CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy

Böhm, Johann; Lornage, Xavière; Chevessier, Frédéric; Birck, Catherine; Zanotti, Simona; Cudia, Paola; Bulla, Monica; Granger, Florence; Bui, Mai Thao; Sartori, Maxime; Schneider‐Gold, Christiane; Malfatti, Edoardo; Romero, Norma B.; Mora, Marina; Laporte, Jocelyn

doi:10.1007/s00401-017-1775-x

Cited by 32 publications

(22 citation statements)

References 9 publications

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“…In most cases, disease onset is during infancy or childhood, and first and foremost affects the proximal muscles of the lower limbs. Muscle weakness is generally accompanied by elevated serum creatine kinase (CK) levels, indicating moderate fiber degeneration, and myalgia and cramps are often observed as secondary features, but can also occur as isolated signs ( Bohm et al, 2013 ; Bohm et al, 2014 , 2017 , 2018 ; Hedberg et al, 2014 ; Misceo et al, 2014 ; Morin et al, 2014 , 2020 ; Nesin et al, 2014 ; Endo et al, 2015 ; Markello et al, 2015 ; Walter et al, 2015 ; Barone et al, 2017 ; Garibaldi et al, 2017 ; Harris et al, 2017 ; Noury et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Li et al, 2019 ; Claeys et al, 2020 ). Noteworthy, Ca 2+ overload in skeletal muscle fibers has been shown to disrupt excitation-contraction coupling (ECC) ( Lamb et al, 1995 ), which possibly contributes to the reduced muscle force in TAM/STRMK patients.…”

Section: Phenotypic Traits In Crac Channelopathy and Tam/strmk Patienmentioning

confidence: 99%

“…This is supported by the observation that Ca 2+ excess induces the proteolysis of junctophilins, which tether the SR membrane to deep plasma membrane invaginations known as T-tubules to form the triad ( Murphy et al, 2013 ). Further histopathological signs on TAM/STRMK biopsies encompass fiber size variability, type I fiber predominance, type II fiber atrophy, internalized nuclei, vacuoles, and fibrosis ( Bohm et al, 2013 , 2014 , 2017 , 2018 ; Hedberg et al, 2014 ; Morin et al, 2014 , 2020 ; Nesin et al, 2014 ; Endo et al, 2015 ; Markello et al, 2015 ; Walter et al, 2015 ; Harris et al, 2017 ; Noury et al, 2017 ; Borsani et al, 2018 ; Li et al, 2019 ; Claeys et al, 2020 ).…”

Section: Phenotypic Traits In Crac Channelopathy and Tam/strmk Patienmentioning

confidence: 99%

“…In turn, Ca 2+ store depletion promotes depolymerization, and the calsequestrin monomers sequester STIM1 and hence negatively regulate SOCE ( Wang et al, 2015 ). Specific missense mutations in CASQ1 interfere with the polymerization and depolymerization dynamics of calsequestrin, lower the Ca 2+ buffer capacities of the reticulum and impair calsequestrin monomerization, leading to an increase in SOCE activity ( Barone et al, 2017 ; Bohm et al, 2018 ). As calsequestrin expression is restricted to skeletal muscle, patients with CASQ1 mutations show a mild form of TAM/STRMK with late-onset muscle weakness, myalgia, and abundant tubular aggregates, but without additional multi-systemic signs ( Bohm and Laporte, 2018 ; Bohm et al, 2018 ).…”

Section: Soce Regulators Associated Diseases and Animal Modelsmentioning

confidence: 99%

“…All GoF mutations are missense mutations affecting highly conserved amino acids in the Ca 2+ -binding EF hands (H72Q, N80T, G81D, D84G, D84E, S88G, L92V, L96V, Y98C, F108I, F108L; H109N, H109R, H109Y, I115F) ( Bohm et al, 2013 , 2014 ; Hedberg et al, 2014 ; Markello et al, 2015 ; Walter et al, 2015 ; Harris et al, 2017 ; Noury et al, 2017 ; Li et al, 2019 ; Claeys et al, 2020 ; Morin et al, 2020 ) or in the luminal coiled-coil domains of STIM1 (R304W, R304Q) ( Misceo et al, 2014 ; Morin et al, 2014 ; Nesin et al, 2014 ; Markello et al, 2015 ; Harris et al, 2017 ; Alonso-Jimenez et al, 2018 ; Borsani et al, 2018 ; Sura et al, 2020 ), or in the ORAI1 transmembrane domains forming the channel pore or concentric rings surrounding the pore (G97C, G98S, V107M, L138F, T184M, P245L) ( Nesin et al, 2014 ; Endo et al, 2015 ; Bohm et al, 2017 ; Garibaldi et al, 2017 ; Figure 1 ). Missense mutations in the muscle-specific SR Ca 2+ buffer calsequestrin ( CASQ1 ) have moreover been reported in patients with late-onset muscle weakness and myalgia, forming the mild end of the TAM/STRMK spectrum ( Barone et al, 2017 ; Bohm et al, 2018 ; Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

Silva-Rojas

Laporte

2020

Front. Physiol.

