB variants, which may explain her nemaline bodies.
    evidence:
    - reference: PMID:41313434
      reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A variant in CASQ1, p.(Glu89Lys), was found in all patients, whereas the proband had also two compound heterozygous variants in NEB."
      explanation: Segregation of the variant and the confounding NEB genotype.
    - reference: PMID:41313434
      reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In electron microscopy, there were morphological changes in the triads and the SR-feet in all patients."
      explanation: Ultrastructural finding in this family.
  - name: p.Val256Met
    description: Reported in one patient with distal-predominant upper limb weakness and rare vacuoles.
    evidence:
    - reference: PMID:36514469
      reference_title: "CASQ1-related myopathy: The first report from China and the literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Next-generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1."
      explanation: Case report identifying the allele.
  - name: p.Gly383Alafs*39
    description: C-terminal frameshift that extends the protein; the extended protein aggregates in transfected cells.
    evidence:
    - reference: PMID:41313434
      reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Cell-transfection studies showed that the variant protein forms aggregates."
      explanation: Functional evidence for the frameshift allele.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous CASQ1 variants segregate as an autosomal dominant trait in families.
    De novo occurrence has been reported.
  evidence:
  - reference: PMID:26136523
    reference_title: "A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 10 patients from three Italian families with autosomal dominant benign vacuolar myopathy and hyperCKaemia"
    explanation: Dominant segregation in three families.
  - reference: PMID:41313434
    reference_title: "Characterization of novel CASQ1 variants in two families with unusual phenotypic features."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "To date, seven pathogenic variants have been described, all dominant missense variants."
    explanation: Summarises the dominant inheritance of known alleles.
  - reference: PMID:38818562
    reference_title: "[Identification of a novel variant in a patient with Calsequestrin 1 related myopathy]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The same variant was not found in his unaffected parents."
    explanation: A de novo occurrence.
progression:
- phase: Adult onset and slow progression
  notes: >-
    Symptoms usually begin in adulthood, often in the sixth decade, with exercise
    intolerance and myalgia. Weakness, when it develops, is mild to moderate and slowly
    progressive; some patients have only hyperCKaemia.
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging."
    explanation: Natural history in the largest cohort.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  notes: Orphanet worldwide point-prevalence class below 1 in 1,000,000.
  evidence:
  - reference: ORPHA:88635
    reference_title: "Vacuolar myopathy with sarcoplasmic reticulum protein aggregates"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | PMID:16714317"
    explanation: Orphanet epidemiology table.
diagnosis:
- name: Muscle biopsy
  description: >-
    The vacuoles look empty on routine stains but stain for sarcoplasmic reticulum
    proteins, so immunostaining or electron microscopy of biopsy tissue helps recognise
    them. Patients whose only sign is hyperCKaemia may go undiagnosed
    without a biopsy.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:26136523
    reference_title: "A CASQ1 founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed, and the condition could be more common than supposed."
    explanation: Authors stress the role of biopsy in recognising the disease.
- name: Genetic testing
  description: Exome or targeted sequencing identifies the heterozygous CASQ1 variant.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:41699400
    reference_title: "Vacuolar myopathy caused by CASQ1 p.Asp244His: pathogenic evidence from two unrelated Chinese families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing identified an identical heterozygous CASQ1 variant, c.730G > C (p.Asp244His), located at a highly conserved residue."
    explanation: Exome sequencing established the diagnosis.
differential_diagnoses:
- name: STIM1- and ORAI1-related tubular aggregate myopathy
  description: >-
    Tubular aggregates also occur with gain-of-function STIM1 and ORAI1 variants and
    with PGAM2, SCN4A and ALG14 variants, so tubular aggregates on biopsy do not point
    to CASQ1 alone.
  evidence:
  - reference: PMID:34908252
    reference_title: "Genetic defects are common in myopathies with tubular aggregates."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14."
    explanation: Genetic heterogeneity of myopathies with tubular aggregates.
animal_models:
- name: Casq1 p.Asp244Gly knock-in mouse
  species: Mouse
  genotype: Casq1 D244G heterozygous knock-in
  publication: PMID:33786938
  description: >-
    Heterozygous knock-in mice develop a late, progressive fast-twitch myopathy with
    CASQ1 mislocalisation, reduced calcium release, ER stress and impaired clearance of
    aggregated proteins.
  modeled_mechanisms:
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: ER stress markers rise in fast-twitch muscle of older mice.
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, ER stress markers sXbp1, BiP, and CHOP were significantly elevated in the EDL muscle of 8-month-old DG compared to WT mice"
      explanation: Direct measurement in the model.
  - target: Reduced Sarcoplasmic Reticulum Calcium Release
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Junctional CASQ1 loss reduces calcium release in mouse fibres.
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Decreased junctional CASQ1 reduces SR Ca2+ release."
      explanation: Direct measurement in the model.
  - target: Reduced Junctional CASQ1 Localisation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Mutant CASQ1 partly leaves the junctional sarcoplasmic reticulum.
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)."
      explanation: Direct observation in the model.
  - target: Fast-Twitch Muscle Fibre Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Late, progressive loss of fast-twitch force.
    limitations: >-
      Onset is after one year in mice; the human disease typically presents in the sixth
      decade, so the time course is compressed.
    evidence:
    - reference: PMID:33786938
      reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "display a progressive myopathy characterized by decreased activity, decreased ability of fast twitch muscles to generate force and low body weight after one year of age"
      explanation: Direct measurement in the model.
discussions:
- discussion_id: casq1_cardiac_involvement
  prompt: >-
    Are the subclinical cardiac abnormalities seen in some CASQ1 myopathy patients part
    of the disease, given that the heart expresses CASQ2 rather than CASQ1?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#Myopathy Due To Calsequestrin And SERCA1 Protein Overload
  rationale: >-
    Three of 22 patients in the largest cohort had subclinical cardiac findings, but the
    report gives no mechanism, and a later literature review notes that cardiac
    insufficiency is rarely seen. No cardiac phenotype is recorded in this entry.
  evidence:
  - reference: PMID:30258016
    reference_title: "The clinical spectrum of CASQ1-related myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients presented subclinical cardiac abnormalities."
    explanation: The cohort report of cardiac findings.
  - reference: PMID:36514469
    reference_title: "CASQ1-related myopathy: The first report from China and the literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Despite experimental evidence suggesting that CASQ1 deficiency is causally related to malignant hyperthermia-like arrhythmia, respiratory and cardiac insufficiency have rarely appeared in CASQ1-related cases."
    explanation: Literature review finding cardiac involvement uncommon.
- discussion_id: casq1_calcium_versus_proteotoxic_drivers
  prompt: >-
    How much of the vacuolar myopathy is driven by reduced sarcoplasmic reticulum calcium
    release, and how much by ER stress and failed clearance of aggregated protein?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reduced Sarcoplasmic Reticulum Calcium Release
  - pathophysiology#Endoplasmic Reticulum Stress and Unfolded Protein Response
  - pathophysiology#Impaired Clearance of Aggregated Proteins
  rationale: >-
    In the knock-in mouse both processes are present and appear to act through largely
    separate pathways, but their relative weight has not been tested, for example by
    relieving ER stress without changing calcium handling.
  evidence:
  - reference: PMID:33786938
    reference_title: "Pathological mechanisms of vacuolar aggregate myopathy arising from a Casq1 mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Differentiating between the contributions to the disease process of altered Ca2+ signaling and changes driven by ER stress and uncleared protein aggregates requires further study."
    explanation: The model's authors state the question as open.
references:
- reference: PMID:16714317
  title: "SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy."
  findings:
  - statement: First description of the disease as a surplus-protein myopathy with SERCA1 and calsequestrin inclusions, before CASQ1 was identified as the gene.
- reference: PMID:25116801
  title: A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates.
  findings:
  - statement: Identifies CASQ1 p.Asp244Gly and shows it impairs polymerisation and forms aggregate-filled SR vacuoles.
- reference: PMID:30258016
  title: The clinical spectrum of CASQ1-related myopathy.
  findings:
  - statement: Largest clinical cohort, 22 patients from 12 families.
📚

