Evaluation of cardiac and respiratory involvement in sarcoglycanopathies

Politano, Luisa; Nigro, Vincenzo; Passamano, Luigia; Petretta, Vito R.; Comi, L.I.; Papparella, Serenella; Nigro, G; Rambaldi, Pier Francesco; Raia, Pasquale; Pini, Antonella; Mora, Marina; Giugliano, M. A. M.; Esposito, Maria; Nigro, Gerardo

doi:10.1016/s0960-8966(00)00174-7

Cited by 144 publications

(112 citation statements)

References 29 publications

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“…This is being critically evaluated for cystic fibrosis (13)(14)(15)(16) and muscular dystrophy (17)(18)(19)(20)(21)(22). After animal studies, gentamicin-induced CFTR protein was recently reported to improve transmembrane conductance across the nasal mucosa in a group of 10 patients with homozygous PTC mutations in the CTRF gene; patients with the more common del508F mutation were used as controls and showed no improvement of conductance (16).…”

Section: Discussionmentioning

confidence: 99%

Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons

Lai

Chun

Nahas

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

146

102

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Cells were irradiated with 10 Gy and were incubated for 45 min at 37°C before fixation on coverslips. ATM pS1981 IRIFs were not observed in untreated cells; maximum intensity of staining was seen in the nuclei of cells exposed to 75 g͞ml. Nonirradiated cells, untreated or exposed to comparable concentrations of geneticin, showed only occasional foci. A taxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with onset in early childhood, resulting from mutations in the A-T mutated (ATM) gene (1). The ATM protein is a hierarchical serine-threonine kinase, phosphorylating many substrates involved in repair of doublestranded DNA breaks, control of cell cycle checkpoints, and responses to oxidative stress, as well as in radiosensitivity, cancer susceptibility, immune function, and neurological development (2). ATM protein levels are undetectable in the cells of most A-T patients by conventional testing. However a few patients, often with a milder phenotype, have some detectable ATM protein (3,4). This finding encouraged us to seek compounds, such as aminoglycosides, that have the potential to read through premature termination codons and restore ATM protein function (5, 6).To test these effects, we selected 13 lymphoblastoid cell lines (LCLs) with primary premature termination codon (PTC) mutations from a repository of Ͼ400 lines derived from A-T patients. Herein, we show representative data from 5 of the 13 LCLs. Using protein truncation testing (PTT) driven by plasmid templates containing PTC mutations in the ATM gene (7), we observed in vitro read-through effects of various magnitudes with three of four aminoglycosides tested. Full-length ATM protein was also documented ex vivo by immunoprecipitation. Correction of radioresistant DNA synthesis and radiosensitivity, as well as autophosphorylation of ATM, suggested that this readthrough produces functional ATM protein. Experimental ProceduresCell Lines. Lymphoblastoid cell lines were maintained in RPMI medium 1640 (Invitrogen) with 15% FBS (HyClone) and 1% penicillin͞streptomycin (Invitrogen) at 37°C and 5% CO 2 . In ex vivo experiments, aminoglycosides were added daily into culture media at the indicated doses and times. Because streptomycin is also an aminoglycoside that can perturb proofreading by binding to another ribosomal site, ex vivo experiments were performed with or without streptomycin; no differences were noted.Mutations. We selected only PTC mutations that resulted directly from the mutation, i.e., primary PTC mutations, and not those caused indirectly by upstream mutations or aberrant splicing, because the latter would have no potential therapeutic benefits. The LCLs carried the following mutations (www.benaroyaresearch.org͞bri investigators͞atm.htm): AT185LA, homozygous 3673C 3 T (a UAA G stop codon in PTT fragment 4); TAT51, homozygous 5623C 3 T (a UGA C stop codon in PTT fragment 5); AT187LA, homozygous 5908C 3 T (a UAA G stop codon in PTT fragment 6); AT153LA, homozygous 8977C 3 T (a UGA A stop codon in fragment 8); and AT...

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Section: Discussionmentioning

confidence: 99%

Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons

Lai

Chun

Nahas

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

146

102

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“…11 Similar to the animal models for d-sarcoglycan-deficiency, the cardiomyopathic hamster models and the d-sarcoglycan knock-out mouse, patients can already present severe cardiomyopathy at young age in addition to muscular dystrophy. 23,24 Cardiomyopathy is not a core component of LGMD2F and there have been reports of several patients without cardiac involvement.…”

Section: Discussionmentioning

confidence: 99%

“…8 -10 Patients with LGMD2C-F, in particular with b-sarcoglycandeficient LGMD2E and d-sarcoglycan-deficient LGMD2F, often develop a progressive and potentially fatal dilated cardiomyopathy (DCM) in association with muscular dystrophy. 11 Mutations in the e-sarcoglycan gene are associated with a dominant form of myoclonus dystonia syndrome, 12 whereas so far no disease has been associated with mutations in the z-sarcoglycan gene. Dominant inheritance has not been reported in sarcoglycan-deficient LGMD.…”

Section: Introductionmentioning

confidence: 99%

Does δ-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?

et al. 2009

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In this study we clinically and genetically characterize a consanguineous family with a homozygous novel missense mutation in the d-sarcoglycan gene and a second d-sarcoglycan mutation that has previously been reported to cause severe autosomal-dominant dilated cardiomyopathy. We identified a novel missense mutation in exon 6 (p.A131P) of the d-sarcoglycan gene, which in a homozygous state leads to the clinical picture of a limb girdle muscular dystrophy. In four heterozygous carriers for the mutation, aged 3-64 years, a second sequence variant in exon 6 (p.S151A) of the d-sarcoglycan gene was detected on the other allele. This second missense change had previously been reported to be responsible for fatal autosomal-dominant dilated cardiomyopathy at young age. Comprehensive clinical and cardiac investigation in all of the compound heterozygous family members revealed no signs of cardiomyopathy or limb girdle muscular dystrophy. Our findings demonstrate that, even in the presence of a second disease-causing mutation, the p.S151A mutation in the d-sarcoglycan gene does not result in cardiomyopathy. This finding questions the pathological relevance of this sequence variant for causing familial autosomal-dominant dilated cardiomyopathy and thereby the role of the d-sarcoglycan gene in general as a disease-causing gene for autosomal-dominant dilated cardiomyopathy.

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“…In addition to skeletal muscle symptoms, many LGMD patients show cardiac involvement (45,46). Analysis of skeletal muscle tissue biopsies from these patients reveals the loss or dramatic reductions in the expression of all the sarcoglycans when there is a disease-related mutation in a single sarcoglycan family member.…”

Section: Discussionmentioning

confidence: 99%

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

Woodman

Park

Cohen

et al. 2002

Journal of Biological Chemistry

268

242

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A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane microdomains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (؊/؊) knockout mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, ␣-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.

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Evaluation of cardiac and respiratory involvement in sarcoglycanopathies

Cited by 144 publications

References 29 publications

Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons

Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons

Does δ-sarcoglycan-associated autosomal-dominant cardiomyopathy exist?

Caveolin-3 Knock-out Mice Develop a Progressive Cardiomyopathy and Show Hyperactivation of the p42/44 MAPK Cascade

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