The discovery of dystrophin, the protein product of the Duchenne muscular dystrophy gene

Figures

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  Fig. 1. Timelines. (A) Timeline of DMD gene and dystrophin protein discovery. Shown is a timeline of key milestones in the identification of the DMD gene (top) and dystrophin protein (bottom). Citations relevant to each milestone are provided in the text. Figure inserts. DMD genomic locus (upper right) shows a schematic of the genomic locus and chromosomal walks (top), cDNA/mRNA map (middle), and patient gene deletions (bottom). Taken from Koenig et al. (1987) (fig. 3) [7]. TrpE fusions to dystrophin for antibodies. Affinity‐purified, region‐specific dystrophin antibodies produced against dystrophin. A schematic of the 427 kDa dystrophin protein, with its four constituent domains, is shown. Taken from Hoffman et al. (1990) (fig. 1) [41]. Dystrophin immunostaining. Dystrophin immunofluorescence showing membrane localization in normal skeletal muscle and loss of dystrophin in DMD muscle. Taken from Bonilla et al. (1989) figs 1a, 2a). Bar = 50 µm [11]. (B) Timeline of dystrophin‐enabled pathophysiology and therapeutics. Shown is a timeline of increased knowledge of the pathophysiological consequences of dystrophin deficiency and the emergence of therapeutic approaches. Citations relevant to…

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  Fig. 2. Dystrophin rescue by exon skipping in a viltolarsen clinical trial in DMD. (A) reverse transcription–polymerase chain reaction (RT‐PCR) of participant muscle biopsies taken before treatment and after treatment with viltolarsen. RT‐PCR products showing unskipped ‘out‐of‐frame’ mRNA transcript were seen pretreatment, while viltolarsen‐induced exon skipping led to a smaller skipped ‘in‐frame’ mRNA. (B) immunoblots for dystrophin [D], with protein loading controls for myosin heavy chain, M and alpha‐actinin, A. Standard curves for dystrophin are shown from mixed normal and DMD skeletal muscle samples. Clinical trial participant muscle biopsies, pretreatment and post‐viltolarsen treatment, were tested in a blinded manner. Pretreatment biopsies showed no dystrophin, whereas post‐treatment biopsies showed viltolarsen‐induced ‘Becker‐like’ dystrophin rescue. Taken from Clemens et al. (2020) (fig. 2) [27].