Congenital Myopathy Research in the Beggs Laboratory

The fundamental goals of the Beggs Laboratory are to understand the molecular basis for congenital myopathies and use this information to develop improved diagnostic and therapeutic methods. The congenital myopathies are a group of rare genetic disorders that result in muscular weakness, often from birth. Severe cases may lead to death in early infancy, often from an inability to breathe independently. Patients with milder cases may survive infancy and learn to walk, however, significant muscle weakness persists for life. Some of the specific diseases we study include myotubular myopathy, centronuclear myopathy and nemaline myopathy and we are generally interested in other forms of congenital myopathy, including undefined cases without firm diagnoses.

To attain our goals, we are taking three complementary approaches in the laboratory. The first is to find and study new muscle-specific genes and proteins and learn as much as possible about their basic biology, including their normal structure and function. The underlying assumption is that these new genes are likely to include ones that are defective in patients with various congenital myopathies. After learning about the normal genes, we are then in a position to look for abnormalities of these genes in patients with muscle weakness, as described below.

The second major project is to find and enroll patients and families with various congenital myopathies into our research program and then study their genetic material (DNA) and muscle to find the causes of their disorders. In the past few years, we have made much progress in understanding the causes of another related condition called nemaline myopathy, including the identification of three genes involved in this disorder. Finding the causative mutation allows us to confirm the diagnosis and identify other family members who may be at risk to develop the disorder or pass it on to their children. For those who are interested, it opens the possibility for them to undergo genetic counseling and prenatal diagnosis for any future pregnancies. Finally, we hope that knowing the genetic basis for each congenital myopathy will allow us to design specific and effective treatments for some of these diseases.

The third complementary approach is to learn as much as possible about the physiologic state of diseased muscle from patients with congenital myopathy. One frustrating aspect of medical genetics today, is that knowing the exact genetic defect has often not allowed us to fully understand how the disease is caused and, more importantly, how we can cure it. Utilizing recent advances in microarray technology, we are studying the expression of thousands of different genes simultaneously to understand the “downstream” or secondary consequences of particular genetic mutations. In particular, patients with myotubular myopathy have a defect in their “myotubularian” gene that results in incomplete muscle maturation. If we can learn about each of the results of myotubularian defects, we hope to identify critical pathways of muscle differentiation which may be targets for pharmacologic treatment.