A<i>CASQ1</i>founder mutation in three Italian families with protein aggregate myopathy and hyperCKaemia

Blasi, Carlos Hernández; Sansanelli, Serena; Ruggieri, Alessandra; Moriggi, Manuela; Vasso, Michele; D’Adamo, Pio; Blasevich, Flavia; Zanotti, Simona; Paolini, Cecilia; Protasi, Feliciano; Tezzon, Frediano; Gelfi, Cecilia; Morandi, Lucia; Pessia, Mauro; Mora, Marina

doi:10.1136/jmedgenet-2014-102882

Cited by 10 publications

(30 citation statements)

References 36 publications

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“…Proteases can be used at low concentrations to distinguish folded from unfolded proteins, based on the observation that unfolded proteins are cut more rapidly than structured proteins due to the inability of proteases to access buried sites. To investigate CASQ1 proteins conformation/aggregation at increasing Ca 2+ concentrations, recombinant CASQ1 proteins containing the three different TAM mutations were purified from bacteria together with the WT and the p.Asp244Gly previously reported in vacuolar aggregate myopathy (Di Blasi et al., ; Rossi et al., ). CASQ1 aggregation propensity was analyzed by limited trypsin proteolysis in absence or presence of increasing Ca 2+ concentrations.…”

Section: Resultsmentioning

confidence: 99%

“…P values ≤0.05 and 0.005 are indicated by * and **, respectively. Experiments were repeated three times proteins conformation/aggregation at increasing Ca 2+ concentrations, recombinant CASQ1 proteins containing the three different TAM mutations were purified from bacteria together with the WT and the p.Asp244Gly previously reported in vacuolar aggregate myopathy (Di Blasi et al, 2015;Rossi et al, 2014b). CASQ1 aggregation propensity was analyzed by limited trypsin proteolysis in absence or presence of increasing Ca 2+ concentrations.…”

Section: Pasp44asn and Pgly103asp Proteins Are More Susceptible To mentioning

confidence: 99%

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Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Barone

Gamberucci

et al. 2017

Human Mutation

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Here, we report the identification of three novel missense mutations in the calsequestrin-1 (CASQ1) gene in four patients with tubular aggregate myopathy. These CASQ1 mutations affect conserved amino acids in position 44 (p.(Asp44Asn)), 103 (p.(Gly103Asp)), and 385 (p.(Ile385Thr)). Functional studies, based on turbidity and dynamic light scattering measurements at increasing Ca concentrations, showed a reduced Ca -dependent aggregation for the CASQ1 protein containing p.Asp44Asn and p.Gly103Asp mutations and a slight increase in Ca -dependent aggregation for the p.Ile385Thr. Accordingly, limited trypsin proteolysis assay showed that p.Asp44Asn and p.Gly103Asp were more susceptible to trypsin cleavage in the presence of Ca in comparison with WT and p.Ile385Thr. 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. Expression of CASQ1 mutations in eukaryotic cells revealed a reduced ability of all these CASQ1 mutants to store Ca and a reduced inhibitory effect of p.Ile385Thr and p.Asp44Asn on store operated Ca entry. These results widen the spectrum of skeletal muscle diseases associated with CASQ1 and indicate that these mutations affect properties critical for correct Ca handling in skeletal muscle fibers.

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Section: Resultsmentioning

confidence: 99%

Section: Pasp44asn and Pgly103asp Proteins Are More Susceptible To mentioning

confidence: 99%

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Barone

Gamberucci

et al. 2017

Human Mutation

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“…The main clinical features of these patients were myalgia, muscle cramps or mild muscle weakness, and mild to moderate elevation of serum CK. Recently, a heterozygous missense mutation in the CASQ1 gene, involving an evolutionarily-conserved residue of the CASQ1 protein (p.D244G), has been identified [ 3 , 4 ]. Nevertheless, the pathophysiological mechanisms related to this mutation remain mostly unclear.…”

Section: Introductionmentioning

confidence: 99%

A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release

et al. 2016

Self Cite

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An autosomal dominant protein aggregate myopathy, characterized by high plasma creatine kinase and calsequestrin-1 (CASQ1) accumulation in skeletal muscle, has been recently associated with a missense mutation in CASQ1 gene. The mutation replaces an evolutionarily-conserved aspartic acid with glycine at position 244 (p.D244G) of CASQ1, the main sarcoplasmic reticulum (SR) Ca2+ binding and storage protein localized at the terminal cisternae of skeletal muscle cells. Here, immunocytochemical analysis of myotubes, differentiated from muscle-derived primary myoblasts, shows that sarcoplasmic vacuolar aggregations positive for CASQ1 are significantly larger in CASQ1-mutated cells than control cells. A strong co-immuno staining of both RyR1 and CASQ1 was also noted in the vacuoles of myotubes and muscle biopsies derived from patients. Electrophysiological recordings and sarcoplasmic Ca2+ measurements provide evidence for less Ca2+ release from the SR of mutated myotubes when compared to that of controls. These findings further clarify the pathogenic nature of the p.D244G variant and point out defects in sarcoplasmic Ca2+ homeostasis as a mechanism underlying this human disease, which could be distinctly classified as “CASQ1-couplonopathy”.

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“…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%

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

Cited by 10 publications

References 36 publications

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

A Calsequestrin-1 Mutation Associated with a Skeletal Muscle Disease Alters Sarcoplasmic Ca2+ Release

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

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