Journal ArticleDOI
Dystrophin and mutations: one gene, several proteins, multiple phenotypes
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TLDR
Current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions are focused on.Abstract:
Summary A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle isoform, the best-known protein product of this locus. These mutations result in the Duchenne and Becker muscular dystrophies (DMD and BMD). However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. Mutations affecting the correct expression of these tissue-specific isoforms have been associated with the CNS involvement common in DMD. Rare mutations also account for the allelic disorder X-linked dilated cardiomyopathy, in which dystrophin expression or function is affected mostly or exclusively in the heart. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has provided insights into several regulatory mechanisms governing the gene expression profile. Here, we focus on current understanding of the genotype–phenotype relation for mutations in the dystrophin gene and their implications for gene functions.read more
Citations
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Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
Katharine Bushby,Richard S. Finkel,David J. Birnkrant,Laura E. Case,Paula R. Clemens,Linda H. Cripe,Ajay Kaul,Kathi Kinnett,Craig M. McDonald,Shree Pandya,James Poysky,Frederic Shapiro,Jean Tomezsko,Carolyn M. Constantin +13 more
TL;DR: These recommendations provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care.
Journal ArticleDOI
RNA therapeutics: beyond RNA interference and antisense oligonucleotides
TL;DR: Three RNA-based therapeutic technologies exploiting various oligonucleotides that bind to RNA by base pairing in a sequence-specific manner yet have different mechanisms of action and effects are discussed.
Journal ArticleDOI
Local Dystrophin Restoration with Antisense Oligonucleotide PRO051
Judith C.T. van Deutekom,Anneke A.M. Janson,Ieke B. Ginjaar,Wendy S. Frankhuizen,Annemieke Aartsma-Rus,Mattie Bremmer-Bout,Johan T. den Dunnen,Klaas Koop,Anneke J. van der Kooi,Nathalie Goemans,Sjef J. de Kimpe,Peter F. Ekhart,Edna H. Venneker,Gerard Johannes Platenburg,Jan J.G.M. Verschuuren,Gert-Jan B. van Ommen +15 more
TL;DR: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.
Journal ArticleDOI
RNA mis-splicing in disease
TL;DR: An overview of RNA splicing mechanisms is provided followed by a discussion of disease-associated errors, with an emphasis on recently described mutations that have provided new insights into splicing regulation.
Journal ArticleDOI
Systemic administration of PRO051 in Duchenne's muscular dystrophy.
Nathalie Goemans,Mar Tulinius,Johanna T van den Akker,Brigitte E Burm,Peter F. Ekhart,Niki Heuvelmans,Tjadine Holling,Anneke A.M. Janson,Gerard Johannes Platenburg,Jessica A. Sipkens,J M Ad Sitsen,Annemieke Aartsma-Rus,Gert-Jan B. van Ommen,Gunnar Buyse,Niklas Darin,Jan J.G.M. Verschuuren,G. Campion,Sjef J. de Kimpe,Judith C.T. van Deutekom +18 more
TL;DR: Systemically administered PRO051 showed dose-dependent molecular efficacy in patients with Duchenne's muscular dystrophy, with a modest improvement in the 6-minute walk test after 12 weeks of extended treatment.
References
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Journal ArticleDOI
The muscular dystrophies.
TL;DR: Meryon’s observations were neglected for many years for various reasons, and the disorder became eponymously associated with Duchenne in Paris, who detailed the clinical and muscle histology some years later.
Journal ArticleDOI
An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus.
TL;DR: A molecular mechanism to explain the clinical difference in severity between DMD and BMD patients who bear partial deletions of the same gene locus is presented and is applicable to potential 5' and 3' intron splice mutations and their effect on protein production and clinical phenotype.
Journal ArticleDOI
Profiles of neuromuscular diseases. Duchenne muscular dystrophy.
Craig M. McDonald,Richard T. Abresch,Gregory T. Carter,William M. Fowler,E. R. Johnson,David D. Kilmer,B. J. Sigford +6 more
TL;DR: A tremendous heterogeneity of severity among males with Becker's muscular dystrophy is suggested, with mean intellectual and neuropsychologic function within normal limits, but with a large variability in intelligence quotient scores.
Journal Article
The molecular basis for duchenne versus becker muscular dystrophy: correlation of severity with type of deletion
M. Koenig,Alan H. Beggs,M. Moyer,S. Scherpf,K. Heindrich,T. Bettecken,G Meng,C. R. Müller,M. Lindlöf,H. Kaariainen,A. de la Chapelle,A. Kiuru,M.-L. Savontaus,H. Gilgenkrantz,D. Récan,J. Chelly,Jean-Claude Kaplan,A. E. Covone,N. Archidiacono,Giovanni Romeo,S. Liechti-Gallati,V. Schneider,Suzanne Braga,H. Moser,Basil T. Darras,Patricia E. Murphy,Uta Francke,J. D. Chen,Graeme Morgan,Margaret Denton,Cheryl R. Greenberg,Klaus Wrogemann,L. A. J. Blonden,H.M.B. van Paassen,G.J.B. van Ommen,Louis M. Kunkel +35 more
TL;DR: The distribution and frequency of deletions spanning the entire locus suggests that many "in-frame" deletions of the dystrophin gene are not detected because the individuals bearing them are either asymptomatic or exhibit non-DMD/non-BMD clinical features.
Journal ArticleDOI
Association of dystrophin and an integral membrane glycoprotein
Kevin P. Campbell,Steven D. Kahl +1 more
TL;DR: The results indicate that the function of dystrophin could be to link this glycop protein to the underlying cytoskeleton and thus help either to preserve membrane stability or to keep the glycoprotein non-uniformly distributed in the sarcolemma.