References & Deep Research

References

3
PMID:16714317
SERCA1 and calsequestrin storage myopathy: a new surplus protein myopathy.
1 finding
First description of the disease as a surplus-protein myopathy with SERCA1 and calsequestrin inclusions, before CASQ1 was identified as the gene.
PMID:25116801
A mutation in the CASQ1 gene causes a vacuolar myopathy with accumulation of sarcoplasmic reticulum protein aggregates.
1 finding
Identifies CASQ1 p.Asp244Gly and shows it impairs polymerisation and forms aggregate-filled SR vacuoles.
PMID:30258016
The clinical spectrum of CASQ1-related myopathy.
1 finding
Largest clinical cohort, 22 patients from 12 families.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Myopathy_Due_To_Calsequestrin_And_SERCA1_Protein_Overload · 2026-10-15T18:31:26Z · View source

New entry for CASQ1-related myopathy (MONDO:0014546, OMIM:616231), claimed in issue 14385. Scope decision: one Disease entry. MONDO has a single term for CASQ1 muscle disease, so the vacuolar aggregate presentation (p.Asp244Gly founder allele, p.Asp244His) and the tubular aggregate presentation (p.Asp44Asn, p.Gly103Asp, p.Ile385Thr) are recorded as allelic has_subtypes. The pathograph shares a polymerisation-defect root and branches: aggregation, junctional mislocalisation, ER stress and failed aggregate clearance for the vacuolar alleles; reduced calcium storage and loss of CASQ1 inhibition of store-operated calcium entry for the tubular aggregate alleles. Knock-in p.Asp244Gly mice show no SOCE increase (PMID:33786938), which supports keeping the branches separate. Deep research: OpenScientist (research/Myopathy_Due_To_Calsequestrin_And_SERCA1_Protein_Overload-deep-research-openscientist.md). preflight-dr PASS (CASQ1 mentioned 58 times). Its reference validation resolved 14/14 PMIDs; one quote attributed to PMID:26416891 was stitched across an ellipsis and was not reused. Its term validation flagged four wrong CURIEs (UBERON:0011907, NCIT:C15336, NCIT:C15682, NCIT:C98225); none were used. The report did not describe the SOCE mechanism of the tubular aggregate alleles; that branch comes from PMID:28895244 and PMID:39126637. Its Casq1-knockout and malignant-hyperthermia material (PMID:22130610, 26132720, 29062464, 22049211, 28465322, 36311237) concerns loss of CASQ1 function and was not curated into the entry. Additional primary literature beyond the report: PMID:28895244, 39126637, 36514469, 41313434, 38818562, 34908252, and ORPHA:88635 (Orphadata release 2026-06-23, newer than the manifest pin). PMID:29039140 (Bohm 2018) could not be retrieved with quotable text and is not cited. No GeneReviews chapter exists (check-genereviews --online: NO_CHAPTER). No treatment has been evaluated in patients, so there is no treatments section. Validation: just validate passes (schema, terms, references); count-verified-snippets all verified; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-block-scalar-comments pass. A red-team review before the PR found a false note claiming HPO had no non-rimmed vacuole term (HP:6000978 exists and is now used), an edge from calcium storage to SOCE that the source treats as parallel, and ER-stress edge evidence attached to the wrong edge; all were fixed.

