Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Vannoy, Charles H.; Xu, Lei; Keramaris, Elizabeth; Peng, Lu; Xiao, Xiao; Lü, Qi

doi:10.1089/hgtb.2013.151

Cited by 33 publications

(38 citation statements)

References 42 publications

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“…Indeed, several studies are in clinical trials and have shown the potential of this method. [41][42][43][44][45][46] This shows the importance of having a diagnosis for these patients.…”

Section: Discussionmentioning

confidence: 96%

Molecular diagnosis of muscular diseases in outpatient clinics

et al. 2020

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ObjectiveTo evaluate the diagnostic yield of an 89-gene panel in a large cohort of patients with suspected muscle disorders and to compare the diagnostic yield of gene panel and exome sequencing approaches.MethodsWe tested 1,236 patients from outpatient clinics across Canada using a gene panel and performed exome sequencing for 46 other patients with sequential analysis of 89 genes followed by all mendelian genes. Sequencing and analysis were performed in patients with muscle weakness or symptoms suggestive of a muscle disorder and showing at least 1 supporting clinical laboratory.ResultsWe identified a molecular diagnosis in 187 (15.1%) of the 1,236 patients tested with the 89-gene panel. Diagnoses were distributed across 40 different genes, but 6 (DMD, RYR1, CAPN3, PYGM, DYSF, and FKRP) explained about half of all cases. Cardiac anomalies, positive family history, age <60 years, and creatine kinase >1,000 IU/L were all associated with increased diagnostic yield. Exome sequencing identified a diagnosis in 10 (21.7%) of the 46 patients tested. Among these, 3 were attributed to genes not included in the 89-gene panel. Despite differences in median coverage, only 1 of the 187 diagnoses that were identified on gene panel in the 1,236 patients could have been potentially missed if exome sequencing had been performed instead.ConclusionsOur study supports the use of gene panel testing in patients with suspected muscle disorders from outpatient clinics. It also shows that exome sequencing has a low risk of missing diagnoses compared with gene panel, while potentially increasing the diagnostic yield of patients with muscle disorders.

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“…Indeed, several studies are in clinical trials and have shown the potential of this method. [41][42][43][44][45][46] This shows the importance of having a diagnosis for these patients.…”

Section: Discussionmentioning

confidence: 96%

Molecular diagnosis of muscular diseases in outpatient clinics

et al. 2020

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“…Ribitol significantly enhanced the expression of matriglycan, but yet this enhancement is associated with neither reduced cell proliferation, nor clear alteration in cell cycle progression and the capacity of growth in Matrigel of the cancer cells. It is possible that the levels of matriglycan induced by ribitol in the cell culture remain insufficient to achieve significant inhibition as LARGE-induced hyperglycosylation which is known to be considerably higher than normal levels in any cells 31,40 . Another obvious difference is the nature of the enhanced matriglycan.…”

Section: Discussionmentioning

confidence: 99%

“…Another obvious difference is the nature of the enhanced matriglycan. LARGE overexpression enhances matriglycan through extended biglycan repeats as indicated by the significant increase in MW of α-DG when compared to the α-DG in corresponding normal tissues 31,40 . In contrast, ribitol treatment apparently only increases the matriglycan of normal sizes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Ribitol enhances matriglycan of α-dystroglycan in breast cancer cells without affecting cell growth

