Abstract
Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).
Highlights
Duchenne muscular dystrophy (DMD) is a severe, X-linked, progressive neuromuscular disease caused by mutations in the DMD gene (DMD; MIM #310200) [Hoffman et al, 1988]
Mutations in this gene give rise to two forms of muscular dystrophy depending on whether the translational reading frame is lost or maintained: severe DMD, due to out of frame mutations leading to loss of protein function, or a milder form of muscular dystrophy known as Becker muscular dystrophy (BMD; MIM #300376), caused by a reduction in the amount and/or size of dystrophin protein due to frame maintaining mutations [Koenig et al, 1989]
Resources existed for DMD prior to the creation of the TREATNMD DMD Global database, the Leiden muscular dystrophy pages in the Netherlands [Aartsma-Rus et al, 2006], and the UMD-DMD in France [Cotton et al, 2008]
Summary
Duchenne muscular dystrophy (DMD) is a severe, X-linked, progressive neuromuscular disease caused by mutations in the DMD gene (DMD; MIM #310200) [Hoffman et al, 1988]. One example of a genetic-based potential therapy is nonsense stop codon readthrough therapy [Howard et al, 2000; Wagner et al, 2001; Hirawat et al, 2007; Welch et al, 2007]. These treatments include aminoglycosides and ataluren (previously PTC124), and work by selectively inducing ribosomal read-through of premature stop codons but not normal stop codons. Translarna recently obtained conditional marketing authorization from the European Medicine Agency for use in ambulant Duchenne patients over 5 years of age, and as such is the first drug to be approved for DMD
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