A Mutation in the<i>CASQ1</i>Gene Causes a Vacuolar Myopathy with Accumulation of Sarcoplasmic Reticulum Protein Aggregates

Rossi, Daniela; Vezzani, Bianca; Galli, Lucia; Paolini, Cecilia; Toniolo, Luana; Pierantozzi, Enrico; Spinozzi, Simone; Barone, Virginia; Pegoraro, Elena; Bello, Luca; Cenacchi, Giovanna; Vattemi, Gaetano; Tomelleri, Giuliano; Ricci, Giulia; Siciliano, Gabriele; Protasi, Feliciano; Reggiani, Carlo; Sorrentino, Vincenzo

doi:10.1002/humu.22631

Cited by 51 publications

(77 citation statements)

References 31 publications

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“…The causation of MH by Casq1 absence is consistent with the observations in cardiac muscle as both are mechanistically similar diseases of enhancement and loss of control of Ca 2ϩ release (19), and polymorphic ventricular tachycardia is, in most cases, associated with severe deficits in the amount of protein present (16). (ii) A missense mutation, D244G, is linked to a myopathy characterized by the presence of vacuoles containing SR protein inclusions (20). The patients experience muscle weakness, and their cells show altered Ca 2ϩ dynamics.…”

Section: Calsequestrin 1 Is the Principal Casupporting

confidence: 78%

Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy

Lewis

Ronish

Rı́os

et al. 2015

Journal of Biological Chemistry

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Background: Hereditary mutations (D244G and M87T) of skeletal calsequestrin have been associated with skeletal myopathies. Results: The D244G mutation loses Ca 2ϩ , resulting in structural instability. M87T inhibits polymerization of calsequestrin by altering the Casq1 dimer interface. Conclusion: D244G is largely dysfunctional, whereas the Ca 2ϩ binding capacity of M87T is mildly reduced. Significance: Altered characteristics of Casq1 mutants are congruent with their associated disease phenotypes.

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Section: Calsequestrin 1 Is the Principal Casupporting

confidence: 78%

Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy

Lewis

Ronish

Rı́os

et al. 2015

Journal of Biological Chemistry

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“…Relationship analysis using KING software revealed that families 1 and 2 were more closely related. It is likely that remote consanguinity and a founder effect may also be shared with the other Italian sporadic and familial cases described by Rossi et al ,8 all having the common CASQ1 mutation. In our families 1 and 3, two individuals had normal CK (although one had vacuoles in the muscle biopsy sample and the other complained of muscle cramps and showed lower limb muscle hypertrophy), indicating that the condition entails a certain degree of intrafamilial variability.…”

Section: Discussionmentioning

confidence: 89%

ACASQ1founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia

Blasi¹,

Sansanelli²,

Ruggieri³

et al. 2015

J Med Genet

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We show, by Sanger and exome sequencing, that the protein aggregate myopathy with benign evolution and muscle inclusions composed of excess CASQ1, affecting three Italian families, is due to the D244G heterozygous missense mutation in the CASQ1 gene. Investigation of microsatellite markers revealed a common haplotype in the three families indicating consanguinity and a founder effect. Results from immunocytochemistry, electron microscopy, biochemistry and transfected cell line investigations contribute to our understanding of pathogenetic mechanisms underlining this defect. The mutation is common to other Italian patients and is likely to share a founder effect with them. HyperCKaemia in the CASQ1-related myopathy is common and sometimes the sole overt manifestation. 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.

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“…Two isoforms of calsequestrin have been identified: calsequestrin1 that is predominantly expressed in fast twitch skeletal muscles and calsequestrin 2 that is expressed in cardiac and slow twitch muscle. Mutations in CSQ2 (the gene encoding calsequestrin 2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), sudden cardiac arrest and heart failure [33,34] and will not be discussed in this review, whereas mutations in CSQ1 (the gene encoding calsequestrin 1) have been implicated in rare cases of malignant hyperthermia and vacuolar aggregate myopathy [35,36].…”

Section: Excitation-contraction Couplingmentioning

confidence: 99%

“…In the past two years, two reports have appeared linking one mutation in CASQ1 to vacuolar aggregate myopathy [35,73]. Patients carrying the heterozygous CASQ1 p.D244G mutation, affecting a residue that lies within the Ca 2+ binding domain of calsequestrin 1, have a mild myopathy, suffer from muscle cramps, elevated CK levels, reduced muscle strength and fatigue.…”

Section: Casq1 Mutations and Vacuolar Aggregate Myopathymentioning

confidence: 99%

“…Patients carrying the heterozygous CASQ1 p.D244G mutation, affecting a residue that lies within the Ca 2+ binding domain of calsequestrin 1, have a mild myopathy, suffer from muscle cramps, elevated CK levels, reduced muscle strength and fatigue. From a functional point of view, muscle fibers isolated from these patients show (i) decreased Ca 2+ release following caffeine administration, (ii) increased glycogen content and misoriented SR junctions, (iii) an increase by approximately 25% of calsequestrin 1 content and (iv) a lower content of polymerized calsequestin [35,73]. Interestingly a report on the physicochemical properties of wild type and p.D244G mutated CASQ1 showed that the mutation reduces the Ca 2+ binding properties of calsequestrin 1 and causes it to form large aggregates in vitro [36].…”

Section: Casq1 Mutations and Vacuolar Aggregate Myopathymentioning

confidence: 99%

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

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

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

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A Mutation in theCASQ1Gene Causes a Vacuolar Myopathy with Accumulation of Sarcoplasmic Reticulum Protein Aggregates

Cited by 51 publications

References 31 publications

Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy

Characterization of Two Human Skeletal Calsequestrin Mutants Implicated in Malignant Hyperthermia and Vacuolar Aggregate Myopathy

ACASQ1founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia

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

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