OpenScientist ▸
Myopathy Due To Calsequestrin And SERCA1 Protein Overload — Comprehensive Disease Report
openscientist-autonomous 12 citations 2026-10-15T17:56:32.523848

Myopathy Due To Calsequestrin And SERCA1 Protein Overload — Comprehensive Disease Report

Disease: Myopathy due to calsequestrin and SERCA1 protein overload MONDO ID: MONDO:0014546 | OMIM: 616231 ("Myopathy, vacuolar, with CASQ1 aggregates; VMCQA") Causal gene: CASQ1 (calsequestrin-1), chromosome 1q21 Category: Mendelian (autosomal dominant) Date: 2026-10-15

Summary

Myopathy due to calsequestrin and SERCA1 protein overload is an ultra-rare, autosomal dominant, adult-onset, benign and slowly progressive skeletal-muscle disease caused by heterozygous missense mutations in CASQ1, the gene encoding the fast-twitch skeletal-muscle isoform of calsequestrin. The disorder was first defined morphologically in 2006 as a "surplus protein myopathy" in which muscle fibers contained non-staining vacuolar inclusions immunoreactive for the sarco/endoplasmic reticulum Ca²⁺-ATPase SERCA1 (ATP2A1) and/or calsequestrin (PMID: 16714317). Eight years later the causal lesion was identified as the heterozygous missense mutation CASQ1 c.731A>G, p.Asp244Gly (D244G), segregating as a founder mutation in Italian families (PMID: 25116801, PMID: 26136523).

Mechanistically, the Asp244 residue sits within a high-affinity Ca²⁺-binding site in Domain II of calsequestrin. The mutation causes the protein to lose Ca²⁺ binding and aggregate abnormally into electron-dense sarcoplasmic reticulum (SR) vacuoles that co-sequester SERCA1 and the ryanodine receptor RyR1, predominantly within type II (fast) fibers. Aggregated calsequestrin dissociates from the junctional SR, reducing SR Ca²⁺ storage and impairing Ca²⁺ release — a defect that has been termed a "CASQ1-couplonopathy" (PMID: 27196359). The downstream clinical picture is exercise intolerance, myalgia, mild-to-moderate slowly progressive proximal weakness, and mild-to-moderate elevation of serum creatine kinase (hyperCKemia), often presenting in the sixth decade of life (PMID: 30258016).

The disease is benign in prognosis and does not shorten life expectancy. There is no approved disease-specific therapy; management is supportive and includes physiotherapy, cardiac surveillance (rare subclinical cardiac findings), and genetic counseling for the dominant trait. A theoretical malignant-hyperthermia/heat-sensitivity concern arises from the related Casq1-null mouse model, in which antioxidants and estrogens are protective; these pharmacologic strategies remain unproven in humans. The disease is modeled by D244G knock-in and Casq1-knockout mice.

1. Disease Information

Overview. This is a hereditary vacuolar myopathy of skeletal muscle characterized by intracellular accumulation ("overload") of two terminal-cisternae SR proteins — calsequestrin-1 (CASQ1) and SERCA1 (ATP2A1) — forming inclusions within muscle fibers. It was originally delineated purely by muscle biopsy morphology and immunohistochemistry as a "SERCA1 and calsequestrin storage myopathy" / "surplus protein myopathy" (PMID: 16714317), and later unified genetically under mutations in CASQ1.

Key identifiers.

Resource Identifier
MONDO MONDO:0014546
OMIM (phenotype) 616231 — "MYOPATHY, VACUOLAR, WITH CASQ1 AGGREGATES; VMCQA"
Orphanet ORPHA:88635
GARD 0016770
MedGen / UMLS 864061 / C4015624
SNOMED CT 724095006

Synonyms / alternative names: - Myopathy due to calsequestrin and SERCA1 protein overload - Vacuolar myopathy with CASQ1 aggregates (VMCQA) - CASQ1-related myopathy - SERCA1 and calsequestrin storage myopathy - Protein aggregate myopathy with CASQ1 aggregates - CASQ1-couplonopathy (mechanistic designation)

Information source. Knowledge is derived from aggregated disease-level resources (OMIM, Orphanet, MONDO) and from individual patient reports/case series in the primary literature (Italian and Chinese families), not from large EHR datasets. The total reported experience worldwide is on the order of 30–40 patients.

2. Etiology

Disease causal factors. The disease is purely genetic (Mendelian, monogenic). It is caused by heterozygous gain-of-function/dominant missense mutations in CASQ1. There is no infectious or primary environmental cause.

Genetic risk factors. The principal causal variant is CASQ1 p.Asp244Gly (c.731A>G), a founder mutation in Italian families sharing a common haplotype (PMID: 26136523). Additional pathogenic alleles at the same or nearby residues broaden the allelic spectrum: - p.Asp244His (c.730G>C) — reported in two unrelated Chinese families (PMID: 41699400), establishing residue 244 as a mutational hotspot. - p.Gly103Asp — reported in one Italian family, with a distinctive tubular-aggregate histology (PMID: 30258016). - p.Met87Thr — a separate variant weakly associated with malignant hyperthermia susceptibility rather than the overload myopathy (PMID: 26416891).

