Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Wagner, Kathryn R.

doi:10.1016/j.nurt.2008.08.013

Cited by 38 publications

(25 citation statements)

References 104 publications

(100 reference statements)

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“…Table S3 for VHL-associated nonsense mutations and the downstream nucleotides). Trials of gentamicin for the treatment of Duchenne and Becker Muscular Dystrophy have been performed [Wagner, 2008;Wagner et al, 2001], but unfortunately, high drug levels are needed and thus drug toxicity limits successful generation of the full length protein. PTC-124 is an orally bioavailable drug that can be used at significantly lower dosages to obtain higher levels of read-through compared with aminoglycosides [Du et al, 2008].…”

Section: Future Prospectsmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Section: Future Prospectsmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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“…2 The main clinical manifestations of dystrophinopathies are loss of skeletal and cardiac muscle strength and elasticity and respiratory insufficiency. 3 Cardiomyopathies are observed in 90% of dystrophic patients, and 20% die from cardiac complications. 4 Dystrophin, a 427 kDa cytoskeletal protein, plays a major structural role in muscle cells.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the Cardiac Sodium Channel Nav1.5 by Utrophin in Dystrophin Deficient Mice

et al. 2010

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AimsDuchenne muscular dystrophy (DMD) is a severe striated muscle disease due to the absence of dystrophin. Dystrophin deficiency results in dysfunctional sodium channels and conduction abnormalities in hearts of mdx mice. Disease progression in the mdx mouse only modestly reflects that of DMD patients, possibly due to utrophin up-regulation. Here, we investigated mice deficient in both dystrophin and utrophin [double knockout (DKO)] to assess the role of utrophin in the regulation of the cardiac sodium channel (Na v 1.5) in mdx mice. Methods and resultsCo-immunoprecipitation studies in HEK293 cells showed that utrophin interacts with Na v 1.5 via syntrophin proteins, an interaction abolished by deletion of the PDZ (PSD-95, Dlg, and Zona occludens) domain-binding motif of Na v 1.5. We also provide evidence for such interaction in mouse heart using Na v 1.5 C-terminus fusion proteins. In hearts of DKO mice, Na v 1.5 protein levels were decreased by 25 + 8%, together with a 42 + 12% reduction of syntrophins compared with mdx, where utrophin was up-regulated by 52 + 9% compared with C57BL/10 control mice. Sodium current was found to be reduced by 41 + 5% in DKO cardiomyocytes compared with mdx, representing a loss of 63 + 3% when compared with C57BL/10 wild-type control mice. Decreased Na v 1.5 protein and current in DKO were reflected in a significant slowing of 27 + 6% of maximal upstroke velocity of the cardiac action potential compared with mdx. ConclusionUtrophin plays a central role in the regulation of Na v 1.5 in mdx mice. These findings provide support for therapeutic strategies aimed at overexpressing utrophin in the hopes of reducing cardiac pathology in DMD patients.--

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“…1,2 Dystrophic muscles show a prominent inflammatory infiltrate and, even before onset of symptoms, a generalized up-regulation of many inflammation-related genes is observed. 1,3 Myofiber necrosis is the primary cause of inflammation in DMD muscles.…”

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confidence: 99%

Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy

Pasquale

D’Amico²,

Verardo

et al. 2012

Neurology

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Objectives: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status.

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Approaching a New Age in Duchenne Muscular Dystrophy Treatment

Cited by 38 publications

References 104 publications

Genetic analysis of von Hippel-Lindau disease

Genetic analysis of von Hippel-Lindau disease

Regulation of the Cardiac Sodium Channel Nav1.5 by Utrophin in Dystrophin Deficient Mice

Increased muscle expression of interleukin-17 in Duchenne muscular dystrophy

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