The muscular dystrophies in humans and animals: genes, pathophysiology, and post-gene applications towards therapeutics

摘要

Duchenne muscular dystrophy is the most common childhood-lethal disorder of humankind. The high incidence is due to the strikingly high mutation rate of the causative gene; 1 in 10,000 sperm and eggs of all humans have the gene destroyed as a new event (spontaneous mutation). The high mutation rate dictates a high incidence in all world populations, with none of the population-specificity seen in many other common inherited disorders. Duchenne muscular dystrophy is an X-linked recessive trail and most patients are young boys. Clinical presentation is in early school age, with proximal muscle weakness leading to difficulty in running or climbing stairs. Muscle wasting is progressive, with most muscle groups experiencing relentless destruction of muscle. This leads to patients becoming wheelchair-bound in the middle of their second decade, with death due to respiratory failure typically occurring before age 20 yrs. Patients can be mechanically ventilated and fed, which can substantially increase lifespan, although there is little function of limb-muscles preserved. Duchenne muscular dystrophy became the first successful target for "positional cloning" of a disease gene: identification of the responsible gene and protein based only on the locationin the genomic DNA of patients. Genetic landmarks which aided the identification of the gene included female X:autosome translocation patients (the translocation disabled one of their genes, while the other was preferentially inactivated due to chromosomal dosage problems), and large deletion mutations in affected males, some of which were cytogenetically detectable. This led to the identification of fragments of DNA that were altered in the female patients, and/or deleted from the male patients, suggesting that the responsible gene lay nearby (see Hoffman, 2000). The identification of the responsible gene, and the protein product of this gene, dystrophin, soon followed. All patients with Duchenne muscular dystrophy show complete dystrophin deficiency(loss-of-function), while patients with a milder disease called Becket muscular dystrophy show present but abnormal dystrophin (abnormal quantity and/or quality). Female manifesting carriers all show skewed X inactivation, leading to a high proportion ofmyofibers showing dystrophin deficiency.