Environmental risk factors. None established as causal. Theoretical triggers relevant to muscle Ca²⁺ handling — strenuous exercise, heat exposure, and volatile anesthetics — are implicated only from the Casq1-null mouse (see Section 15), not confirmed in the human overload myopathy.

Protective factors. No human genetic or environmental protective factors are established. In the Casq1-null mouse model, estrogens reduce oxidative stress and protect against lethal hyperthermic episodes (PMID: 29062464), and antioxidants (N-acetylcysteine, Trolox) are protective (PMID: 26132720) — but these pertain to the knockout MH phenotype, not the overload myopathy in humans.

Gene–environment interactions. Not formally characterized for the human disease. The mechanistic hypothesis — that a Ca²⁺-handling defect might be unmasked by heat/anesthetic/exercise stress — derives from the knockout model and remains inferred, not demonstrated, for patients.

3. Phenotypes

The clinical spectrum is best defined by the largest cohort to date: 22 CASQ1-mutated patients from 12 families (21 with p.Asp244Gly, 1 with p.Gly103Asp) (PMID: 30258016).

Phenotype Type Onset Severity Progression Frequency HPO suggestion
Exercise intolerance Symptom 6th decade Mild–moderate Slowly progressive Common presenting feature HP:0003546 (Exercise intolerance)
Myalgia Symptom 6th decade Mild Fluctuating Common presenting feature HP:0003326 (Myalgia)
Proximal muscle weakness Clinical sign Adult/late Mild–moderate Slowly progressive Develops later in most HP:0003701 (Proximal muscle weakness)
Quadriceps atrophy Physical Adult/late Mild–moderate Progressive Characteristic HP:0003327 (Axial muscle weakness)/quadriceps wasting
Scapular winging Clinical sign Adult/late Mild Progressive Characteristic HP:0003691 (Scapular winging)
HyperCKemia (elevated serum CK) Lab abnormality Adult Mild–moderate Stable/fluctuating Very common; sometimes sole feature HP:0003236 (Elevated serum creatine kinase)
Subclinical cardiac abnormality Lab/clinical Adult Mild Stable 3/22 (~14%) HP:0011675 (Arrhythmia)/HP:0001637 (Abnormal myocardium)

Key quotes. "Patients usually presented in the sixth decade with exercise intolerance and myalgias and later developed mild to moderate, slowly progressive proximal weakness with quadriceps atrophy and scapular winging" (PMID: 30258016). "Three patients presented subclinical cardiac abnormalities" (ibid.).

Quality-of-life impact. Because the disease is mild and slowly progressive, functional impact is limited; most patients remain ambulant. HyperCKemia may be the only manifestation, and many carriers are likely under-ascertained ("it is likely that CASQ1 mutations may remain undiagnosed if a muscle biopsy is not performed" — PMID: 30258016). No disease-specific QoL instrument (EQ-5D/SF-36/PROMIS) data are available.

4. Genetic/Molecular Information

Causal gene — CASQ1 (calsequestrin-1):

Annotation Value
HGNC HGNC:1512
OMIM (gene) 114250
NCBI Gene 844
Ensembl ENSG00000143318
UniProt P31415 (CASQ1_HUMAN)
Cytoband 1q21 (GRCh38 chr1:160,190,212–160,201,886)

Pathogenic variants.

Variant (protein) cDNA Type Population Phenotype Classification
p.Asp244Gly c.731A>G Missense Italian founder Vacuolar aggregate myopathy Pathogenic
p.Asp244His c.730G>C Missense Chinese (2 families) Vacuolar myopathy Pathogenic/likely pathogenic
p.Gly103Asp — Missense Italian (1 family) Myopathy w/ tubular aggregates Pathogenic
p.Met87Thr — Missense — Weak MH susceptibility (not overload myopathy) Risk variant

Variant classification notes. The Domain-II residue Asp244 is highly conserved ("a highly conserved residue" — PMID: 41699400); recurrence across independent populations (Italy, China) supports pathogenicity under ACMG criteria (PS1/PM1/PM5 — same residue, different substitutions).

Allele frequency. These are private/ultra-rare variants, essentially absent from population databases (gnomAD); the Italian cases share a single founder haplotype.

Somatic vs germline. All reported variants are germline, segregating in an autosomal dominant fashion.

Functional consequences. The mutation is best characterized as a dominant, toxic gain-of-function / dominant-negative aggregation defect combined with loss of normal Ca²⁺-buffering at the junctional SR: mutant CASQ1 loses high-affinity Ca²⁺ binding and aggregates abnormally, sequestering wild-type CASQ1 and partner proteins (SERCA1, RyR1).

Modifier genes. None established.

Epigenetic information / chromosomal abnormalities. Not applicable/not reported; this is a point-mutation monogenic disorder with no described epigenetic or structural chromosomal component.

5. Environmental Information

Environmental factors. None causally established. The disorder is monogenic. As a theoretical consideration (extrapolated from the knockout model, not the human overload myopathy), heat stress and volatile halogenated anesthetics could stress skeletal-muscle Ca²⁺ homeostasis.

Lifestyle factors. Strenuous exercise is a presenting trigger of symptoms (exercise intolerance, myalgia) but is not a disease cause.

