What were the researchers aiming to do?
Individuals with CMS have faults in genes that affect a specialised area of the muscle called the neuromuscular junction. It is here that the nerve passes the signal to the muscle that tells it to contract. Prof Beeson and his colleagues had previously had indications that mutations in a new gene named DOK7, whose function had yet to be fully understood, might underlie a new subgroup of CMS. In this particular form of CMS muscle weakness appears similar to limb girdle muscular dystrophy. The gene is thought to carry the instructions for a protein which helps to place another crucial protein, called the acetylcholine receptor (AChRs) in the correct location at the neuromuscular junction. Exactly how the fault in DOK7 causes disease, however, is unknown. Using a model system established in their laboratory they aimed to firstly confirm whether mutations in the DOK7 gene definitely cause CMS. If this was confirmed they then planned to study how the mutation affected the functioning of the neuromuscular junction.
What did their research show?
Prof Beeson and his colleagues found that faults in a gene called DOK7 can give rise to congenital myasthenic syndrome. They also found that treating this group of patients with the drug ephedrine had a major impact on their daily lives by relieving many of the symptoms of their CMS. Ephedrine is a drug already available in the clinic as it has been used in the past to treat conditions such as asthma and bronchitis.
Although it is now known that faults in the DOK-7 gene can cause CMS, precisely how they cause the condition is still not fully understood. Researchers will continue to investigate this and look into exactly why ephedrine is of benefit to this group of people and what the long term effects are. Another drug, salbutamol, has similar effects and it will be important to establish which of the two is most effective, or indeed, if there are other better drugs available. Understanding this should improve the ability of clinicians to effectively treat many more individuals with CMS.
How will the outcomes of the research benefit patients?
At present many patients with DOK7 mutations are misdiagnosed and do not respond well to current treatments. Informing doctors about the typical features and symptoms of these patients has enabled many more to think of CMS as a possible diagnosis, and in many cases has led to definitive genetic diagnosis for patients and their families. Identifying the genes involved and understanding how mutations cause disease enables clinicians to offer patients genetic counselling, to provide a prognosis for the condition and to provide the knowledge required for developing therapies. In this research project it was also first observed that patients with DOK7 mutations respond well to treatment with ephedrine, which was then confirmed in a definitive study. As a result clinicians now recommend ephedrine or the similar drug salbutamol, for these patients.
Background information
The inherited and acquired myasthenias, which include myasthenia gravis and the congenital myasthenic syndromes, have in common a problem with the signal that comes from the nerve and tells the muscle to contract.
The place where the nerve and muscle meet is called the neuromuscular junction and in order for the muscle to contract, the nerve must send a signal across the neuromuscular junction. The signal travels down the nerve and causes it to release a chemical signal called acetylcholine. The acetylcholine then binds to proteins on the muscle membrane called receptors which set in motion the chain of events that allows the muscle to contract. Once the muscle has contracted, the signal must be “switched off” allowing the muscle to relax. This is done by an enzyme called acetylcholinesterase which breaks down the acetylcholine that is left in the neuromuscular junction.
Diagram showing how the nerve signals the muscle to contract at the neuromuscular junction
In order for this process to function properly, many different proteins play a role in making sure that the acetylcholine receptors and the acetylcholinesterase are correctly positioned at the neuromuscular junction. Mutations in the genes that carry the instructions for any of these proteins can cause one of the congenital myasthenic syndromes. In myasthenia gravis, it is antibodies attacking the proteins at the neuromuscular junction that are the cause of the problem. Both of these problems result in a weaker signal reaching the muscle leading to the muscle weakness and fatigue seen in these conditions.
Grant information
Project Leader: Prof David Beeson
Location: University of Oxford
Condition: Myasthenia gravis and congenital myasthenic syndromes
Duration: 3 years, completed September 2009
Total Project Cost: £336,712
Official Title: Mutations of MuSK-interacting proteins and molecular mechanisms underlying inherited myasthenic syndrome
Further information and links
Read more about the myasthenias
Find out more about Prof Beeson’s research
Read a news article about Prof Beeson’s research
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