Entries in the Leiden Duchenne muscular dystrophy mutation database: An overview of mutation types and paradoxical cases that confirm the reading‐frame rule

The severe Duchenne and milder Becker muscular dystrophy are both caused by mutations in the DMD gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle‐fiber membranes. In 1988, Monaco and colleagues postulated an explanation for the phenotypic difference between Duchenne and Becker patients in the reading‐frame rule: In Duchenne patients, mutations induce a shift in the reading frame leading to prematurely truncated, dysfunctional dystrophins. In Becker patients, in‐frame mutations allow the synthesis of internally deleted, but largely functional dystrophins. Currently, over 4700 mutations have been reported in the Leiden DMD mutation database, of which 91% are in agreement with this rule. In this study we provide an update of the mutational variability in the DMD gene, particularly focusing on genotype–phenotype correlations and mutations that appear to be exceptions to the reading‐frame rule. Muscle Nerve, 2006

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[9]  F. Muntoni,et al.  Multiple exon skipping and RNA circularisation contribute to the severe phenotypic expression of exon 5 dystrophin deletion , 2003, Journal of medical genetics.

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[26]  H. Nishio,et al.  A Japanese boy with myalgia and cramps has a novel in‐frame deletion of the dystrophin gene , 1996, Neurology.

[27]  J. T. Dunnen,et al.  Dystrophin nonsense mutation induces different levels of exon 29 skipping and leads to variable phenotypes within one BMD family , 2000, European Journal of Human Genetics.

[28]  Dejan Stefanović,et al.  Proximal Dystrophin Gene Deletions and Protein Alterations in Becker Muscular Dystrophy , 2005, Annals of the New York Academy of Sciences.

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[33]  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.

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[35]  F. Muntoni,et al.  X-linked dilated cardiomyopathy and the dystrophin gene , 1999, Neuromuscular Disorders.

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[37]  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.

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[41]  T. Tsukahara,et al.  A severe muscular dystrophy patient with an internally deleted very short (110 kD) Dystrophin: Presence of the binding site for dystrophin-associated glycoprotein (DAG) may not be enough for physiological function of dystrophin , 1995, Neuromuscular Disorders.

[42]  Johan T den Dunnen,et al.  Comprehensive detection of genomic duplications and deletions in the DMD gene, by use of multiplex amplifiable probe hybridization. , 2002, American journal of human genetics.

[43]  C. Caskey,et al.  Molecular and clinical correlations of deletions leading to Duchenne and Becker muscular dystrophies , 1989, Neurology.

[44]  A. Monaco,et al.  The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein , 1988, Cell.

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

[46]  E Bakker,et al.  Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands: a cohort study , 1999, The Lancet.

[47]  V. Dubowitz,et al.  Dystrophin in frameshift deletion patients with Becker muscular dystrophy. , 1992, American journal of human genetics.

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[49]  Eric P. Hoffman,et al.  Dystrophin: The protein product of the duchenne muscular dystrophy locus , 1987, Cell.

[50]  Jinhua Wang,et al.  ESEfinder: a web resource to identify exonic splicing enhancers , 2003, Nucleic Acids Res..

[51]  K. Fischbeck,et al.  Familial X‐linked myalgia and cramps , 1989, Neurology.

[52]  N. Bresolin,et al.  Cognitive impairment in Duchenne muscular dystrophy , 1994, Neuromuscular Disorders.

[53]  D. Bentley,et al.  Direct detection of dystrophin gene rearrangements by analysis of dystrophin mRNA in peripheral blood lymphocytes. , 1991, American journal of human genetics.

[54]  J. Oosterwijk,et al.  Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy , 1999, Neuromuscular Disorders.

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

[56]  Mayana Zatz,et al.  Intrafamilial variability in dystrophin abundance correlated with difference in the severity of the phenotype , 1993, Journal of the Neurological Sciences.

[57]  K. Campbell,et al.  Forced expression of dystrophin deletion constructs reveals structure- function correlations , 1996, The Journal of cell biology.

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