Paul Gillan (BSc, MSc)

Thesis title: High resolution genotype phenotype correlations for severe paediatric disease caused by mutations in eEF1A2

MRC Precision Medicine Doctoral Training Programme

Year of study: 1

  • Centre for Genomic and Experimental Medicine
  • MRC Institute of Genetics and Molecular Medicine

Contact details

PhD supervisors:

Address

Street

Centre for Genomic and Experimental Medicine
MRC Institute of Genetics and Molecular Medicine
University of Edinburgh
Western General Hospital
Crewe Rd South

City
Edinburgh
Post code
EH4 2XU

Biography

Qualifications

BSc Genetics: University of Glasgow

MSc Stratified Medicine and Pharmacological Innovation: University of Glasgow

Research summary

My main research interest is understanding the genetic cause of neurodevelopmental disorders like Autism Spectrum Disorders (ASD) and Intellectual Disability (ID) through the precision medicine approach, apply the use of genetics to provide new mechanistic insights and develop therapeutic strategies to provide more effective support and higher quality of life. My interest in these subjects stems from a young age, my brother who inspires me down this career path and his community have been a continuing inspiration throughout my life and I consider it a priveledge and honour to do my part to support them after all they have done for me.

Current research interests

Currently I am studying multiple mutations within a single gene, using the concept of allelic heterogeneity within this gene as a paradigm for the precision medicine approach. The gene I am studying is eEF1A2, a translation factor only expressed in neurons, muscle and heart. There are so far ~40 children with severe epilepsy and moderate/severe ID known to have de novo missense heterozygous mutations in EEF1A2 and additional symptoms also include autism, ataxia and some are wheelchair-bound. A more recent description of a family with three children with severe epilepsy revealed all three children had a homozygous missense mutation and died in early childhood from dilated cardiomyopathy. EEF1A2 is predicted to be responsible for 1/500 cases of moderate/severe ID. Understanding how mutations in EEF1A2 can cause this range of disorders will provide insight on the common molecular pathways shared between affected individuals which could provide promising avenues for drug targeting. Precision medicine applied to develop anti-epileptic treatments targeted to underlying genetic causes of epilepsy has already been applied for other specific gene mutations which shows promise for eEF1A2 but it is vital to experimentally establish whether missense mutations result in loss of function or a gain of function/dominant negative effect before any treatment strategy can be designed.

Past research interests

During my BSc and MSc experience I have covered a broad range of research interests and focuses through projects. The organisms I have worked with range from mosquitoes, E. coli and cells and focused on proteins with varying functions which include malaria resistance, transposases from transposons and monoclonal antibody (mAb) for therapeutic intervention.

Project activity

During my BSc Genetics degree I did a summer placement funded by a Wellcome Trust Vacation Scholarship at Glasgow University Institute of Infection, Immunity and Inflammation supervised by Dr Lisa Ranford-Cartwright. My work was developing a homozygous APL1A line of mosquito refractory to infection from the Plasmodium falciparum parasite using genotype-directed breeding.

 

My BSc Genetics Honours project was in the Glasgow University Institute of Molecular Cell and Systems Biology supervised by Dr Sean Colloms. I worked on transposons, developing a more pure/soluble version of the ISY100 transposase protein from two mutant variants to compare activity with wild-type Tn5 transposase and potential use in vitro. I generated three new plasmid constructs, each contained one of three transposase variants with an N-terminal SUMO attached to promote correct folding conformation and increased solubility/activity.

 

During my MSc Stratfied Medicine and Pharmacoligical Innovation I did an industrial placement at Sartorius Stedim BioOutsource under supervision of Dr Martin DeCecco. I worked on structural characterisation of monoclonal antibody (mAb) therapeutics, assessment of glycosylation in mAb therapeutics and implications for biological activity.

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