The DMD gene contains instructions for making dystrophin, a protein primarily found in skeletal muscles and heart muscle. Mutations in the DMD gene are responsible for muscle disorders, including Duchenne muscular dystrophy and the generally milder Becker muscular dystrophy, both characterized by progressive muscle weakness.
The Role of Dystrophin
Dystrophin acts as a molecular anchor, connecting a muscle fiber’s internal framework to its surrounding proteins. This connection provides structural support and stability, protecting muscle cells from damage during contractions.
Without functional dystrophin, muscle fibers become fragile and prone to injury. Each contraction damages cells, leading to tissue breakdown. Over time, injured cells weaken and die, replaced by fibrous tissue and fat.
This progressive replacement of muscle with non-contractile tissue results in characteristic weakness in Duchenne and Becker muscular dystrophies. Lack of dystrophin also impacts heart muscle, contributing to cardiac problems.
Types of Genetic Changes
Mutations in the DMD gene can occur in several forms, each altering the gene’s instructions. The most common type involves large deletions, where one or more sections of the gene, called exons, are missing. These deletions account for approximately 60% to 70% of Duchenne muscular dystrophy cases.
Other changes include large duplications, where a segment of the DMD gene is copied. Duplications are less frequent than deletions, occurring in about 10% of cases.
Smaller alterations, such as point mutations, account for the remaining 15% to 30% of DMD gene mutations. One common type is a nonsense mutation, which introduces a premature “stop” signal in the gene’s instructions. This signal halts protein production too early, resulting in little or no functional dystrophin.
Inheritance and Spontaneous Mutations
The DMD gene is located on the X chromosome. This means Duchenne muscular dystrophy follows an X-linked recessive inheritance pattern. Males, with only one X chromosome, are more affected if it carries a DMD gene mutation.
Females have two X chromosomes; if one carries a mutation, the other can often compensate, leading to milder or no symptoms. These females are considered carriers. A carrier mother has a 50% chance of passing the mutated gene to each son, and a 50% chance to each daughter (who would become a carrier).
Not all cases are inherited. About one-third of Duchenne muscular dystrophy cases arise from spontaneous mutations. These occur randomly in the child without family history.
Diagnosis and Genetic Testing
Diagnosis for Duchenne muscular dystrophy often begins with a blood test measuring creatine kinase (CK) levels. CK is an enzyme that leaks from damaged muscle cells; elevated blood levels indicate muscle injury. While high CK levels suggest muscle damage, they are not specific to muscular dystrophy.
Definitive diagnosis relies on genetic testing, analyzing a blood sample for DMD gene mutations. Techniques like Multiplex Ligation-Dependent Probe Amplification (MLPA) detect large deletions or duplications. If common mutations are not found, full gene sequencing can identify smaller point mutations.
Historically, muscle biopsy (removal of a muscle sample) was a common diagnostic step. However, with genetic testing advancements, muscle biopsies are less frequent. Genetic testing precisely identifies the underlying mutation, important for diagnosis and guiding treatment.
Therapeutic Approaches Targeting the Gene
Therapeutic strategies for Duchenne muscular dystrophy focus on addressing genetic defects, rather than just managing symptoms. One approach, “exon skipping,” uses drugs called antisense oligonucleotides. These drugs prompt cellular machinery to “skip over” a mutated DMD gene section during protein production.
Skipping the faulty exon restores the gene’s reading frame, allowing production of a shorter, partially functional dystrophin protein. This partially functional protein offers stability to muscle cells and can slow disease progression. Several exon-skipping therapies target DMD gene mutations.
Another strategy, gene therapy, aims to deliver a functional DMD gene to muscle cells. Because the full DMD gene is too large for delivery, gene therapy often uses modified, smaller versions (micro-dystrophins). These micro-dystrophin genes are delivered to muscle cells using viral vectors like adeno-associated viruses (AAV).