Complementary DNA probes for the Duchenne muscular dystrophy locus demonstrate a previously undetectable deletion in a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia.

McCabe, Edward R.B.; Towbin, Jeffrey A.; Chamberlain, Jeffrey S.; Baumbach, L.; Witkowski, Jan; Ommen, G.J.B. van; Kœnig, M.; Kunkel, Louis M.; Seltzer, William

doi:10.1172/jci113890

Cited by 55 publications

(35 citation statements)

References 25 publications

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“…It is clear from the instance of a BMD patient lacking exons 73 -79 27 that loss of the entire 3'UTR is compatible with a fairly mild muscle phenotype. We note, however, that one patient has been described 28 in whom a 13-nucleotide deletion in the D78 coding region is expected to lead to substitution of the C-terminal 21 D78 codons with five new ones (DDLGRAMESLVSVMTDEEGAE* ?…”

Section: Discussionmentioning

confidence: 99%

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

et al. 2002

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The 3'-untranslated region (3'UTR) of some vertebrate dystrophin genes shows an extraordinary degree and extent of conservation (better than that of many coding regions), a phenomenon that remains unexplained. We examine novel sequence and mutational data to explore the possible reasons for this. We show that loss of the human dystrophin 3'UTR is sufficient to cause Becker muscular dystrophy with pronounced reduction in dystrophin protein levels. The acquisition of dystrophin 3'UTR sequence from an amphibian and a cartilaginous fish allows us to refine previously identified functionally constrained regions which might account for the observed phenotype. These comprise (a) the open reading frame encoding the ancestral 'alternative' amphipathic C-terminal a-helix, normally removed from adult dystrophin by inclusion of a poorly conserved frameshifting penultimate exon, and (b) two highly conserved untranslated regions ('Lemaire A', 350 nucleotides and 'Lemaire D', 250 nucleotides) separated by a non-conserved 700 -2000-nucleotide spacer. We consider the possibility that the 3'UTR may represent a significant target for pathogenic mutations.

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Section: Discussionmentioning

confidence: 99%

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

et al. 2002

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“…The finding calls into question the hypothesis that the 3Ј exons of the DMD gene and the 3Ј untranslated region of the gene are essential for protein function (27,30 ). Moreover, our patient's phenotype may be consistent with the reported phenotypic variability seen in affected patients, with variations in the most distal DMD exons (17,(27)(28)(29)32 ). In conclusion, we designed a simple, easy-to-perform, multiplex PCR assay for the detection and mapping of the responsible deletion in a patient with complex GKD.…”

Section: Discussionmentioning

confidence: 53%

“…Because the contiguous deletion extends to include all or part of exon 75, this patient must be contrasted with other reported patients who have DMD or BMD caused by variations in this region of the gene (17,(27)(28)(29)(30)(31)(32)(33)(34). The finding calls into question the hypothesis that the 3Ј exons of the DMD gene and the 3Ј untranslated region of the gene are essential for protein function (27,30 ).…”

Section: Discussionmentioning

confidence: 94%

“…Few central region deletions extending 3Ј beyond exon 60 have been found in DMD or BMD patients. However, causative point variations, internal deletions, and contiguous gene deletions involving the most 3Ј dystropin exons or the 3Ј untranslated region of the gene have been reported in DMD and BMD patients (17,(27)(28)(29)(30)(31)(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

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A Multiplex Assay for the Detection and Mapping of Complex Glycerol Kinase Deficiency

et al. 2006

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Background: Glycerol kinase deficiency (GKD) is an X-linked recessive disorder that presents in both isolated and complex forms. The contiguous deletion that leads to GKD also commonly affects NR0B1 (DAX1), the gene associated with adrenal hypoplasia congenita, and DMD, the Duchenne muscular dystrophy gene. Molecular testing to delineate this deletion is expensive and has only limited availability. Methods: We designed a multiplex PCR assay for the detection and mapping of a contiguous deletion potentially affecting the IL1RAPL1, NR0B1, GK, and DMD genes in a 29-month-old male patient with GKD. Results: Multiplex PCR detected a contiguous deletion that involved the IL1RAPL1, NR0B1, GK, and DMD genes. Although the patient had a creatine kinase concentration within the reference interval, further mapping with PCR revealed that exon 74 was the last intact exon at the 3 end of the DMD gene. Conclusions: Multiplex PCR is an effective and inexpensive way to detect and map the contiguous deletion in cases of complex GKD. The extension of a deletion to include DMD exon 75 in a patient with a creatine kinase concentration within the reference interval suggests that this region of the gene may not be essential for protein function.

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“…Truncation of the N-terminal actin-binding domain severely disrupts the stability and function of dystrophin [52][53][54]. However, the Cterminal domain has been found to be nonessential in mice and humans [55]. Truncation within the dystroglycan-binding domain completely ablated stable assembly of the DGC [53,56,57].…”

Section: Functional Truncated Dystrophin Isoforms Can Rescue Dystropmentioning

confidence: 99%

Gene therapy for Duchenne muscular dystrophy

1998

Inpharma Wkly.

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Introduction-Duchenne muscular dystrophy (DMD) is a relatively common inherited disorder caused by defective expression of the protein dystrophin. The most direct approach to treating this disease would be to restore dystrophin production in muscle. Recent progress has greatly increased the prospects for successful gene therapy of DMD, and here we summarize the most promising developments.Areas Covered-Gene transfer using vectors derived from adeno-associated virus (AAV) has emerged as a promising method to restore dystrophin production in muscles bodywide, and represents a treatment option applicable to all DMD patients. Using information gleaned from PubMed searches of the literature, attendance at scientific conferences and results from our own lab, we provide an overview of the potential for gene therapy of DMD using AAV vectors including a summary of promising developments and issues that need to be resolved prior to largescale therapeutic implementation.Expert Opinion-Of the many approaches being pursued to treat DMD and BMD, gene therapy based on AAV-mediated delivery of microdystrophin is the most direct and promising method to treat the cause of the disorder. The major challenges to this approach are ensuring that microdystrophin can be delivered safely and efficiently without eliciting an immune response.

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Complementary DNA probes for the Duchenne muscular dystrophy locus demonstrate a previously undetectable deletion in a patient with dystrophic myopathy, glycerol kinase deficiency, and congenital adrenal hypoplasia.

Cited by 55 publications

References 25 publications

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

The 3′-untranslated region of the dystrophin gene – conservation and consequences of loss

A Multiplex Assay for the Detection and Mapping of Complex Glycerol Kinase Deficiency

Gene therapy for Duchenne muscular dystrophy

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