1st International Workshop on Clinical trial readiness for sarcoglycanopathies 15–16 November 2016, Evry, France

Marsolier, Justine; Laforêt, Pascal; Pegoraro, Elena; Vissing, John; Richard, Isabelle; Barnérias, Christine; Carlier, Robert‐Yves; Díaz‐Manera, Jordi; Fayssoil, Abdallah; Galy, Anne; Gazzerro, Elisabetta; Górecki, Dariusz C.; Guglieri, Michela; Hogrel, Jean‐Yves; Israeli, David; Leturcq, F.; Moussu, Hélène; Prigent, Hélène; Sandonà, Dorianna; Schoser, Benedikt G. H.; Semplicini, Claudio; Talim, Beril; Tasca, Giorgio A.; Urtizberea, Andoni; Udd, Bjarne

doi:10.1016/j.nmd.2017.02.011

Cited by 12 publications

(8 citation statements)

References 90 publications

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“…First, β-SG is the second sarcoglycan protein with the most frequently reported missense mutations. Therefore, evidence of therapeutic efficiency for rescue of missense mutations gathered for this protein will have an impact for more patients that for γ–sarcoglycan for which most of the mutations induce a frameshift or for δ-sarcoglycan for which very few patients have been reported so far [ 19 ]. Second, T151R β-SG mutant induces a severe phenotype in patients often associated with cardiomyopathy and sometimes associated with respiratory insufficiency [ 20 ], indicating a high impact of the mutation on the protein and thus theoretically increasing the chance to obtain a phenotype in mouse.…”

Section: Resultsmentioning

confidence: 99%

Different outcome of sarcoglycan missense mutation between human and mouse

et al. 2018

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Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycan (α, β, δ, and γ-sarcoglycans). Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex that protects sarcolemma against muscle contraction-induced damages. Absence of one of the sarcoglycan at the plasma membrane induces the disappearance of the whole complex and perturbs muscle fiber membrane integrity. We previously demonstrated that point mutations in the human sarcoglycan genes affects the folding of the corresponding protein, which is then retained in the endoplasmic reticulum by the protein quality control and prematurely degraded by the proteasome. Interestingly, modulation of the quality control using pharmacological compounds allowed the rescue of the membrane localization of the mutated sarcoglycan. Two previously generated mouse models, knock-in for the most common sarcoglycan mutant, R77C α-sarcoglycan, failed in reproducing the dystrophic phenotype observed in human patients. Based on these results and the need to test therapies for these fatal diseases, we decided to generate a new knock-in mouse model carrying the missense mutation T151R in the β-sarcoglycan gene since this is the second sarcoglycan protein with the most frequently reported missense mutations. Muscle analysis, performed at the age of 4 and 9-months, showed the presence of the mutated β-sarcoglycan protein and of the other components of the dystrophin-associated glycoprotein complex at the muscle membrane. In addition, these mice did not develop a dystrophic phenotype, even at a late stage or in condition of stress-inducing exercise. We can speculate that the absence of phenotype in mouse may be due to a higher tolerance of the endoplasmic reticulum quality control for amino-acid changes in mice compared to human.

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Section: Resultsmentioning

confidence: 99%

Different outcome of sarcoglycan missense mutation between human and mouse

et al. 2018

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“…Otherwise, for some variables we were able to describe a lifetime trend. As it has been recently demonstrated that patients with truncating mutations, and therefore lower proteins' concentrations, show a severer clinical progression ( 15 ), and in view of our preliminary observations, we tried to highlight any genotype-phenotype correlation. On this purpose, patients were analyzed both as total and as grouped in genetic subgroups: group A, for patients carrying in homozygosis or in compound heterozygosis a specific truncating mutation in exon 3 (c.377_384duplCAGTAGGA), known to cause severe disease ( 4 , 18 ), and group B for patients with every other kind of alteration.…”

Section: Methodsmentioning

confidence: 99%

“…Recently Alonso-Pérez et al ( 13 ) established that early onset and low protein expression in muscle biopsy (<30%) are independent risk factors for loss of ambulation before 18 years of age in sarcoglycanopathies. Nonetheless, the evaluation of lung function and respiratory muscle activity during disease progression should prevent ventilatory insufficiency improving the quality of life and could be a marker for new gene-modifying and pharmacological therapeutic strategies ( 14 , 15 ). However, despite broad acceptance of the prognostic significance of cardiac and respiratory involvement in sarcoglycanopathies ( 7 , 10 , 16 , 17 ), there remains little knowledge on the course of these symptoms over natural history of disease.…”

Section: Introductionmentioning

confidence: 99%

Clinical Determinants of Disease Progression in Patients With Beta-Sarcoglycan Gene Mutations

2021

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Background: Limb-girdle muscular dystrophy 2E (LGMD 2E), recently renamed as autosomal recessive limb-girdle muscular dystrophy-4 (LGMDR4), is characterized by the lack of beta-sarcoglycan, normally expressed in skeletal muscles and cardiomyocytes. We hypothesized that progressive respiratory and left ventricular (LV) failure in LGMDR4 could be associated with the age and interrelated phenomena of the disease's natural history.Methods: We conducted a retrospective review of the records of 26 patients with LGMDR4. Our primary objective was to compare the rates of decline among creatine phosphokinase (CPK) values, pulmonary function test (PFT) measures, and echocardiographic estimates and to relate them to patients' age.Results: The rates of decline/year of CPK, PFTs, and LV function estimates are significatively bound to age, with the LV ejection fraction (EF) being the strongest independent variable describing disease progression. Moreover, the rate of decline of CPK, PFTs, and LV differed in patients grouped according to their genetic mutations, demonstrating a possible genotype–phenotype correlation. The parallel trend of decline in CPK, PFT, and EF values demonstrates the presence in LGMDR4 of a simultaneous and progressive deterioration in muscular, respiratory, and cardiac function.Conclusions: This study expands the current knowledge regarding the trend of CPK values and cardiac and respiratory impairment in patients with LGMDR4, to optimize the monitoring of these patients, to improve their quality of life, and to provide clinical indices capable of quantifying the effects of any new gene or drug therapy.

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“…As for all the LGMDs, the correct molecular diagnosis is of great importance for adequate care management, planning the genetic counselling, scheduling the correct follow-up and allowing enrolment in ongoing and future gene therapy trials 2. Sarcoglycanopathies can have a paediatric or adult age of onset and show overlapping features with other muscular dystrophies, for example, dystrophinopathies or alpha-dystroglycanopathies, being characterised by high creatine kinase (CK) level, a similar distribution of weakness, calf muscle hypertrophy and not infrequently cardiomyopathy 1 3.…”

Section: Introductionmentioning

confidence: 99%

MRI in sarcoglycanopathies: a large international cohort study

Tasca

Monforte

Díaz‐Manera

et al. 2017

J Neurol Neurosurg Psychiatry

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Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

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1st International Workshop on Clinical trial readiness for sarcoglycanopathies 15–16 November 2016, Evry, France

Abstract: Review on current states on clinical trial readiness for sarcoglycanopathies

Cited by 12 publications

References 90 publications

Different outcome of sarcoglycan missense mutation between human and mouse

Different outcome of sarcoglycan missense mutation between human and mouse

Clinical Determinants of Disease Progression in Patients With Beta-Sarcoglycan Gene Mutations

MRI in sarcoglycanopathies: a large international cohort study

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