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ContactCongenital myasthenic syndromes - Prof D. Beeson
Group/Researcher: Prof D Beeson
The congenital myasthenic syndromes (CMS) are a set of inherited disorders with a common symptom of fatigable muscle weakness.
CMS arises due to problems with the conduction of signals at specialised structures called neuromuscular junctions (NMJ). At the NMJ, the nerve cell transmits a chemical signal - using a molecule called acetylcholine - to the muscle fibre. When the molecules of acetylcholine reach the muscle fibre they bind to ion channels called acetylcholine receptors (AChRs) which change this chemical signal into an electrical signal that tells the muscle to contract.
Individuals with CMS carry mutations in genes that affect AChRs in different ways. Prof Beeson and his colleagues recently have identified mutations in a new gene named ‘MuSK-interacting protein’ whose function has yet to be fully understood. They believe that mutations in this gene might cause a particular form of CMS, the ‘limb girdle’ CMS. It is thought to code for a protein which helps to place the acetylcholine receptors at the correct location at the NMJ, but exactly how it causes disease is unknown. In their previous work they already established a model cell culture system for investigating different proteins involve in placing AChRs at the NMJ. The first aim of this work is to confirm that mutations in this gene definitely cause CMS. If this is the case, the next aim is to determine what effect the mutations have on the protein and how this affects the NMJ.
At present many patients with these mutations are misdiagnosed and do not respond well to current treatments. Identifying the genes involved and understanding how mutations cause disease enables clinicians to offer patients genetic counselling and provides the knowledge required for developing alternative therapies. Success in this project would help with the diagnosis of some individuals with CMS and may allow us to understand why some patients do not respond to current therapies. It will also allow investigation of other, new therapeutic approaches.
Value of Grant: Year 1 - £116,468
The congenital myasthenic syndromes (CMS) are a set of inherited disorders with a common symptom of fatigable muscle weakness.
CMS arises due to problems with the conduction of signals at specialised structures called neuromuscular junctions (NMJ). At the NMJ, the nerve cell transmits a chemical signal - using a molecule called acetylcholine - to the muscle fibre. When the molecules of acetylcholine reach the muscle fibre they bind to ion channels called acetylcholine receptors (AChRs) which change this chemical signal into an electrical signal that tells the muscle to contract.
Individuals with CMS carry mutations in genes that affect AChRs in different ways. Prof Beeson and his colleagues recently have identified mutations in a new gene named ‘MuSK-interacting protein’ whose function has yet to be fully understood. They believe that mutations in this gene might cause a particular form of CMS, the ‘limb girdle’ CMS. It is thought to code for a protein which helps to place the acetylcholine receptors at the correct location at the NMJ, but exactly how it causes disease is unknown. In their previous work they already established a model cell culture system for investigating different proteins involve in placing AChRs at the NMJ. The first aim of this work is to confirm that mutations in this gene definitely cause CMS. If this is the case, the next aim is to determine what effect the mutations have on the protein and how this affects the NMJ.
At present many patients with these mutations are misdiagnosed and do not respond well to current treatments. Identifying the genes involved and understanding how mutations cause disease enables clinicians to offer patients genetic counselling and provides the knowledge required for developing alternative therapies. Success in this project would help with the diagnosis of some individuals with CMS and may allow us to understand why some patients do not respond to current therapies. It will also allow investigation of other, new therapeutic approaches.
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