Data for this review were identified by searches of MEDLINE with the search terms “dystrophin”, “gene”; “genomic organisation”, “mutations”, “gene expression”, “mental retardation”, “brain”, “dilated cardiomyopathy”, and “retina”. This search identified 942 articles. Orginal articles were selected wherever possible; subsequent papers publishede in high-impact-factor journals(eg, Naturegenetics, Human Molecular Genetics, AmericanJournal of Human Genetics) were also included. Important
ReviewDystrophin and mutations: one gene, several proteins, multiple phenotypes
Section snippets
Long isoforms of dystrophin
Full-length dystrophin is a large rod-shaped protein with a molecular weight of 427 kDa that comprises four domains (figure 1). The amino-terminal domain has homology with α-actinin and contains between 232 and 240 amino-acid residues depending on the isoform. The central—rod—domain is a succession of 25 triple-helical repeats similar to spectrin and contains about 3000 residues. There is a cysteinerich domain of 280 residues. The last—carboxy-terminal—domain comprises 420 residues.15, 17, 18,
Short isoforms of dystrophin
The dystrophin gene also has at least four internal promoters that give rise to shorter dystrophin proteins lacking the actin-binding terminus but retaining the cysteine rich and carboxy-terminus domains that contain the binding sites for dystroglycan, dystrobrevin, and syntrophin. Each of these internal promoters uses a unique first exon that splices into exons 30, 45, 56, and 63 to generate protein products of 260 kDa (Dp260), 140 kDa (Dp140), 116 kDa (Dp116), and 71 kDa (Dp71). Dp260 is
Mutations in the dystrophin gene
The most common changes in dystrophin are intragenic deletions, which account for 65% of dystrophin mutations. Deletions and, more rarely, duplications can happen almost anywhere in the dystrophin gene; however, two deletion hotspots are known—one located towards the central part of the gene and the other towards the 5′ end. The former is the most commonly mutated region and includes exons 45–55 with genomic breakpoints (ie, the endpoint of where the deletions actually occurs) lying within
Disease severity: deletions, duplication and the frame-shift hypothesis
There is no simple relation between the size of the deletion and the resultant clinical disease. For example, the deletion of small exons, such as exon 44, typically results in classic DMD. However, large deletions, which may involve nearly 50% of the gene, have been described in patients with BMD.46, 47, 48 The central and distal rod domains seem to be almost dispensable functionally with some deletions in this region being associated with myalgia and muscle cramps, but not weakness. Some
Exceptions to the reading-frame hypothesis
Exceptions to the reading-frame hypothesis do exist and these include patients with BMD who carry frame-shift deletions or duplications and patients with DMD with inframe deletions or duplications.
Patients with BMD with frame-shift mutations
Patients with BMD with frame-shift mutations have several well-characterised deletions or duplications in the 5′ end of the gene (exons 3–7; 5–7; 3–6) or further downstream (exons 51, 49–50, 47–52, 44 or 45).55, 57, 58, 59, 60 The most common event that allows these patients to produce at least some dystrophin is exon skipping, which occurs via alternative splicing; the carboxy-terminus is always preserved in these patients.61 Diagnosis with a purely molecular genetic approach may be difficult
Exon-skipping events
The mechanisms that lead to exon skipping in patients with out-of-frame mutations are poorly understood and are likely to be caused by several factors. Exon-skipping events limited to a few fibres are routinely found in the dystrophin deficient mdx mice and in about 50% of children with DMD.62, 65, 66 The finding of revertant fibres (in which the mutations are suppressed and functional dystrophin is produced) in a patient is compatible with a diagnosis of DMD. However, several patients with
Patients with DMD with in-frame deletion mutations
Although there is a relation between disease phenotype and the ability to produce dystrophin, there are rare exceptions. This is particularly true for large deletions in the 5′ region that extend into the middle of the rod domain—such as deletions of exons 3–31, 3–25, 4–41, or 4–18.88 This contrasts with the mild BMD phenotype observed for large deletions that do not involve the 5′ principal putative actin binding site of dystrophin but instead remove regions of the rod domain.46, 47, 48, 89
Point mutations
20–35% of patients with DMD and BMD do not have deletions or duplications of the dystrophin gene.94 The identification of mutations in these patients has been hampered by the size of the dystrophin gene. One of the specialist techniques used is the protein truncation test, which can be applied to muscle RNA.95 A few studies have been done with this technique, which is currently offered by one accredited diagnostic laboratory in the UK (Guy's Hospital Clinical Genetic Centre, London).94, 96, 97,
X-linked dilated cardiomyopathy
Although cardiac involvement is invariably associated with DMD and BMD, rare mutations cause an almost exclusive cardiac involvement. The only hint of skeletal muscle involvement in these patients is the high concentrations of creatine kinase in the plasma;112 although one patient with X-linked dilated cardiomyopathy and normal creatine kinase concentrations is on record.113 Although X-linked dilated cardiomyopathy is a rare disorder, the analysis of the mutations that result in this phenotype
CNS involvement in DMD and BMD
Both the brain and the retina are affected by the lack of dystrophin. However, the range of abnormalities found is very significant. Some patients with DMD, for example, may have severe mental retardation and this, when present, is concordant in affected relatives, suggesting a primary role of the mutated dystrophin in that particular family. However, other individuals with DMD have entirely normal intellectual function.
There have been several studies of IQ in affected boys, the results of
Retinal involvement and dystrophin
Although affected boys have normal visual acuity, electroretinography has shown significant defects in several patients. Different dystrophin isoforms are expressed in the retina but do not overlap in their distribution, which suggests non-redundant different functional roles.138 The main retinal isoform is the Dp260,34, 138 which localises to the outer plexiform layer together with Dp427.138 In contrast, Dp71 is localised to the inner limiting membrane and to retinal blood vessels. Several
Conclusion
The dystrophin gene is a huge and fascinating gene with a complexity in transcriptional regulation, function, and protein–protein interactions that we are only beginning to fully appreciate. The relation between genotype and phenotype is particularly important not only to diagnostic and counselling viewpoints, but also to the understanding of the pathways and mechanisms that regulate expression. Improvements in knowledge about these features point the way towards a future treatment for this
Search strategy and selection criteria
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