Infectious agents. Not applicable — no infectious etiology.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. A heterozygous CASQ1 missense mutation at/near a Domain-II high-affinity Ca²⁺-binding site (p.Asp244Gly, p.Asp244His, or p.Gly103Asp) arises in the germline → leads to a structurally altered calsequestrin monomer.
  2. Loss of two coordinating Ca²⁺ ions in the mutant structure weakens the hydrophobic core of Domain II (demonstrated crystallographically for D244G) → results in loss of high-affinity Ca²⁺ binding at elevated Ca²⁺ (PMID: 26416891).
  3. Impaired Ca²⁺ binding reduces the ability of CASQ1 to form normal elongated polymers and instead causes abrupt, abnormal aggregation (PMID: 26416891).
  4. Aggregated mutant (and co-recruited wild-type) CASQ1 leads to the formation of electron-dense SR vacuoles that co-sequester SERCA1 (ATP2A1) and RyR1, preferentially in type II fibers (PMID: 25116801).
  5. In parallel (branch), the mutation causes CASQ1 to partially dissociate from the junctional SR and accumulate in the ER (shown in the D244G knock-in mouse) → reduces junctional CASQ1 content and SR Ca²⁺ stores (PMID: 33786938).
  6. Reduced junctional calsequestrin and disrupted couplon architecture result in less Ca²⁺ release from the SR of mutant fibers compared with controls (patient-derived myotubes) → defining a "CASQ1-couplonopathy" (PMID: 27196359).
  7. Chronically altered Ca²⁺ handling and protein overload lead to the clinical phenotype: exercise intolerance, myalgia, mild proximal weakness, and hyperCKemia (PMID: 30258016).
CASQ1 D244G/D244H/G103D (germline, heterozygous)
│  (Domain II high-affinity Ca2+ site)
▼
Loss of 2 Ca2+ ions → weakened Domain II hydrophobic core   [crystallography, in vitro]
│
├──────────────► Abnormal/abrupt aggregation; loss of normal polymerization
│                        │
│                        ▼
│                Electron-dense SR vacuoles sequestering CASQ1 + SERCA1 + RyR1
│                (type II fibers)  → "surplus protein / overload"
│
└──────────────► Partial dissociation of CASQ1 from junctional SR → ER accumulation [KI mouse]
                 │
                 ▼
    ↓ Junctional CASQ1, ↓ SR Ca2+ store → ↓ SR Ca2+ release ("couplonopathy")
                 │
                 ▼
  Adult-onset, slowly progressive, mild proximal myopathy + hyperCKemia

Detail by category

  • Molecular pathways. Excitation–contraction (EC) coupling: SR Ca²⁺ storage/release through the RyR1–DHPR couplon; Ca²⁺ reuptake via SERCA1. Calsequestrin is the principal luminal Ca²⁺ buffer that modulates RyR1 gating.
  • Cellular processes. Protein aggregation / proteostasis failure in the SR; vacuole formation; altered intracellular Ca²⁺ signaling. GO suggestions: GO:0006874 (cellular calcium ion homeostasis), GO:0051209 (release of sequestered calcium ion into cytosol), GO:0005513 (detection of calcium ion), GO:0006457 (protein folding).
  • Protein dysfunction. Loss of high-affinity Ca²⁺ binding, impaired polymerization, and toxic aggregation — a mixed loss-of-buffer + gain-of-aggregation mechanism. Normal CASQ1 binds ~80 Ca²⁺ ions and polymerizes to form the SR terminal-cisternae matrix.
  • Metabolic changes. Secondary; chronically impaired Ca²⁺ cycling can affect fatigue resistance/energy metabolism in fast fibers (exercise intolerance), though not directly profiled in patients.
  • Immune system involvement. None; this is a non-inflammatory, non-autoimmune protein-aggregate myopathy.
  • Tissue damage mechanisms. Chronic vacuolar accumulation and Ca²⁺ dysregulation in type II fibers; mild myofiber stress releasing CK. In the knockout MH model, oxidative stress is central — but that is the loss-of-function phenotype.
  • Biochemical abnormalities. Defective luminal SR Ca²⁺ buffering (ion-handling defect) rather than an enzyme deficiency.
  • Subcellular localization. SR terminal cisternae / junctional SR lumen (GO:0033018 sarcoplasmic reticulum lumen region, GO:0014701 junctional sarcoplasmic reticulum membrane); pathologic mislocalization to the ER (GO:0005783 endoplasmic reticulum).

Cell types involved. Skeletal muscle fibers, specifically fast-twitch type II fibers — CL:0000190 (fast muscle cell) / CL:0008002 (skeletal muscle fiber).

7. Anatomical Structures Affected

  • Organ/system level. Primary: skeletal muscle (musculoskeletal system). Distribution is proximal and bilateral/symmetric — quadriceps (anterior thigh), scapular/periscapular muscles (scapular winging). Secondary: heart — subclinical cardiac abnormalities in ~14% (3/22) (PMID: 30258016).
  • Tissue/cell level. Striated muscle tissue; predominantly type II (fast-twitch) fibers contain the vacuolar aggregates.
  • Subcellular level. Sarcoplasmic reticulum terminal cisternae / junctional SR; abnormal accumulation in the endoplasmic reticulum.
  • UBERON/CL suggestions. UBERON:0001134 (skeletal muscle tissue), UBERON:0011907 (quadriceps femoris), UBERON:0000948 (heart, secondary), UBERON:0002349 (myocardium); CL:0000190 (fast muscle cell). GO cellular component: GO:0016529 (sarcoplasmic reticulum), GO:0033018, GO:0005783.
  • Lateralization. Bilateral, symmetric proximal involvement.

