Advanced therapeutic approaches in sarcoglycanopathies

Scano, Martina; Benetollo, Alberto; Dalla Barba, Francesco; Sandonà, Dorianna

doi:10.1016/j.coph.2024.102459

Current Opinion in Pharmacology

2024

DOI: 10.1016/j.coph.2024.102459

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Advanced therapeutic approaches in sarcoglycanopathies

Martina Scano,

Alberto Benetollo,

Francesco Dalla Barba

et al.

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2024

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Cited by 3 publications

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Histopathological analysis of gamma sarcoglycanopathy in Moroccan patients: A case series

Ouazzani,

Zouaidia,

Cherradi

et al. 2024

International Journal of Surgery Case Reports

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Histopathological analysis of gamma sarcoglycanopathy in Moroccan patients: A case series

Ouazzani,

Zouaidia,

Cherradi

et al. 2024

International Journal of Surgery Case Reports

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Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

Janßen,

Erbe,

Kneifel

et al. 2024

IJMS

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Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations.

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Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy—Assessment of Patient’s Primary Myotubes

Scano,

Benetollo,

Dalla Barba

et al. 2024

IJMS

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Limb–girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the SGCB gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin–proteasome system. These data, collected using HEK-293 cells expressing either the I119F- or Y184C mutants of β-SG, were subsequently confirmed in primary myotubes derived from an LGMD2E/R4 patient carrying a homozygous I92T mutation. The knowledge that β-SG with an amino acid substitution shares a pathway of degradation with α-SG mutants, allowed us to explore the pharmacological approach successfully tested in LGMD2D/R3. Several CFTR correctors, particularly corrector C17, preserved β-SG mutants from degradation and promoted localization at the sarcolemma of the entire SG complex. The presence of the complex, despite containing a mutated subunit, improved sarcolemma integrity, as evidenced by the reduced creatine kinase release from myotubes under hypoosmotic stress. These results suggest that β-SG missense mutants undergo proteasomal degradation as α-SG mutants, and that CFTR correctors, particularly C17, may be used as a potential therapeutic option for recovering and stabilizing the SG complex in patients with sarcoglycanopathies.

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Advanced therapeutic approaches in sarcoglycanopathies

Cited by 3 publications

References 46 publications

Histopathological analysis of gamma sarcoglycanopathy in Moroccan patients: A case series

Histopathological analysis of gamma sarcoglycanopathy in Moroccan patients: A case series

Compound Heterozygous RYR1 Variants in a Patient with Severe Congenital Myopathy: Case Report and Comparison with Additional Cases of Recessive RYR1-Related Myopathy

Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy—Assessment of Patient’s Primary Myotubes

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