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Genetics: Exploring the genetic contribution to malignant hyperthermia susceptibility and related myopathies

PGR-P-457

Key facts

Type of research degree
4 year PhD
Application deadline
Ongoing deadline
Country eligibility
International (outside UK)
Funding
Non-funded
Supervisors
Professor Philip Hopkins and Dr Marie-Anne Shaw
Schools
School of Medicine
Research groups/institutes
Leeds Institute of Medical Research at St James's
<h2 class="heading hide-accessible">Summary</h2>

Malignant hyperthermia (MH) is a potentially lethal form of heat illness, pharmacogenetically triggered during general anaesthesia in susceptible individuals. The dramatic hyperthermic and hypermetabolic response results from skeletal muscle Ca2+ dysregulation. Although MH is a rare intraoperative event it is invariably fatal unless it is recognised immediately and treated aggressively. MH susceptible patients typically exhibit no overt phenotype unless exposed to any of the commonly used potent inhalational anaesthetics. Whilst the majority of MH susceptible individuals carry a missense variant in the gene coding for the skeletal muscle isoform of the ryanodine receptor, RYR1, a number of other genes are thought to modify the phenotype. In particular we are interested in people who carry a pathogenic variant but do not display the affected phenotype, and phenotypically normal individuals who carry a pathogenic variant.

<h2 class="heading hide-accessible">Full description</h2>

<p paraeid="{e1c0298c-ca68-46f4-8ec5-268c0f46a3d1}{193}" paraid="34811970">Currently, MH diagnosis is made using an in vitro contracture test (IVCT) where tissue taken from a skeletal muscle biopsy is exposed to incremental concentrations of halothane and caffeine. The MH Unit, here at Leeds, is the UK reference centre, and holds the largest collection of patient-derived phenotypic data and material worldwide. We have exome sequence for patients and family members. In addition we have conducted RNAseq analysis on MH susceptible and normal samples, before and after exposure to halothane and caffeine, where we have identified differentially expressed genes that my be directly involved in MH and related myopathies. The initial project will explore the relevance of some of these genes to MH in greater depth. A student will learn about RNAseq analysis and undertake quantitative PCR techniques to measure expression of selected genes. This will be followed by use of bioinformatics tools to identify potential regulators of gene expression. Variants of interest identified through sequence analysis, and tagged regulatory elements, will be genotyped using our extensive sample resource and a &lsquo;case-control&rsquo; association approach. &nbsp;</p> <p paraeid="{e1c0298c-ca68-46f4-8ec5-268c0f46a3d1}{193}" paraid="34811970">This investigation of variants will be followed by characterisation of selected, predicted myopathic variants&nbsp;in vitro using a CRISPR-Cas9 NHEJ system.&nbsp;Genes of interest will be knocked out in mouse myoblasts carrying a pathogenic RyR1 variant. Edited myoblasts will be differentiated into myotubes and transiently transduced with lentiviral constructs containing genes/variants of interest. Ca2+&nbsp;imaging will be used to assess the response to RyR1 agonists of myotubes which carry the pathogenic RyR1 variants in combination with the&nbsp;additional&nbsp;variants&nbsp;implicated in MH&nbsp;</p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{4}" paraid="2006068013">The student will analyse complex phenotypic data in relation to genetic background, whilst working in a group with diverse interests pertaining to&nbsp;Ca2+&nbsp;regulation.&nbsp;</p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{4}" paraid="2006068013"><strong>References</strong></p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{22}" paraid="1551113878">MERRITT A, BOOMS P, SHAW M-A, MILLER DM, DALY C, BILMEN JG, STOWELL KM, ALLEN PD, STEELE DS, HOPKINS PM (2017) Assessing the pathogenicity of RYR1 variants in malignant hyperthermia. Brit. J. Anaesthesia&nbsp;118, 533-543.&nbsp;</p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{32}" paraid="883174463">MILLER DM, DALY C, ABOELSAOD EM, GARDNER L, HOBSON SJ, RIASAT K, SHEPHERD S, ROBINSON RL, BILMEN JG, GUPTA PK, SHAW M-A, HOPKINS PM (2018)&nbsp;Genetic epidemiology of malignant hyperthermia in the United Kingdom.&nbsp;Brit. J.&nbsp;Anaesthesia&nbsp;121, 944-952.&nbsp;</p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{54}" paraid="1836719241">CHANG L, DALY C, MILLER DM, ALLEN PD, BOYLE JP, HOPKINS PM, SHAW M-A (2019)&nbsp;Permeabilized skeletal muscle reveals mitochondrial deficiency in Malignant Hyperthermia susceptible individuals.&nbsp;Brit. J.&nbsp;Anaesthesia&nbsp;122, 613-621.&nbsp;</p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{54}" paraid="1836719241">This project is part of the&nbsp;<a href="https://medicinehealth.leeds.ac.uk/leeds-institute-research-st-james/doc/international-phd-academy-medical-research">International PhD Academy: Medical Research</a></p> <p paraeid="{e1da352c-fcf8-48b9-9830-7f3e9154d0d7}{54}" paraid="1836719241"><strong>In line with the bespoke nature of our International PhD Academy a modified PhD project can be proposed dependent on students interests and background.</strong></p>

<h2 class="heading">How to apply</h2>

<p>Please note these are not standalone projects and applicants must apply to the PhD academy directly.</p> <p>Applications can be made at any time. To apply for this project applicants should complete an <a href="http://www.leeds.ac.uk/info/130206/applying/91/applying_for_research_degrees">online application form</a> and submit this&nbsp;alongside a full academic CV, degree transcripts (or marks so far if still studying) and degree certificates. Please make it clear in the research information section that you are applying for the International PhD Academy: Medical Research, as well as the title of the project you wish to be considered for.</p> <p>We also require 2 academic references to support your application. Please ask your referees to send these <a href="https://medicinehealth.leeds.ac.uk/downloads/download/130/faculty_graduate_school_-_scholarship_reference_form">references</a> on your behalf, directly to <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p> <p>If English is not your first language, you must provide evidence that you meet the University&#39;s minimum English language requirements (below).</p>

<h2 class="heading heading--sm">Entry requirements</h2>

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject may also be required in some areas of the Faculty. For entry requirements for all other research degrees we offer, please contact us.

<h2 class="heading heading--sm">English language requirements</h2>

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements in IELTS and TOEFL tests for PhD, MSc, MPhil, MD are: &bull; British Council IELTS - score of 6.5 overall, with no element less than 6.0 &bull; TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

<h2 class="heading">Contact details</h2>

<p>Informal enquires about regarding the bespoke taught first year of the PhD programme and research projects can be made by contacting LIMRPhD@leeds.ac.uk</p> <p>Enquiries regarding the application process should be directed to the Faculty of Medicine and Health Graduate School&nbsp;Office&nbsp;e: <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a>, t: +44 (0)113 343 8221.</p>


<h3 class="heading heading--sm">Linked funding opportunities</h3>
<h3 class="heading heading--sm">Linked research areas</h3>