8. Temporal Development

  • Onset. Adult, typically the sixth decade; onset is insidious/chronic. HyperCKemia may precede or exist without overt weakness.
  • Progression. Slowly progressive; weakness remains mild-to-moderate; patients generally remain ambulant. Muscle MRI shows a recurrent fibrofatty substitution pattern (reported in 11 patients) (PMID: 30258016).
  • Disease course. Chronic, lifelong, but benign; no reported end-stage/wheelchair-dependent phase as a rule.
  • Patterns. No spontaneous remission; no relapsing-remitting pattern. Symptoms (myalgia, exercise intolerance) may fluctuate with activity. Critical periods for intervention are not defined because no disease-modifying therapy exists.

9. Inheritance and Population

  • Epidemiology. Ultra-rare. The world literature totals roughly 30–40 reported patients, concentrated in Italy (founder p.Asp244Gly) plus isolated Chinese families. Orphanet prevalence: unknown, <1/1,000,000. Likely under-ascertained because mild cases escape biopsy (PMID: 30258016).
  • Inheritance pattern. Autosomal dominant (heterozygous missense variants).
  • Penetrance / expressivity. Appears high but with variable expressivity (ranging from isolated hyperCKemia to symptomatic proximal weakness); formal penetrance estimates are not established.
  • Genetic anticipation / mosaicism. Not applicable (not a repeat-expansion disorder); germline mosaicism not reported.
  • Founder effects. Yes — a shared Italian founder haplotype for p.Asp244Gly (PMID: 26136523).
  • Consanguinity / carrier frequency. Not relevant to a dominant disorder; carrier frequency not meaningfully defined.
  • Population demographics. Italian (founder) and Chinese families reported; both sexes affected; adult age distribution (sixth decade typical).

10. Diagnostics

  • Laboratory. Serum creatine kinase mildly-to-moderately elevated (hyperCKemia), sometimes the sole abnormality (HP:0003236).
  • Muscle biopsy (diagnostic cornerstone). Vacuoles in type II fibers appearing "empty" on H&E, Gomori trichrome, and NADH-tetrazolium reductase stains, but strongly positive for SR proteins (SERCA1/ATP2A1 and calsequestrin) by immunohistochemistry; immunoblot shows increased SERCA1 and calsequestrin (PMID: 16714317; PMID: 30258016). The p.Gly103Asp variant additionally shows NADH-positive tubular aggregates. Electron microscopy: electron-dense SR vacuoles.
  • Imaging. Muscle MRI shows a recurrent fibrofatty substitution pattern.
  • Electrophysiology. EMG may show myopathic features; patient-derived myotubes show reduced SR Ca²⁺ release on Ca²⁺ imaging/electrophysiology (research setting) (PMID: 27196359).
  • Genetic testing. Confirmatory. Recommended approach: single-gene testing of CASQ1 (targeting the Asp244 hotspot) or a myopathy/limb-girdle gene panel; WES/WGS are useful for undiagnosed cases, especially given the characteristic biopsy. Chromosomal microarray, karyotyping, FISH, mtDNA testing, and repeat-expansion testing are not applicable.
  • Clinical criteria / differential diagnosis. No formal consensus criteria; diagnosis rests on the triad of (1) adult-onset mild proximal myopathy/hyperCKemia, (2) SR-protein-positive type II fiber vacuoles, and (3) a pathogenic CASQ1 variant. Differential diagnoses: tubular aggregate myopathies (STIM1/ORAI1), other protein-aggregate/vacuolar myopathies, limb-girdle muscular dystrophies, and idiopathic hyperCKemia.
  • Screening. Cascade genetic testing of at-risk relatives in known families. No population newborn/carrier screening (ultra-rare, dominant, benign).

11. Outcome/Prognosis

  • Survival/mortality. Benign; life expectancy is not reported to be reduced; no disease-specific mortality established.
  • Morbidity/function. Mild-to-moderate proximal weakness with slow progression; most patients remain ambulant and functionally independent. Rare subclinical cardiac abnormalities (~14%) warrant surveillance but have not been linked to adverse outcomes.
  • Disease course/complications. Chronic but stable-to-slowly-progressive. Theoretical anesthetic/heat risk is extrapolated from the knockout model and remains unproven in patients.
  • Prognostic factors. None validated. Genotype may influence histology (tubular aggregates with p.Gly103Asp) but not clearly prognosis.
  • Supporting quote. Patients "later developed mild to moderate, slowly progressive proximal weakness" (PMID: 30258016).

12. Treatment

  • Pharmacotherapy. No approved disease-specific or targeted drug. Management is supportive.
  • Advanced therapeutics (gene/cell/RNA). None in clinical use; the dominant aggregation mechanism could in principle be amenable to allele-specific knockdown (ASO/siRNA) in the future, but no such program is reported.
  • Supportive/rehabilitative. Physiotherapy, graded exercise modification for exercise intolerance/myalgia, periodic cardiac surveillance given rare subclinical cardiac findings.
  • Experimental / mechanistic leads. From the Casq1-null mouse (loss-of-function MH model, distinct from the overload disease): antioxidants (N-acetylcysteine, Trolox) protected against lethal halothane/heat-triggered hypermetabolic episodes, reducing mortality from ~79–86% to ~20–33% (PMID: 26132720), and estrogens reduced oxidative stress and mortality (PMID: 29062464). These suggest antioxidant strategies and anesthetic/heat precautions as rational but unproven approaches in humans.
  • Treatment outcomes / adverse events. Not applicable (no disease-specific therapy).
  • NCIT suggestions. NCIT:C15336 (Supportive Care), NCIT:C15682 (Physical Therapy), NCIT:C98225 (Genetic Counseling), NCIT:C265 (Antioxidant) — all general/supportive.

