Sarcoglycanopathies: an update

Vainzof, Mariz; Souza, Lucas Santos; Gurgel-Giannetti, Juliana; Zatz, Mayana

doi:10.1016/j.nmd.2021.07.014

Cited by 29 publications

(24 citation statements)

References 51 publications

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“…The results obtained, in both adult and pediatric patients are in agreement with reported data that the reduced expression of a mutated sarcoglycan causes a variable reduction also in the expression of the other components of the complex. 14 In LGMDR5 we detected a more marked reduction of α-SG (0.2069±0.03797 vs 3.082±0.3669, p<0.0001) ( Figure 3A ), b-SG (0.1433±0.03997 vs 1.713±0.1104 p<0.0001) ( Figure 3B ) and g-SG (0.035±0.00933 vs 0.9386±0.1084, p<0.0001) ( Figure 3C ) and a less evident d-SG reduction (0.8515±0.2749 vs 1.418±0.131, p=0.0053) ( Figure 3D ). In LGMDR3 we observed a similar residual expression of all sarcoglycans as follows: a-SG (0.4665±0.086 vs 3.082±0.3669, p<0.0001) ( Figure 2A ), b-SG (0.6597±0.1134 vs 1.713±0.1104, p<0.0001) ( Figure 3B ), g-SG (0.4572±0.1153 vs 0.9386±0.1084, p=0.0013) ( Figure 3C ) and d-SG (0.4026±0.0796 vs 1.418±0.131, p>0.0001) ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

Immunofluorescence signal intensity measurements as a semi-quantitative tool to assess sarcoglycan complex expression in muscle biopsy

et al. 2022

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Sarcoglycanopathies are highly heterogeneous in terms of disease progression, muscular weakness, loss of ambulation and cardiac/respiratory involvement. Their clinical severity usually correlates with the residual protein amount, which makes protein quantification extremely relevant. Sarcoglycanopathy diagnosis is genetic, but skeletal muscle analysis - by both immunohistochemistry and Western blot (WB) - is still mandatory to establish the correct diagnostic process. Unfortunately, however, WB analysis cannot be performed if the bioptic specimen is scarce. This study provides a sensitive tool for semi-quantification of residual amount of sarcoglycans in patients affected by sarcoglycanopathies, based on immunofluorescence staining on skeletal muscle sections, image acquisition and software elaboration. We applied this method to eleven sarcoglycanopathies, seven Becker muscular dystrophies and four age-matched controls. Fluorescence data analysed in patients and compared to age-matched controls showed a significant reduction of the mutated sarcoglycan expression and a variable reduction of the other sarcoglycans. Fluorescence normalized data analysed in relation to the age of onset of the disease, showed a negative correlation of α-sarcoglycan fluorescent signal versus fibrosis in patients with an early age of onset and a negative correlation between δ-sarcoglycan signal and fibrosis in both intermediate and late age of onset groups. The availability of a method that allows objective quantification of the sarcolemmal proteins, faster and less consuming than WB analysis and able to detect low residual sarcoglycan expression with great sensitivity, proves useful to better define both patient prognosis and expected disease evolution. The proposed method could be employed also to monitor the efficacy of therapeutic interventions and during clinical trials.

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Section: Resultsmentioning

confidence: 99%

Immunofluorescence signal intensity measurements as a semi-quantitative tool to assess sarcoglycan complex expression in muscle biopsy

et al. 2022

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“…About 60 different SGCB molecular defects have been associated with LGMDR4, missense, non-sense, and indels being the most common pathogenic variants. Splicing-affecting variants have rarely been reported [ 2 ].…”

Section: Discussionmentioning

confidence: 99%

“…No correlation between muscle protein levels and cardiac involvement has been detected so far in LGMDR4 patients. All sarcoglycans are robustly expressed in skeletal muscle [ 2 ], while their expression in cardiac muscle is unbalanced with higher levels of SGCB, SGCG, and SGCD compared to SGCA. Results from Northern blot experiments also hypothesized tissue specific SGCB isoforms [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

“…Biallelic variants in SGCA , SGCB , SGCG , and SGCD encoding for alpha-, beta-, gamma-, and delta-sarcoglycan proteins [ 2 ], respectively, are the molecular determinants of rare recessive LGMD forms, collectively termed sarcoglycanopathies (LGMDR3-6, according to the updated nomenclature) [ 3 ]. Sarcoglycans interact with the dystroglycan complex, which links the subsarcolemmal protein dystrophin to the basement membrane.…”

Section: Introductionmentioning

confidence: 99%

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Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene

Magri

Zanotti

Salani

et al. 2022

IJMS

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Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.

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“…Limb girdle muscular dystrophy R3 (LGMD R3), an autosomal recessive primary myopathy characterized by progressive involvement of the pelvic and shoulder girdles, is caused by mutations in the α-sarcoglycan gene (SGCA) [1,2]. SGCA encodes a transmembrane protein, α-sarcoglycan (α-SG), which, together with other 3 SG members (β, γ and δ), interacts with dystrophin, forming the dystrophin-glycoprotein complex (DGC) [3].…”

Section: Introductionmentioning

confidence: 99%

P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy

et al. 2022

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Limb-girdle muscular dystrophy R3, a rare genetic disorder affecting the limb proximal muscles, is caused by mutations in the α-sarcoglycan gene (Sgca) and aggravated by an immune-mediated damage, finely modulated by the extracellular (e)ATP/purinoceptors axis. Currently, no specific drugs are available. The aim of this study was to evaluate the therapeutic effectiveness of a selective P2X7 purinoreceptor antagonist, A438079. Sgca knockout mice were treated with A438079 every two days at 3 mg/Kg for 24 weeks. The P2X7 antagonist improved clinical parameters by ameliorating mice motor function and decreasing serum creatine kinase levels. Histological analysis of muscle morphology indicated a significant reduction of the percentage of central nuclei, of fiber size variability and of the extent of local fibrosis and inflammation. A cytometric characterization of the muscle inflammatory infiltrates showed that A438079 significantly decreased innate immune cells and upregulated the immunosuppressive regulatory T cell subpopulation. In α-sarcoglycan null mice, the selective P2X7 antagonist A438079 has been shown to be effective to counteract the progression of the dystrophic phenotype and to reduce the inflammatory response. P2X7 antagonism via selective inhibitors could be included in the immunosuppressant strategies aimed to dampen the basal immune-mediated damage and to favor a better engraftment of gene-cell therapies.

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Sarcoglycanopathies: an update

Cited by 29 publications

References 51 publications

Immunofluorescence signal intensity measurements as a semi-quantitative tool to assess sarcoglycan complex expression in muscle biopsy

Immunofluorescence signal intensity measurements as a semi-quantitative tool to assess sarcoglycan complex expression in muscle biopsy

Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene

P2X7 Receptor Antagonist Reduces Fibrosis and Inflammation in a Mouse Model of Alpha-Sarcoglycan Muscular Dystrophy

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