Journal ArticleDOI
Very mild muscular dystrophy associated with the deletion of 46% of dystrophin.
England S,L. V. B. Nicholson,M. A. Johnson,S.M. Forrest,Donald R. Love,E. E. Zubrzycka-Gaarn,Dennis E. Bulman,John Harris,Kay E. Davies +8 more
TLDR
A deletion of the dystrophin gene is described in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the DystrophIn gene encompassing 5,106 base pairs of coding sequence, almost half the coding information.Abstract:
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene, a 14 kilobase (kb) transcript which is spread over more than 2 megabases of the human X chromosome. The corresponding protein, dystrophin, has a relative molecular mass of 400,000. Most mutations causing DMD and BMD are deletions and deletions associated with both phenotypes are observed throughout the gene sequence. This observation led to the suggestion that DMD patients possess deletions that disrupt the reading frame of the protein, whereas BMD patients have deletions that retain the translational reading frame and enable the muscle cells to produce altered dystrophin products. This theory is supported by immunoblotting studies, which show that DMD patients lack dystrophin in their muscle cells or that dystrophin is present at very low levels, whereas BMD patients produce a protein with reduced abundance or abnormal size. Here we describe a deletion of the dystrophin gene in a family segregating for very mild BMD, one member of which was still ambulant at age 61 years, which removes a central part of the dystrophin gene encompassing 5,106 base pairs of coding sequence, almost half the coding information. Immunological analysis of muscle from one of the patients demonstrates that this mutation results in the production of a truncated polypeptide localized correctly in the muscle cell. These results are particularly significant in the context of gene therapy which, if it is ever envisaged, would be facilitated by the replacement of the very large dystrophin gene with a more manipulatable mini-gene construct.read more
Citations
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Journal ArticleDOI
Function and genetics of dystrophin and dystrophin-related proteins in muscle
TL;DR: The role of the dystrophin complex and protein family in muscle is discussed and the physiological processes that are affected in Duchenne muscular dystrophy are described.
Journal ArticleDOI
Adeno-associated virus vector as a platform for gene therapy delivery
TL;DR: The fundamentals of AAV and vectorology are discussed, focusing on current therapeutic strategies, clinical progress and ongoing challenges.
Journal ArticleDOI
Dystrophin and mutations: one gene, several proteins, multiple phenotypes
TL;DR: Current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions are focused on.
Journal ArticleDOI
In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.
Christopher E. Nelson,Chady H. Hakim,David G. Ousterout,Pratiksha I. Thakore,Eirik A. Moreb,Ruth M. Castellanos Rivera,Sarina Madhavan,Xiufang Pan,F. Ann Ran,F. Ann Ran,Winston X. Yan,Winston X. Yan,Winston X. Yan,Aravind Asokan,Feng Zhang,Dongsheng Duan,Charles A. Gersbach +16 more
TL;DR: In this paper, an adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mouse model of Duchenne muscular dystrophy (DMD) to remove the mutated exon 23 from the dystrophin gene.
In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy
Christopher E. Nelson,Chady H. Hakim,David G. Ousterout,Pratiksha I. Thakore,Eirik A. Moreb,Ruth M. Castellanos Rivera,Sarina Madhavan,X. Pan,F. A. Ran,Winston X. Yan,Aravind Asokan,Feng Zhang,Dongsheng Duan,Charles A. Gersbach +13 more
TL;DR: This work establishes CRISPR-Cas9–based genome editing as a potential therapy to treat DMD and partially restored dystrophin protein expression in skeletal and cardiac muscle and improved skeletal muscle function.
References
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Journal ArticleDOI
Dystrophin: The protein product of the duchenne muscular dystrophy locus
TL;DR: The identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype, and the protein dystrophin is named because of its identification via the isolation of the Duchenne muscular dystrophy locus.
Journal ArticleDOI
Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals.
TL;DR: The 14 kb human Duchenne muscular dystrophy cDNA corresponding to a complete representation of the fetal skeletal muscle transcript has been cloned and the majority of deletions are concentrated in a single genomic segment corresponding to only 2 kb of the transcript.
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 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
Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy
Eric P. Hoffman,Fischbeck Kh,Robert H. Brown,Mark D. Johnson,Medori R,John D. Loike,Jason B. Harris,R Waterston,Brooke M,Linda A. Specht +9 more
TL;DR: These data show the clinical consequences of both quantitative alterations (in Duchenne's and intermediate dystrophy) in a single protein, and the biochemical assay for dystrophin should prove helpful in delineating myopathies that overlap clinically with DuchenNE's and Becker's Dystrophies and shows promise as an accurate diagnostic tool.
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Dystrophin: The protein product of the duchenne muscular dystrophy locus
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