13. Prevention

  • Primary prevention. None for a Mendelian disorder.
  • Secondary prevention. Early detection via cascade genetic testing in known families; recognition of isolated hyperCKemia prompting biopsy/genetics.
  • Tertiary prevention. Cardiac surveillance; prudent anesthetic and heat precautions (theoretical, extrapolated from the knockout model).
  • Immunization / public health / environmental interventions. Not applicable.
  • Counseling. Genetic counseling for autosomal dominant inheritance (50% transmission risk); theoretical prenatal/preimplantation genetic testing is possible but rarely indicated given the benign course.

14. Other Species / Natural Disease

  • Taxonomy / orthologs. Mouse ortholog Casq1: MGI:1309468, NCBI Gene 12372, Ensembl ENSMUSG00000007122. CASQ1 is highly conserved across mammals.
  • Natural disease in other species. No naturally occurring animal homolog of this specific overload myopathy is reported (OMIA). Disease knowledge in animals comes from engineered models (Section 15).
  • Comparative biology. Calsequestrin's role in SR Ca²⁺ storage and EC coupling is evolutionarily conserved, underpinning the translational relevance of mouse models.
  • Transmission. Not applicable (non-communicable genetic disease; no zoonotic potential).

15. Model Organisms

Two complementary mouse models anchor the mechanistic understanding, and cellular systems recapitulate the aggregation phenotype.

Model Type Key phenotype Relevance to human disease
D244G knock-in mouse Mammalian, knock-in CASQ1 partially dissociates from junctional SR and accumulates in ER; reduced junctional CASQ1 and SR Ca²⁺ (PMID: 33786938) Directly models the human overload/couplonopathy mechanism
Casq1-null (knockout) mouse Mammalian, knockout (loss of function) Viable, normal motor activity, moderate atrophy; profound EC-coupling remodeling (shrunken jSR, proliferating SR/T-tubule contacts, ↑RyR density); lethal MH-like hypermetabolic episodes on halothane/heat (PMID: 22130610; PMID: 26132720) Models malignant-hyperthermia/heat susceptibility; oxidative-stress mechanism; estrogen/antioxidant protection
COS-7 cells, myotubes, patient-derived myotubes In vitro/cellular Mutant CASQ1 forms electron-dense SR vacuoles with CASQ1/RyR1 aggregates; reduced polymerization; less SR Ca²⁺ release (PMID: 25116801; PMID: 27196359) Recapitulates aggregation and the Ca²⁺-release defect
Recombinant protein / crystallography Biophysical D244G lacks two Ca²⁺ ions, weakened Domain II core, abrupt aggregation (PMID: 26416891) Structural basis of the defect

Rescue evidence. Re-introduction of wild-type CASQ1 by cDNA electrotransfer in Casq1-null muscle restores junctional SR targeting, terminal-cisternae ultrastructure, and Ca²⁺ transient amplitude (PMID: 22049211) — confirming CASQ1's causal role in both Ca²⁺ homeostasis and terminal-cisternae structure.

Model limitations. The Casq1-null mouse models loss of function and its dominant feature is MH/heat susceptibility, which is not the primary human overload phenotype; the knock-in D244G mouse better reflects the human dominant aggregation/couplonopathy. Resources: MGI (Casq1, MGI:1309468).

Mechanistic Model / Interpretation

The convergent human (biopsy, patient-myotube electrophysiology, 22-patient cohort), in vitro (crystallography, cell aggregation), and mouse (D244G knock-in, Casq1 knockout) evidence defines a single coherent model:

A heterozygous CASQ1 missense mutation at/near a Domain II high-affinity Ca²⁺ site (D244G / D244H / G103D) → loss of Ca²⁺ binding + abnormal aggregation → electron-dense SR/ER vacuoles sequestering CASQ1, SERCA1, and RyR1 in type II fibers → dissociation of CASQ1 from the junctional SR → reduced SR Ca²⁺ storage and release (CASQ1-couplonopathy) → adult-onset, slowly progressive, mild proximal myopathy with hyperCKemia.

Upstream events are molecular/biophysical (the mutation, loss of Ca²⁺ coordination, aggregation); downstream events are physiological and clinical (impaired EC coupling, weakness, CK leak). The disease unifies two apparently opposite effects — a gain of toxic protein (the "overload"/surplus protein storage) and a loss of functional junctional buffering (the couplonopathy) — into one pathogenic cascade. Notably, calsequestrin dysfunction produces two divergent human phenotypes depending on the allele: the benign dominant overload myopathy (D244G/D244H/G103D) versus a weak malignant-hyperthermia association (M87T), with the knockout mouse illustrating the MH/heat-stress extreme of the loss-of-function axis.

Evidence Base

PMID Title (abbrev.) Evidence type Supports
16714317 SERCA1 and calsequestrin storage myopathy Human (biopsy) Original morphological definition (surplus SR-protein myopathy)
25116801 CASQ1 mutation causes vacuolar myopathy Human genetics + cellular Causal D244G; vacuoles; altered Ca²⁺ release
26136523 CASQ1 founder mutation, 3 Italian families Human genetics Founder effect; benign evolution
41699400 CASQ1 p.Asp244His, 2 Chinese families Human genetics Second hotspot variant; conserved residue
26416891 Characterization of two CASQ1 mutants Biophysical/crystallography Structural basis: loss of Ca²⁺, abnormal aggregation; D244G vs M87T
27196359 CASQ1 mutation alters SR Ca²⁺ release Patient myotubes Reduced SR Ca²⁺ release; "CASQ1-couplonopathy"
33786938 Pathological mechanisms from Casq1 mutation D244G knock-in mouse jSR→ER mislocalization; reduced SR Ca²⁺
30258016 Clinical spectrum of CASQ1 myopathy Human cohort (n=22) Onset, weakness distribution, histology, cardiac, MRI
22130610 Lessons from Casq1 ablation Knockout mouse EC-coupling remodeling
26132720 Antioxidants protect Casq1-null mice Knockout mouse MH/heat phenotype; antioxidant protection
29062464 Estrogens protect Casq1-null mice Knockout mouse Estrogen protection; sex difference
22049211 CASQ1 rescues Casq1-null muscle Knockout + rescue Confirms CASQ1 role in Ca²⁺ and structure
28465322 Exercise triggers MH-like response Mouse (RyR1/MH) Exercise as a trigger in MH-susceptible muscle
36311237 Ablation of Calsequestrin-1 Mouse CASQ1 ablation effects

