Genotype–phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD–DMD database: a model of nationwide knowledgebase

UMD–DMD France is a knowledgebase developed through a multicenter academic effort to provide an up‐to‐date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD–DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype‐based therapies allowed the prediction of a new multiexon skipping (del 45–53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development. Hum Mutat 30:1–12, 2009. © 2009 Wiley‐Liss, Inc.

[1]  N. Bresolin,et al.  A region in the dystrophin gene major hot spot harbors a cluster of deletion breakpoints and generates double-strand breaks in yeast , 2006 .

[2]  A. Nakamura,et al.  Follow-up of three patients with a large in-frame deletion of exons 45–55 in the Duchenne muscular dystrophy (DMD) gene , 2008, Journal of Clinical Neuroscience.

[3]  E. McNally,et al.  The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. , 2004, Circulation research.

[4]  I. Hausmanowa-Petrusewicz,et al.  A dystrophin missense mutation showing persistence of dystrophin and dystrophin‐associated proteins yet a severe phenotype , 1998, Annals of neurology.

[5]  K. Davies,et al.  ZZ domain is essentially required for the physiological binding of dystrophin and utrophin to beta-dystroglycan. , 2004, Human molecular genetics.

[6]  Francesco Muntoni,et al.  Dystrophin and mutations: one gene, several proteins, multiple phenotypes , 2003, The Lancet Neurology.

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

[8]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[9]  B. Katirji.  Diagnostic Criteria for Neuromuscular Disorders , 1994, Neurology.

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

[11]  A. Monaco,et al.  Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene , 1986, Nature.

[12]  M. W. Thompson,et al.  Duplicational mutation at the Duchenne muscular dystrophy locus: its frequency, distribution, origin, and phenotypegenotype correlation. , 1990, American journal of human genetics.

[13]  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.

[14]  K. Greenwood,et al.  Intelligence and Duchenne muscular dystrophy: full-scale, verbal, and performance intelligence quotients. , 2001 .

[15]  N. Keep,et al.  The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy. , 2000, Structure.

[16]  C. Béroud,et al.  Protein‐ and mRNA‐based phenotype–genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene , 2007, Human mutation.

[17]  C. van Broeckhoven,et al.  Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations. , 1989, Journal of medical genetics.

[18]  C. Béroud,et al.  Dystrophinopathy caused by mid-intronic substitutions activating cryptic exons in the DMD gene , 2004, Neuromuscular Disorders.

[19]  S. Wilton,et al.  Splicing intervention for Duchenne muscular dystrophy. , 2005, Current opinion in pharmacology.

[20]  J. Lupski,et al.  A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders , 2007, Cell.

[21]  Emery.  Diagnostic Criteria for Neuromuscular Disorders , 1997 .

[22]  F. Rivier,et al.  The role of muscle biopsy in analysis of the dystrophin gene in Duchenne muscular dystrophy: experience of a national referral centre , 2004, Neuromuscular Disorders.

[23]  J. Mendell,et al.  Frameshift deletions of exons 3-7 and revertant fibers in Duchenne muscular dystrophy: mechanisms of dystrophin production. , 1995, American journal of human genetics.

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

[25]  G. van Ommen,et al.  Exploring the frontiers of therapeutic exon skipping for Duchenne muscular dystrophy by double targeting within one or multiple exons. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  C. Ishioka,et al.  Locus-specific mutation databases: pitfalls and good practice based on the p53 experience , 2006, Nature Reviews Cancer.

[27]  K. Wee,et al.  Dynamics of Co-Transcriptional Pre-mRNA Folding Influences the Induction of Dystrophin Exon Skipping by Antisense Oligonucleotides , 2008, PloS one.

[28]  T. Bettecken,et al.  On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis. , 1994, Journal of medical genetics.

[29]  S. Abbs,et al.  Loss of a single amino acid from dystrophin resulting in Duchenne muscular dystrophy with retention of dystrophin protein , 2003, Human mutation.

[30]  N. Nevin,et al.  The prevalence of inherited neuromuscular disease in Northern Ireland , 1996, Neuromuscular Disorders.

[31]  M. Claustres,et al.  Point mutations in the dystrophin gene: Evidence for frequent use of cryptic splice sites as a result of splicing defects , 1999, Human mutation.

[32]  Matthew Mort,et al.  A meta‐analysis of nonsense mutations causing human genetic disease , 2008, Human mutation.

[33]  M. Thambyayah,et al.  Prevalence and incidence of Becker muscular dystrophy , 1991, The Lancet.

