The dystrophin protein is an important cytoskeletal protein. It is a rod-shaped protein that localizes in the skeletal and cardiac muscles. Within these cells, dystrophin forms a vital part of a protein complex, called the dystophin-associated protein complex, which connects the cytoskeleton to the extracellular matrix. Proteins associated in this complex include sarcoglycan, dystroglycan, syncoilin, synemin, and others. The major function of this complex is to strengthen the muscle fibers and to protect them from injury as they contract and relax. A small amount of the dystrophin protein is also found in nerve cells. However, here its function is not clearly understood, but suggestions do indicate that it might play a role in maintaining the normal structure and function of synapses.
Defects in the dystrophin protein function are related to some forms of muscular dystrophy, especially the Duchenne (DMD) and Becker (BMD) types. DMD is typically seen in boys as proximal muscle weakness, ultimately resulting in wheelchair confinement. Intellectual impairment is noticed in half of the patients. Similar clinical features are seen in BMD, although in a much more benign form. Dystrophin defects are also associated with X-linked dilated cardiomyopathy, a condition characterized by enlarged and weakened cardiac muscles, resulting in inefficient pumping.
The dystrophin gene is the largest known human gene, measuring 2.4 Mb in size. The gene is located on the X-chromosome, and is comprised of 79 exons encoding dystrophin. The protein is made up of 3,685 amino acids, and weighs about 427 kDa. Dystrophin is a member of the beta-spectrin/alpha-actinin protein family. Four major domains can be identified in the protein; the amino-terminal actin-binding domain, a central rod domain, a cysteine-rich domain, and a c-terminal domain. The rod domain is made up of 24 repeating units that give the protein a flexible rod-like structure.
Several hundred mutations have so far been discovered in the dystrophin gene. About 55-65% of these are deletional mutations. Interestingly, most of these deletional mutations causing DMD or BMD tend to cluster in two regions or hotspots in the gene. Other kinds of mutations include duplications (5-10%) and point mutations. The point mutations, unlike the deletional ones, are spread more or less, all over the gene. In the absence or deficiency of functional dystrophin protein, muscle cells tend to get damaged, resulting in the muscle weakness and cardiac problems typical of muscular dystrophies. In the case of DMD, the gene mutation leaves very little functional protein, while BMD mutations result in some amount of partially functional protein, hence, explaining the milder phenotype of BMD.
Bastaki et al. (1999b) studied 26 Egyptian patients with Duchenne or Becker Muscular Dystrophy to observe any correlation between the size and site of dystrophin gene deletions and the clinical picture of dystrophinopathies. PCR analysis showed that 68% of the Egyptian patients had deletions in the Dystrophin gene. The most common deleted exons among the Egyptian patients were exons 19, 45, 48, and 51. No significant correlation was found between the size or site of the deletion and the clinical severity of the disease in terms of onset of walking, onset of weakness, and average IQ. The average IQ among the Egyptian patients was 90, but involvement of exons 45 and 48 were associated with IQ ranges from 85-86. This association, however, was non-significant.
[See also: Kuwait > Haider et al., 1998; Bastaki et al., 1999b].
Haider et al. (1998) used three different sets of multiplex PCRs to study dystrophin gene deletion mutations among 26 Kuwaiti and 16 Egyptian DMD patients. With the three reactions and individual amplification of exon 22, a total of 25 exons of the gene were analyzed, which included both the distal and the proximal hotspots. Combining the results of all the sets, deletions were detected in 86% of the patients, which was the highest deletion detection rate in DMD patients up until that time. No deletions could be detected in exon 44, Pm (Promoter muscle), or Pb (Promoter brain). The distal hotspot (exons 44-53) contained deletions in 50% of the cases, whereas in 8%, the proximal hostspot (exons 4-17) contained deletions. In an additional 42%, the deletions were scattered over both the regions. This result was different from previously published reports where the deletions were localized to the proximal hotspot alone. Haider et al. (1998) suggested that this pointed towards a population-specific genetic variability among DMD Arab patients.
In their study on 26 Kuwaiti patients with DMD and BMD, Bastaki et al. (1999a) analyzed Dystrophin gene deletions. Among the Kuwait patients, 68% were found to contain deletions in the Dystrophin gene. The most common deleted exons among these patients were exons 81, 45, and 48. No significant correlation was found between the size or site of the deletion and the clinical severity of the disease in terms of onset of walking, onset of weakness, and average IQ. As a continuation of this study, Bastaki et al. (1999b) performed immunohistochemical studies on the muscle biopsies of these patients. Of the 26 Kuwaiti patients, 31% were found to be dystrophin negative, while 8% were partially dystrophin negative.
[See also: Egypt > Bastaki et al., 1999b].
Bosley et al. (2016) reported the case of a 14-year-old Saudi boy suffering from both Duchenne Muscular Dystrophy (DMD) and Duane Retraction Syndrome (DRS). The patient’s parents were not related and the patient had healthy unaffected siblings. Symptoms of DMD included delayed speech development, mild mental retardation, progressive muscle wastage and elevated creatine kinase levels. A muscle biopsy showed significant signs of dystrophy as well as defective histological stains for dystrophin protein. His ophthalmological symptoms included complete abduction defects and bilateral restriction of adduction with globe retraction. The patient also had a history of seizures in infancy. Multiplex Ligand-dependent Probe Amplification (MLPA) studies revealed the presence of duplications of exons 3 and 4 in the Dystrophin gene. The patient’s mother was tested and found not to have these duplications, indicating germ-line mosaicism. The authors noted that this was the third reported case worldwide of a patient suffering from both DMD and DRS and the first case involving neurological features.
Madania et al. (2010) extracted genomic DNA from 51 unrelated Syrian DMD/BMD male patients and analyzed 25 hotspot exons in the Dystrophin gene. Madania et al. (2010) found a deletion in 25 (49%) and a duplication in 5 (10%) out of all 51 patients studied.
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