Notable verbatim support. - "The mutation affects a conserved aspartic acid in position 244 (p.Asp244Gly) located in one of the high-affinity Ca(2+)-binding sites of CASQ1 and alters the kinetics of Ca(2+) release in muscle fibers." (PMID: 25116801) - "D244G aggregates abruptly and abnormally … D244G crystallized in low Ca(2+) concentrations lacks two Ca(2+) ions normally present in wild type that weakens the hydrophobic core of Domain II." (PMID: 26416891) - "Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls." (PMID: 27196359) - "The DG mutation causes CASQ1 to partially dissociate from the junctional sarcoplasmic reticulum (SR) and accumulate in the endoplasmic reticulum (ER)." (PMID: 33786938)

Limitations and Knowledge Gaps

  1. Small evidence base. Only ~30–40 patients worldwide; cohort statistics (e.g., 22-patient series) dominate, so penetrance, true prevalence, and genotype–phenotype correlations are imprecise.
  2. Ascertainment bias. Mild/isolated-hyperCKemia cases likely under-diagnosed without muscle biopsy, so the spectrum may be broader and milder than reported.
  3. Mechanistic duality unresolved in humans. The human overload myopathy vs the knockout MH/heat-stress phenotype are modeled in different systems; whether human D244G patients carry a clinically meaningful anesthetic/heat risk is not demonstrated — the precaution is extrapolated.
  4. No human therapeutic data. Antioxidant/estrogen protection is only shown in Casq1-null mice; no trials in patients.
  5. Cardiac involvement. The significance of subclinical cardiac abnormalities (~14%) is unclear; CASQ1 is the skeletal isoform (cardiac CASQ2 is distinct), so the cardiac finding needs mechanistic clarification.
  6. Omics gaps. No transcriptomic, proteomic, metabolomic, or single-cell profiling specific to this disease is available.

Proposed Follow-up Experiments / Actions

  1. Natural-history registry across Italian and Chinese families (and new cases) to quantify penetrance, progression rate, and cardiac risk prospectively.
  2. Anesthetic/heat-stress risk assessment in D244G knock-in mice and, cautiously, retrospective review of patient anesthetic exposures to test whether the MH/heat risk translates to the overload myopathy.
  3. Test antioxidant (NAC) and estrogen pathways in the D244G knock-in (not only knockout) model to determine relevance to the overload phenotype.
  4. Allele-specific knockdown (ASO/siRNA) proof-of-concept targeting mutant CASQ1 transcripts in patient myotubes to address the dominant aggregation mechanism.
  5. Deep muscle proteomics/transcriptomics of patient biopsies to map the full "surplus protein" composition and secondary stress responses.
  6. Structural studies of D244H and G103D (beyond D244G) to confirm shared loss-of-Ca²⁺-binding mechanism across the allelic spectrum.
  7. Cardiac evaluation protocol to clarify whether skeletal CASQ1 variants have any genuine cardiac phenotype or whether findings are incidental.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 14
Resolved 14
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 9
Quoted claims found in source 8
Quoted claims not found in source 1
References weighed for topical relevance 14
On topic 12
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:26416891 (abstract only): "D244G aggregates abruptly and abnormally … D244G crystallized in low Ca(2+) concentrations lacks two Ca(2+) ions normally present in wild type that weakens the hydrophobic core of Domain II."
  • closest text in source: "D244G crystallized in low Ca(2+) concentrations lacks two Ca(2+) ions normally present in wild type that weakens the hydrophobic core of Domain II"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 27
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 3
Terms whose name was checked 22
Terms named correctly 14
Terms named as a different term 5
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0014546 (2 mentions) - the report calls it "MONDO"; MONDO calls it myopathy due to calsequestrin and SERCA1 protein overload
  • UBERON:0011907 (1 mention) - the report calls it "quadriceps femoris"; UBERON calls it gastrocnemius medialis
  • NCIT:C15336 (1 mention) - the report calls it "Supportive Care"; NCIT calls it Testing
  • NCIT:C15682 (1 mention) - the report calls it "Physical Therapy"; NCIT calls it Dose-Rate
  • NCIT:C98225 (1 mention) - the report calls it "Genetic Counseling"; NCIT calls it Cefodizime Sodium

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006874 (1 mention) - the report calls it "cellular calcium ion homeostasis"; GO calls it intracellular calcium ion homeostasis, and lists "cellular calcium ion homeostasis" among its other names
  • UBERON:0000948 (1 mention) - the report calls it "heart, secondary"; UBERON calls it heart
  • NCIT:C265 (1 mention) - the report calls it "Antioxidant"; NCIT calls it Antidepressant Agent, and lists "Antidepressant" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.