Question

Two related forms of muscular dystrophy-Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD)-are both recessive, X-linked, single-gene conditions caused by point mutations, deletions, and insertion in the dystrophin gene. Bach mutated form of dystrophin is one allele. Of the two diseases, DMD is much more severe. Given your knowledge of mutations, the genetic code, and translation, propose an explanation for why the two disorders differ greatly in severity.

Short answer

Answer: DMD is more severe than BMD due to the nature of the mutations involved. Mutations in DMD lead to a complete loss of dystrophin function, as the resulting protein is truncated and non-functional, while the mutations in BMD usually result in a partially functional protein. The presence of some functional dystrophin protein in BMD helps to alleviate the severity of the disorder, whereas the complete loss of function in DMD results in a more rapid and severe progression of the disease.

Step-by-step solution

Understand the genetic basis of DMD and BMD

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are both caused by mutations in the dystrophin gene located on the X chromosome. As they are X-linked recessive disorders, mainly males are affected, and females can be carriers. The dystrophin gene encodes for the dystrophin protein, which plays a crucial role in maintaining the structural integrity of muscle cells. Mutations in this gene result in the production of a faulty or absent dystrophin protein, leading to the progressive weakening of muscles.

Consider the types of mutations causing the disorders

Both DMD and BMD are caused by point mutations, deletions, and insertions in the dystrophin gene. Point mutations involve the substitution of a single nucleotide, while deletions or insertions involve the removal or addition of one or more nucleotides. These mutations can affect the resulting protein differently, depending on the type and location of the mutation.

Relate mutations to the differences in protein function

Generally, the mutations causing DMD are more severe as they lead to a complete loss of function of the dystrophin protein. In most cases of DMD, the mutations introduce a premature stop codon into the coding sequence, resulting in a truncated, non-functional protein. On the other hand, the mutations in BMD often lead to a partially functional dystrophin protein. For instance, the deletion or insertion mutations in BMD are usually in-frame mutations, meaning the reading frame of the mRNA remains intact, and the affected protein only has a few missing or altered amino acids, allowing it to partially retain its function.

Propose an explanation for the differences in severity

Based on the information provided and our understanding of mutations, the genetic code, and translation, we can propose an explanation for the difference in severity of the two disorders. Duchenne muscular dystrophy (DMD) is more severe than Becker muscular dystrophy (BMD) due to the nature of the mutations involved. The mutations in DMD lead to a complete loss of dystrophin function, as the resulting protein is truncated and non-functional, while the mutations in BMD usually result in a partially functional protein. The presence of some functional dystrophin protein in BMD helps to alleviate the severity of the disorder as it provides some level of protection to the muscle cells, whereas the complete loss of function in DMD results in a more rapid and severe progression of the disease.

Key concepts

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It primarily affects boys due to its X-linked pattern of inheritance. DMD is caused by mutations in the dystrophin gene found on the X chromosome. This gene is responsible for producing the dystrophin protein, which is crucial for stabilizing and protecting muscle cells.

In DMD, these mutations often result in a premature stop codon, leading to a truncated dystrophin protein that is non-functional. The absence of functional dystrophin in muscle cells causes them to become damaged and weakened over time.

Symptoms of DMD usually begin between the ages of three and five. Initial signs include difficulty in running, jumping, and climbing stairs. As the condition progresses, there is a significant loss of mobility, often requiring the use of a wheelchair by adolescence. Management of DMD focuses on treatment options to slow down muscle degeneration and help improve quality of life.

Becker Muscular Dystrophy

Becker Muscular Dystrophy (BMD) is a milder form of muscular dystrophy compared to Duchenne Muscular Dystrophy. Like DMD, BMD is also X-linked, meaning it primarily affects males, while females can carry and transmit the gene without showing symptoms.

In BMD, mutations in the dystrophin gene result in a dystrophin protein that is either partially truncated or altered in such a way that it retains some function. Typically, these mutations are in-frame, meaning the protein's production is mostly maintained, albeit with some alterations.

The symptoms of BMD start later and progress more slowly compared to DMD. The age of onset can vary widely, from adolescence to early adulthood. Individuals with BMD experience muscle weakness predominantly in the pelvis and legs but maintain greater mobility for a longer period. The slower progression of muscle degeneration in BMD is attributed to the presence of partially functional dystrophin.

X-linked Disorders

X-linked disorders are genetic conditions that are associated with mutations in genes on the X chromosome. Since males have only one X chromosome, they are more frequently affected by these disorders if the mutated gene is recessive. Females, having two X chromosomes, are often carriers, which means they have one normal gene that can mask the effects of the defective one.

Examples of X-linked disorders include Duchenne and Becker Muscular Dystrophies. Because these conditions are recessive, a female would need to inherit two copies of the mutated gene to be affected, which is rare. However, female carriers can pass the mutated gene to their sons, who then express the disorder.

Since the X chromosome carries genes that are crucial for normal functioning, mutations can lead to a range of symptoms depending on which gene is affected. Understanding X-linked inheritance is essential for genetic counseling and planning, particularly for families with a history of these conditions.