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Store-operated Ca 2+ entry (SOCE) is a ubiquitous and essential mechanism regulating Ca 2+ homeostasis in all tissues, and controls a wide range of cellular functions including keratinocyte differentiation, osteoblastogenesis and osteoclastogenesis, T cell proliferation, platelet activation, and muscle contraction. The main SOCE actors are STIM1 and ORAI1. Depletion of the reticular Ca 2+ stores induces oligomerization of the luminal Ca 2+ sensor STIM1, and the oligomers activate the plasma membrane Ca 2+ channel ORAI1 to trigger extracellular Ca 2+ entry. Mutations in STIM1 and ORAI1 result in abnormal SOCE and lead to multi-systemic disorders. Recessive loss-of-function mutations are associated with CRAC (Ca 2+ release-activated Ca 2+ ) channelopathy, involving immunodeficiency and autoimmunity, muscular hypotonia, ectodermal dysplasia, and mydriasis. In contrast, dominant STIM1 and ORAI1 gain-of-function mutations give rise to tubular aggregate myopathy and Stormorken syndrome (TAM/STRMK), forming a clinical spectrum encompassing muscle weakness, thrombocytopenia, ichthyosis, hyposplenism, short stature, and miosis. Functional studies on patient-derived cells revealed that CRAC channelopathy mutations impair SOCE and extracellular Ca 2+ influx, while TAM/STRMK mutations induce excessive Ca 2+ entry through SOCE over-activation. In accordance with the opposite pathomechanisms underlying both disorders, CRAC channelopathy and TAM/STRMK patients show mirror phenotypes at the clinical and molecular levels, and the respective animal models recapitulate the skin, bones, immune system, platelet, and muscle anomalies. Here we review and compare the clinical presentations of CRAC channelopathy and TAM/STRMK patients and the histological and molecular findings obtained on human samples and murine models to highlight the mirror phenotypes in different tissues, and to point out potentially undiagnosed anomalies in patients, which may be relevant for disease management and prospective therapeutic approaches.

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Section: Phenotypic Traits In Crac Channelopathy and Tam/strmk Patienmentioning

confidence: 99%

Section: Phenotypic Traits In Crac Channelopathy and Tam/strmk Patienmentioning

confidence: 99%

Section: Soce Regulators Associated Diseases and Animal Modelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

Silva-Rojas

Laporte

2020

Front. Physiol.

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“…They are found in a majority of patients with GFPT1 ‐ and DPAGT1 ‐CMS and were also seen in a single patient with ALG2 ‐CMS . Tubular aggregates, however, are not pathognomonic for these CMS, as they also appear in large numbers in tubular aggregate myopathies caused by mutations in STIM1 , ORAI1 , and CASQ1 , in periodic paralysis, in phosphoglycerate mutase deficiency and less frequently as a nonspecific feature in other myopathies . Hypoglycosylation of STIM1 has been observed in DPAGT1 ‐CMS, indicating that this mechanism may play a role in the formation of tubular aggregates in CMS with glycosylation defects …”

Section: Cmss With Coexisting Myopathymentioning

confidence: 99%

Trouble at the junction: When myopathy and myasthenia overlap

2019

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Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co‐occurrence of myasthenia gravis or Lambert‐Eaton myasthenic syndrome with an immune‐mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.

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CASQ1‐related myopathy: The first report from China and the literature review

Zhang

Duan

et al. 2022

Clinical Case Reports

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Calsequestrin 1 (CASQ1) is the most crucial Ca 2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal muscle. With high capacity and low affinity for Ca 2+ , CASQ1 plays a significant role in maintaining a large amount of Ca 2+ necessary for muscle contraction. However, only five mutations in CASQ1 have been identified to date. Here, we report a 42‐year‐old Chinese female patient who 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. Next‐generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1 . Functional studies confirmed the likely pathogenicity of this variant. Muscle histopathology revealed rare optically empty vacuoles in myofibers and atypical eosinophilic granules in the cytoplasm, which has not been observed before. We also performed a literature review on all the pathogenic mutations in CASQ1 and summarized their genetic and clinical characteristics. This is the first report on CASQ1‐related myopathy from China, further expanding the mutation spectrum of CASQ1 gene and provides new insights into the function of CASQ1.

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CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy

Cited by 32 publications

References 9 publications

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

Trouble at the junction: When myopathy and myasthenia overlap

CASQ1‐related myopathy: The first report from China and the literature review

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