A faulty gene called DOK7 stops muscles from receiving signals from nerves, leaving around 40% of children and adults with hereditary myasthenia without a correct diagnosis. This matters because standard treatments for congenital myasthenic syndromes often make patients with DOK7 mutations worse, not better. The underlying defect prevents acetylcholine receptors from positioning themselves correctly opposite nerve endings at the synapse, so the nerve signal never reaches the muscle. Without knowing the genetic cause, doctors cannot offer effective treatment or accurate genetic counselling. If this research succeeds, it will prevent misdiagnosis and allow clinicians to identify DOK7 mutations early, sparing patients from harmful standard therapies. It will also reveal the molecular mechanism behind receptor placement, which could uncover new genes involved in similar synaptic disorders. This is fundamental science into how synapses malfunction, but the immediate payoff is practical: better diagnosis and tailored treatment for a group of patients who currently go undiagnosed or are given drugs that make them worse.
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Signalling between nerves is achieved largely by the opening and closing of ion channels, in their cell surface, at specialised sites called synapses. We believe an understanding of how synapses malfunction will help in finding the causes of many neurological disorders and in devising new therapies. We study inherited diseases, called congenital myasthenic syndromes, that cause severe disability in children and adults and affect ion channels, called acetylcholine receptors (AChR), located at the connection between nerves and muscles. These inherited mutations cause disease by affecting AChR in different ways. Understanding how the mutations cause disease enables us to give patients correct treatments and genetic counselling, and provides the knowledge base required for exploring new therapies. Several different genes have been shown to cause these disorders but in around 40% of cases the underlying defect is not known. Recently we identified mutations in a new gene, called DOK7. Standard treatments used in congenital myasthenia often make patients with DOK7 mutations worse. It is thought the faulty gene underlies a defect in the process that places the receptor in the correct position opposite the nerve ends. Here, in studies of this process we will learn why the signal from the nerve is not received by the muscle. Knowledge gained will help identify new genes involved in our disease, and help us understand why these patients do not respond to standard treatments. At present many patients with these mutations go undiagnosed or are misdiagnosed. Success in this project should prevent misdiagnosis, and enable us to provide better treatment for our patients.
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