Peng¹,

Tucker²,

Branch³

et al. 2020

Sci Rep

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the laminin-binding glycan (matriglycan) on α-dystroglycan (α-DG) enables diverse roles, from neuronal development to muscle integrity. Reduction or loss of matriglycan has also been implicated in cancer development and metastasis, and specifically associated with high-grade tumors and poor prognoses in breast cancers. Hyperglycosylation of α-DG with LARGE overexpression is shown to inhibit cancer cell growth and tumorigenicity. We recently demonstrated that ribitol, considered to be a metabolic end-product, enhances matriglycan expression in dystrophic muscles in vivo. in the current study, we tested the hypothesis that ribitol could also enhance matriglycan expression in cancer cells. Our results showed for the first time that ribitol is able to significantly enhance the expression of matriglycan on α-DG in breast cancer cells. The ribitol effect is associated with an increase in levels of CDP-ribitol, the substrate for the ribitol-5-phosphate transferases FKRP and FKTN. Direct use of CDPribitol is also effective for matriglycan expression. Ribitol treatment does not alter the expression of FKRP, FKTN as well as LARGEs and ISPD which are critical for the synthesis of matriglycan. the results suggest that alteration in substrates could also be involved in regulation of matriglycan expression. Interestingly, expression of matriglycan is related to cell cycle progression with highest levels in S and G2 phases and ribitol treatment does not alter the pattern. Although matriglycan up-regulation does not affect cell cycle progression and proliferation of the cancer cells tested, the novel substratemediated treatment opens a new approach easily applicable to experimental systems in vivo for further exploitation of matriglycan expression in cancer progression and for therapeutic potential. Dystroglycan (DG) is a major adhesion molecule highly conserved in mammals 1-4. DG is transcribed as a single transcript, and post-translationally cleaved into two subunits, α-DG and β−DG. The transmembrane and cytoplasmic subunit, β-DG, binds to cytoplasmic proteins, whereas α-DG, the extracellular subunit, interacts with laminin-G domain-containing extracellular matrix (ECM) proteins including laminin, agrin and perlecan 5. This interaction is mediated through the laminin-binding glycan (matriglycan) of α-DG (F-α-DG) 6. Matriglycan-modified α-DG is expressed in most tissues and plays diverse roles, from acting as viral receptors to neuronal development 7,8. After nearly 3 decades of intensive pursuit to understand the pathway leading to the synthesis of matriglycan of α-DG, significant progress has been made with the structure of the glycan chain on the core M3 of α-DG delineated: (3GlcA-1-3Xyl-1)n-3GlcA-1-4Xyl-Rbo5P-1Rbo5P-3GalNAc-1-3GlcNAc-1-4(P-6)Man-1-Thr/ser 9-12. The extension of the glycan chain is completed by the following proposed transferase activity sequentially: POMT1 and POMT2 catalyze the initial O-mannosylation of the protein 13 , and further extension of the sugar chain is executed by POMGnT2 (GTDC2) 14,15 and B3GA...

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“…Activation of a downstream enzyme presumably should correct the disease phenotype caused by upstream enzyme deficiency. Vannoy indeed found that AAV-mediated LARGE over-expression not only reduced myopathy in LARGE-deficient congenital muscular dystrophy mice but also improved α-dystroglycan glycosylation in the heart and skeletal muscle of FKRB P448L knock-in mice 193 .…”

Section: Expanding the Armory Of Dystrophic Cardiomyopathy Gene Thmentioning

confidence: 95%

Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

Yue

Binalsheikh

Leach

et al. 2015

Expert Opinion on Orphan Drugs

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Introduction Cardiac involvement is a common feature in muscular dystrophies. It presents as heart failure and/or arrhythmia. Traditionally, dystrophic cardiomyopathy is treated with symptom-relieving medications. Identification of disease-causing genes and investigation on pathogenic mechanisms have opened new opportunities to treat dystrophic cardiomyopathy with gene therapy. Replacing/repairing the mutated gene and/or targeting the pathogenic process/mechanisms using alternative genes may attenuate heart disease in muscular dystrophies. Areas covered Duchenne muscular dystrophy is the most common muscular dystrophy. Duchenne cardiomyopathy has been the primary focus of ongoing dystrophic cardiomyopathy gene therapy studies. Here, we use Duchenne cardiomyopathy gene therapy to showcase recent developments and to outline the path forward. We also discuss gene therapy status for cardiomyopathy associated with limb-girdle and congenital muscular dystrophies, and myotonic dystrophy. Expert opinion Gene therapy for dystrophic cardiomyopathy has taken a slow but steady path forward. Preclinical studies over the last decades have addressed many fundamental questions. Adeno-associated virus-mediated gene therapy has significantly improved the outcomes in rodent models of Duchenne and limb girdle muscular dystrophies. Validation of these encouraging results in large animal models will pave the way to future human trials.

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Adeno-Associated Virus-Mediated Overexpression of LARGE Rescues α-Dystroglycan Function in Dystrophic Mice with Mutations in the Fukutin-Related Protein

Cited by 33 publications

References 42 publications

Molecular diagnosis of muscular diseases in outpatient clinics

Molecular diagnosis of muscular diseases in outpatient clinics

Ribitol enhances matriglycan of α-dystroglycan in breast cancer cells without affecting cell growth

Prospect of gene therapy for cardiomyopathy in hereditary muscular dystrophy

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