The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

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).

Christophe Béroud | Hanns Lochmüller | Petr Brabec | Clemens Bloetzer | Rosário Santos | Kyriaki Kekou | Leanne Lamont | Svetlana Artemieva | Lawrence Korngut | Craig Campbell | Richard Roxburgh | Volker Straub | Kevin M Flanigan | Dina Vojinovic | Manuel Posada | K. Bushby | K. Flanigan | C. Béroud | D. Vojinović | Hanns Lochmüller | M. Bellgard | M. Posada | H. Dawkins | D. Salgado | P. Jeannet | M. Rodrigues | R. Roxburgh | C. Campbell | H. Topaloglu | V. Karcagi | M. Walter | E. Gallardo | V. Straub | S. Monges | J. Zimowski | P. Brabec | J. Díaz-Manera | N. Barišić | Rosário Santos | F. Buccella | V. Rašić | Janusz Zimowski | Anna Lusakowska | Vedrana Milic Rasic | Veronika Karcagi | Marta Garami | Soledad Monges | Teodora Chamova | Velina Guergueltcheva | Miriam Rodrigues | Hugh Dawkins | Jaana Lahdetie | Pierre-Yves Jeannet | David Salgado | Jan Kirschner | Kate Bushby | Jan Verschuuren | Holly L Peay | K. Kosma | J. Kirschner | C. Bloetzer | Catherine L Bladen | Maria E Foncuberta | Konstantina Kosma | Anna J Roy | Sophelia Chan | Yi Dai | Jen Wang | Nina Barišić | Maggie C Walter | Olivia Schreiber-Katz | Venkatarman Viswanathan | Farhad Bayat | Filippo Buccella | En Kimura | Zaïda Koeks | Janneke C van den Bergen | Anna Kostera-Pruszczyk | Elena Neagu | Franziska Joncourt | Jordi Díaz-Manera | Eduard Gallardo | A Ayşe Karaduman | Haluk Topaloğlu | Rasha El Sherif | Angela Stringer | Andriy V Shatillo | Ann S Martin | Matthew I Bellgard | Annemieke Aartsma-Rus | L. Korngut | H. Peay | A. Karaduman | A. Roy | F. Joncourt | S. Chan | V. Guergueltcheva | Olivia Schreiber-Katz | A. Kostera-Pruszczyk | A. Shatillo | K. Kekou | J. Verschuuren | E. Kimura | M. Foncuberta | E. Neagu | T. Chamova | Z. Koeks | Ann S. Martin | R. el Sherif | A. Lusakowska | C. Bladen | Leanne Lamont | J. C. van den Bergen | A. Stringer | Farhad Bayat | A. Aartsma-Rus | J. Lahdetie | S. Artemieva | V. Viswanathan | Y. Dai | M. Garami | Jen Wang | O. Schreiber-Katz | H. Topaloğlu

[1]  Thomas W Prior,et al.  Experience and strategy for the molecular testing of Duchenne muscular dystrophy. , 2005, The Journal of molecular diagnostics : JMD.

[2]  L. Kunkel,et al.  The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion. , 1989, American journal of human genetics.

[3]  M. Vihinen,et al.  Recommendations for locus‐specific databases and their curation , 2008 .

[4]  I. Graham,et al.  Comparative analysis of antisense oligonucleotide sequences for targeted skipping of exon 51 during dystrophin pre-mRNA splicing in human muscle. , 2007, Human gene therapy.

[5]  Domenica Taruscio,et al.  The TREAT‐NMD Duchenne Muscular Dystrophy Registries: Conception, Design, and Utilization by Industry and Academia , 2013, Human mutation.

[6]  R. Waterston,et al.  Characterization of dystrophin in muscle-biopsy specimens from patients with Duchenne's or Becker's muscular dystrophy. , 1988, The New England journal of medicine.

[7]  Livija Medne,et al.  Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort , 2009, Human mutation.

[8]  G. van Ommen,et al.  Advances in therapeutic RNA-targeting. , 2013, New biotechnology.

[9]  K. Bushby,et al.  Standards of care for Duchenne muscular dystrophy: brief TREAT-NMD recommendations. , 2009, Advances in experimental medicine and biology.

[10]  P. Iversen,et al.  Antisense oligonucleotide-induced exon skipping restores dystrophin expression in vitro in a canine model of DMD , 2006, Gene Therapy.

[11]  G. van Ommen,et al.  Theoretic applicability of antisense‐mediated exon skipping for Duchenne muscular dystrophy mutations , 2009, Human mutation.

[12]  Meenal Patel,et al.  PTC124 targets genetic disorders caused by nonsense mutations , 2007, Nature.

[13]  Y. Takeshima,et al.  Oligonucleotides against a splicing enhancer sequence led to dystrophin production in muscle cells from a Duchenne muscular dystrophy patient , 2001, Brain and Development.

[14]  K. Bushby,et al.  Collaborating to bring new therapies to the patient--the TREAT-NMD model. , 2009, Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology.

[15]  Thierry Soussi,et al.  UMD (Universal Mutation Database): 2005 update , 2005, Human mutation.

[16]  S. Peltz,et al.  Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single‐ and Multiple‐Dose Administration to Healthy Male and Female Adult Volunteers , 2007, Journal of clinical pharmacology.

[17]  Christophe Béroud,et al.  Genotype–phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD–DMD database: a model of nationwide knowledgebase , 2009, Human mutation.

[18]  Nathalie Jette,et al.  A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy , 2014, Neuromuscular Disorders.

[19]  G. van Ommen,et al.  Antisense-induced multiexon skipping for Duchenne muscular dystrophy makes more sense. , 2004, American journal of human genetics.

[20]  Y. Takeshima,et al.  Chimeric RNA/ethylene-bridged nucleic acids promote dystrophin expression in myocytes of duchenne muscular dystrophy by inducing skipping of the nonsense mutation-encoding exon. , 2004, Human gene therapy.

[21]  Christophe Béroud,et al.  Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy , 2007, Human mutation.

[22]  F. Baas,et al.  Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients. , 2003, Human molecular genetics.

[23]  K. Flanigan,et al.  Sequence specificity of aminoglycoside‐induced stop codon readthrough: Potential implications for treatment of Duchenne muscular dystrophy , 2000, Annals of neurology.

[24]  R. Jones,et al.  To be Therapeutic. , 1967 .

[25]  N. Laing Molecular genetics and genetic counselling for Duchenne/Becker muscular dystrophy. , 1993, Molecular and cell biology of human diseases series.

[26]  E. Hoffman,et al.  Novel approaches to corticosteroid treatment in Duchenne muscular dystrophy. , 2012, Physical medicine and rehabilitation clinics of North America.

[27]  M Krawczak,et al.  Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. , 1998, American journal of human genetics.

[28]  G. van Ommen,et al.  The therapeutic potential of antisense-mediated exon skipping. , 2008, Current opinion in molecular therapeutics.

[29]  L. Kunkel,et al.  The structural and functional diversity of dystrophin , 1993, Nature Genetics.

[30]  G. van Ommen,et al.  Entries in the Leiden Duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading‐frame rule , 2006, Muscle & nerve.

[31]  K. Fischbeck,et al.  Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations , 2001, Annals of neurology.

[32]  R. Finkel,et al.  DMD pseudoexon mutations: splicing efficiency, phenotype, and potential therapy , 2008, Annals of neurology.