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SELF-FUNDING MSc BY RESEARCH PROJECT: Determination of pathogenicity of pore mutations in potassium channels linked to Long QT Syndrome


   School of Physiology, Pharmacology & Neuroscience

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  Dr S Harmer, Prof J C Hancox  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The correct function of the heart depends on an orderly sequence of electrical excitation with each heart-beat. In turn this depends on the coordinated activity of multiple ion channel proteins and electrogenic transporters. Mutations to the underlying genes lead to electrocardiogram (ECG) abnormalities and malignant, potentially fatal ventricular arrhythmias. Two genes, which encode potassium ion channels, that have been strongly linked to malignant ventricular arrhythmias are KCNQ1 and KCNH2, mutations to which can cause repolarization disorders and sudden death [1-3]. Loss-of-function mutations to these genes lead to the LQT1 and LQT2 forms of long QT syndrome (LQTS). Whilst many variants in KCNQ1 and KCNH2 have been associated with LQTS, only a relatively small fraction of these has undergone functional characterization. The objective of this project is to elucidate the effects of mutations close to the ion selectivity filter in the pore of KCNQ1 and hERG (KCNH2-encoded) channels. For example, both KCNQ1 and hERG possess highly conserved proline (P320 and P632 respectively) and threonine residues (T322 and T634 respectively) in this region. Analogous mutations in this region will be made in each channel and studied using an In/On-Cell Western assay to determine effects on channel trafficking to the surface membrane and with whole-cell patch-clamp to evaluate functional expression [4,5]. This comparison of analogous positions in the two channels will establish whether the regions studied are particularly vulnerable to pathological variation. 


Funding Notes

This project is for students who can fund the project themselves; there is no financial support.
Please apply to the Faculty of Life Sciences, School of Physiology and Pharmacology, selecting the programme 'MSc by Research'
http://www.bristol.ac.uk/study/postgraduate/apply/

References

[1] Hancox JC, Stuart AG and Harmer SC (2020) Functional evaluation of gene mutations in long QT syndrome: strength of evidence from in vitro assays for deciphering variants of unknown significance. J Congen Cardiol, 4(6): https://doi.org/10.1186/s40949-020-00037-9
[2] Modell SM and Lehmann MH (2006) The long QT Syndrome family of cardiac ion channelopathies: aHuGE review. Genet Med, 8(3):143-155.
[3] Harmer SC and Tinker A (2016) The impact of recent advances in genetics in understanding disease mechanisms underlying the long QT syndromes. Biol Chem, 397(7):679-693.
[4] Al-Moubarak E, Zhang Y, Dempsey CE, Zhang H, Harmer SC, Hancox JC (2020) Serine mutation of a conserved threonine in the hERG K+ channel S6-Pore region leads to loss-of-function through trafficking impairment. BBRC, 526: 1085-1091.
[5] Thomas D, Khalil M, Alter M, Schweizer PA, Karle CA, Wimmer A-B, Licka M, Katus HA, Koenen M, Ulmer HE, Zehelein J (2010) Biophysical characterization of P320 mutations linked to long QT syndrome 1. J Mol Cell Cardiol, 48: 230-237

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