[34]  A. Monaco,et al.  An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. , 1988, Genomics.

[35]  M. W. Thompson,et al.  Frame-shift deletions in patients with Duchenne and Becker muscular dystrophy. , 1988, Science.

[36]  Johan T den Dunnen,et al.  Local dystrophin restoration with antisense oligonucleotide PRO051. , 2007, The New England journal of medicine.

[37]  C. Angelini,et al.  Population data on benign and severe forms of X-linked muscular dystrophy , 1987, Human Genetics.

[38]  Christophe Béroud,et al.  UMD‐predictor, a new prediction tool for nucleotide substitution pathogenicity—application to four genes: FBN1, FBN2, TGFBR1, and TGFBR2 , 2009, Human mutation.

[39]  W. King,et al.  Characterization of translational frame exception patients in Duchenne/Becker muscular dystrophy. , 1993, Human molecular genetics.

[40]  K. Davies,et al.  Molecular mechanisms of muscular dystrophies: old and new players , 2006, Nature Reviews Molecular Cell Biology.

[41]  F. Muntoni,et al.  Intronic breakpoint definition and transcription analysis in DMD/BMD patients with deletion/duplication at the 5' mutation hot spot of the dystrophin gene. , 2006, Gene.

[42]  M. Claustres,et al.  Pseudoexon activation in the DMD gene as a novel mechanism for Becker muscular dystrophy , 2003, Human mutation.

[43]  J. Clancy,et al.  Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. , 2001, American journal of respiratory and critical care medicine.

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

[45]  T. Rando.  The dystrophin–glycoprotein complex, cellular signaling, and the regulation of cell survival in the muscular dystrophies , 2001, Muscle & nerve.

[46]  A. Covone,et al.  Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study , 2004, Human Genetics.

[47]  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.

[48]  Luis Garcia,et al.  Rescue of Dystrophic Muscle Through U7 snRNA-Mediated Exon Skipping , 2004, Science.

[49]  J. Ervasti,et al.  Membrane organization of the dystrophin-glycoprotein complex , 1991, Cell.

[50]  F. Rivier,et al.  Mutation spectrum leading to an attenuated phenotype in dystrophinopathies , 2005, European Journal of Human Genetics.

[51]  A. Emery.  Population frequencies of inherited neuromuscular diseases—A world survey , 1991, Neuromuscular Disorders.

[52]  S. Winder,et al.  ZZ domain of dystrophin and utrophin: topology and mapping of a beta-dystroglycan interaction site. , 2007, The Biochemical journal.

[53]  C. Hübner,et al.  A cysteine 3340 substitution in the dystroglycan-binding domain of dystrophin associated with Duchenne muscular dystrophy, mental retardation and absence of the ERG b-wave. , 1996, Human molecular genetics.

[54]  S. Pandya,et al.  The muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): surveillance methodology. , 2006, Birth defects research. Part A, Clinical and molecular teratology.

[55]  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.

[56]  M. Lieber,et al.  The Mechanism of Human Nonhomologous DNA End Joining* , 2008, Journal of Biological Chemistry.

[57]  H Sugita,et al.  Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. , 1991, American journal of human genetics.

[58]  K. Bushby,et al.  Becker muscular dystrophy with onset after 60 years , 1994, Neurology.

[59]  J. Zidar,et al.  Genetic epidemiology of Duchenne and Becker muscular dystrophy in Slovenia , 1997, Clinical genetics.

[60]  J. Lupski,et al.  Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. , 2004, Human molecular genetics.

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

[62]  P. Iversen,et al.  Bmc Molecular Biology Antisense Oligonucleotide Induced Exon Skipping and the Dystrophin Gene Transcript: Cocktails and Chemistries , 2022 .

[63]  R G H Cotton,et al.  The HUGO Mutation Database Initiative , 1998, The Pharmacogenomics Journal.

[64]  F. Pons,et al.  Mosaic expression of two dystrophins in a boy with progressive muscular dystrophy , 1998, Muscle & nerve.

[65]  J. T. Dunnen,et al.  Duplications in the DMD gene , 2006, Human mutation.

[66]  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.

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

[68]  M. Hentze,et al.  A Perfect Message RNA Surveillance and Nonsense-Mediated Decay , 1999, Cell.

[69]  A. Green,et al.  The Duchenne muscular dystrophy population in Denmark, 1977–2001: prevalence, incidence and survival in relation to the introduction of ventilator use , 2003, Neuromuscular Disorders.