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James Fraser Project

Supervisor:  James Fraser

Emma Matthews (UCL Queen Square Institute of Neurology)

 

The role of muscle channelopathies and muscle excitability in sudden infant death 

Voluntary and respiratory movements require coordinated contractions of skeletal muscle fibers only when excited by nerves. Increased excitability results in myotonia, in which spontaneous action potential activity may result in failure of relaxation and involuntary contractions. Decreased excitability may result in failure to excite or propagate APs, leading to weakness or even paralysis. Excitability at rest and during activity is a function of electrophysiological parameters including the conductances, voltage- and time-dependencies of ion channels. However, it is also a function of changing ion concentrations in the extracellular spaces, including the transverse-tubular system. My group has developed a computer model that is uniquely able to determine ion concentrations throughout the complex three-dimensional structure of skeletal muscle fibers, both at rest and during the rapid electrophysiological changes that occur during activity1. The model has previously been used to for example, reproduce, explain and propose treatments for myotonia congenita2.

In collaboration with Dr Emma Matthews, a consultant academic neurologist at UCL, the proposed PhD project will explore the influence of both gain- and loss-of-function NaV1.4 mutations identified by her group as associated with sudden infant death syndrome (SIDS) and characterized using patch clamping of HEK293 cells3. Modelling will allow prediction of the influence of these electrophysiological abnormalities in the context of neonatal and developing diaphragmatic muscle and allow the identification of factors that might aggravate excitability changes. Experimental work employing sharp microelectrodes and patch clamping of muscle from SIDS relatives will be guided by model predictions. The electrophysiological consequences of the channelopathies in other skeletal muscles will be modelled in order to develop non-invasive diagnostic or screening tests. The overall goal of the project will be to improve outcomes for future neonates with similar mutations and will allow the successful student to learn valuable skills including computer modelling and electrophysiological techniques.

Relevant references:

1.  Fraser, J.A.,Huang, C.L.-H. & Pedersen, T.H. 2011. Relationships between resting conductances, excitability, and t-system ionic homeostasis in skeletal muscle. J. Gen. Physiol., 138, 95–116.

2.  Skov, M.,Riisager, A.,Fraser, J.A.,Nielsen, O.B. & Pedersen, T.H. 2013. Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle. Neuromuscul. Disord., 23, 489–502.

3.  Männikkö, R.,Wong, L.,Tester, D.J.,Thor, M.G.,Sud, R.,Kullmann, D.M.,Sweeney, M.G.,Leu, C.,Sisodiya, S.M.,FitzPatrick, D.R.,Evans, M.J.,Jeffrey, I.J.M.,Tfelt-Hansen, J.,Cohen, M.C.,Fleming, P.J.,Jaye, A.,Simpson, M.A.,Ackerman, M.J.,Hanna, M.G.,Behr, E.R. & Matthews, E. 2018. Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. Lancet, 391, 1483–1492.