Genetics of malignant hyperthermia (MH): unravelling gene-gene interactions determining MH phenotypes

One studentship is available in the School of Medicine. It is open to UK applicants and covers fees plus maintenance.<br /> <br /> This fully funded PhD place provides an exciting opportunity to pursue postgraduate research of the rare genetic disease, malignant hyperthermia.<br /> <br /> The School of Medicine invites applications from prospective postgraduate researchers who wish to commence study for a PhD in the academic year 2026/27 for the British Journal of Anaesthesia/Royal Collage of Anaesthetists studentship.<br /> <br /> The award is open to full-time candidates (UK only) who meet the eligibility for a place on a PhD degree at the School of Medicine. We especially welcome applications that connect to the School's core research area of rare diseases and genetics.

<p>Malignant hyperthermia is a rare inherited disorder. Individuals at risk can have a potential lethal reaction to anaesthtics. The genetic basis of the inherited disorder malignant hyperthermia is not fully understood, though three genes important in muscle contraction are central <em>(RYR1, CACNA1S, STAC3)</em>. Consequently, an invasive muscle biopsy is required to performed the gold standard muscle function assessment: the in vitro contracture test (IVCT). </p> <p>MH has been described as a Mendelian disorder, but there is accumulating genetic evidence of further genes involved, and more than one gene may contribute to the clinical phenotype in an individual patient.</p> <p>The project aim is to use a variety of experimental techniques using a model system to determine if combinations of variants of interest can alter the malignant hyperthermia phenotype.</p> <p>This project is based in the Leeds MH Unit which is the UK reference centre and holds the largest collection of patient-derived phenotypic data and material worldwide including DNA, cells, IVCT, exome, and RNASeq data. A highly motivated graduate will have the opportunity to work closely with both clinical and research staff in this internationally renowned unit. The project has the potential to provide functional evidence to improve the genetic diagnostic service.</p> <p>Malignant hyperthermia (MH) is a potentially fatal hypermetabolic and hyperthermic reaction following exposure to anaesthetic drugs. It is an inherited condition however the genetic basis of the condition has not been fully resolved.  Genetically susceptible individuals have an associated genetic variant in <em>RYR1</em> (~75% of cases), <em>CACNA1S</em> and <em>STAC3</em> (<2% and <1% of cases respectively). However, not all individuals with a variant in these three genes are MH susceptible. As a genetic diagnosis is not possible in a large proportion of patients an invasive muscle biopsy is required for the in vitro contracture test (IVCT).</p> <p>Historically MH was described as an autosomal dominant condition due to RYR1 mutations. But the genetic basis now appears more complex, with variants in additional genes causing or contributing to the condition, indicating a requirement to reach a functional threshold for patients to become susceptible (1). Accumulating evidence suggests additional genetic changes are required in patients. Variant combinations acting together to amplify the single variant effect could generate a clinical effect.</p> <p>The three key genes <em>RYR1, CACNA1S</em> and <em>STAC3</em> are key components of excitation-contraction coupling (ECC) that is important in skeletal muscle function. Functionally these genes alter Ca2+ handling inside the cell that results in muscle contraction. Patients with MH have altered Ca2+ levels and flux between the cellular compartments. This is thought to be a central mechanism for MH susceptibility. Our high-throughput genetic screen identified additional alterations in patients, including changes that could exacerbate mitochondrial dysfunction in MH. Preliminary functional data highlighted the key mitochondrial gene <em>PYGM</em>.</p> <p>The aim of the research is to investigate the functional impact of variant combinations in the MH-associated genes (<em>RYR1, CACNA1S, STAC3</em>) and <em>PYGM</em>. Gene variants found in MH patients have been engineered to generate knock-in mice. We will use cells with gene variant combinations from this model system. Immature primary myoblast cells will be differentiated to myotubes with variants singly and in pairs. They will be phenotyped using a number of in vitro cell biology functional assays. These include live cell imaging over time to quantify intracellular Ca2+ changes following exposure to RyR1 agonists (caffeine and inhalational anaesthetic) sensitivity, and the depolariser (KCl); mitochondrial investigations into altered behaviour of components of the electron transport chain and oxidative stress; and bioinformatic analysis of transcriptomic data to identify additional downstream gene changes. This will provide functional evidence for genetic combinations contributing to MH susceptibility, and identify novel genetic contributors to the disease.</p> <h5>References</h5> <ol> <li>Miller et al (2018) Genetic epidemiology of malignant hyperthermia in the UK. British Journal of Anaesthesia 121(4): 944-952</li> </ol> <h5>About the Institute</h5> <p>The Leeds Institute of Medical Research (LIMR) at St. James’s is a vigorous and highly interactive research institute that investigate the causes and treatment of disease at the level of molecules, cells, patients and populations. The Institute research includes basic biology through to clinical trials and outcomes research.</p> <ul> <li><a href="https://medicinehealth.leeds.ac.uk/medicine/staff/278/dr-christine-diggle">Dr Christine Diggle | School of Medicine | University of Leeds</a></li> <li><a href="https://medicinehealth.leeds.ac.uk/medicine/staff/436/phil-hopkins">Phil Hopkins | School of Medicine | University of Leeds</a></li> <li><a href="https://medicinehealth.leeds.ac.uk/medicine/staff/3174/dr-marie-anne-shaw">Dr Marie-Anne Shaw | School of Medicine | University of Leeds</a></li> <li><a href="https://medicinehealth.leeds.ac.uk/medicine/staff/1095/dr-fiona-bartoli">Dr Fiona Bartoli | School of Medicine | University of Leeds</a></li> </ul>

<p>To apply for this scholarship opportunity applicants should complete an <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">online application form</a> and attach the following documentation to support their application:</p> <ul> <li>a full academic CV</li> <li>degree certificate and transcripts of marks</li> <li>Evidence that you meet the University's minimum English language requirements (if applicable)</li> </ul> <p>To help us identify that you are applying for this scholarship project please ensure you provide the following information on your application form;</p> <ul> <li>Select PhD in Medicine as your programme of study</li> <li>Give the full project title and name the supervisors listed in this advert</li> <li>For source of funding please state you are applying for a BJA/RCoA Scholarship</li> </ul> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to this scholarship in the School of Medicine should normally have an Undergraduate degree of 2:1 or above (or international equivalent) in a relevant subject area. A Master’s degree is desirable, but not essential. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Admissions Team prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid.

<p>We are offering 1 full-time PhD scholarship in the School of Medicine for one UK candidate, covering a maintenance grant of £20,780 per year and UK tuition fees for three years. The award will be made for one year in the first instance and renewable for a further period of up to two years, subject to satisfactory academic progress.</p> <ul> <li>Applicants must not have already been awarded or be currently studying for a doctoral degree</li> <li>Awards must be taken up by 1^st September 2026</li> <li>Applicants must live within a reasonable distance of the University of Leeds whilst in receipt of this scholarship</li> </ul>

<p>For further information about the admissions process, please contact <a href="mailto:fmhpgradmissions@leeds.ac.uk">fmhpgradmissions@leeds.ac.uk</a></p>