Dr Claire E. L. Smith


I currently work as part of a collaborative project between the Faculties of Medicine and Health and Chemistry that aims to identify compounds with the ability to restore the occurrence and efficient function of primary cilia in diseases where they are reduced in abundance and/or defective. This is funded by Action Medical Research and utilises high throughput screening methods and a variety of in vitro testing platforms. Two large chemical libraries (totalling 2,160 compounds) were the starting point to try to identify an effective starting chemical for downstream pre-clinical testing for a variety of ciliopathies.

After completing a degree in biology at the University of Nottingham in 2004, I started my research career as a research technician with the Centre for Plant Sciences, Faculty of Biological Sciences, at the University of Leeds. In 2009 I became a research assistant in the Section of Genetics within the Faculty of Medicine and Health studying the expression of PLAGL1, a gene implicated in cancer, transient neonatal diabetes mellitis and intrauterine growth restriction. I then worked as a research technician within Molecular Epidemiology, LICAMM, Faculty of Medicine and Health where I studied the detection of aflatoxin-albumin adducts as an epidemiological marker of aflatoxin exposure.

From 2010 to 2013 I worked as a research assistant within the Section of Genetics on the EU FP7 project; Nuclease Immune Mediated Brain and Lupus-like conditions: natural history, pathophysiology, diagnostic and therapeutic modalities with application to other disorders of autoimmunity. My work specifically focused on producing various cell and animal models of Aicardi Goutières Syndrome and analysing them by RNA sequencing, co-immunoprecipitation, immunofluorescence, immunohistochemistry and western blotting.

In 2013, I began my PhD, studying amelogenesis imperfecta (AI), a genetic condition resulting in defective tooth enamel. My studies focused on a syndromic form of AI, Heimler syndrome. This condition also encompasses sensorineural hearing loss and often also retinal dystrophy. By whole exome sequencing of affected individuals, I identified mutations in the peroxisomal biogenesis factor genes, PEX1 and PEX6, as the cause of disease. I also studied a non-syndromic hypomineralised form of AI and identified a heterozygous multi-exon deletion in the amelotin gene in affected individuals. My thesis was entitled “Blindness, hearing loss and brown crumbly teeth; determining the molecular basis of Heimler and Heimler plus syndromes and other related conditions” and my PhD was awarded in November 2016.

In April 2016 I was awarded Wellcome Trust Institutional Strategic Support funding for 1 year to complete research that followed on from my PhD. During my PhD, I identified AI-causing mutations in over 45 families. Where teeth were available from these families, enamel phenotyping of genotyped AI teeth and matched controls was carried out so that the effects of the mutations on the resulting enamel could be determined. Teeth analysed included those from patients with ACPT, KLK4 and LAMB3 mutations. With an aim to cataloguing all published AI mutations, I established an Leiden Open Variant Database for AI, which can be access here: http://dna2.leeds.ac.uk/LOVD/ I continue to curate published AI variants to provide a useful resource for fellow researchers and clinicians around the world. This database forms the basis of a review on the genetics of AI.

In April 2017 I began research into inherited retinal disease as part of the UK Inherited Retinal Dystrophies Consortium team, jointly funded by charities RP Fighting Blindness and Fight For Sight. This project aimed to identify the human gene variants that underlie Inherited Retinal Dystrophies (IRDs). Methods used include targetted sequencing via capture by use of molecular inversion probe, whole exome sequencing, whole genome sequencing, transcriptomics and metabolomics. This research was a UK wide collaboration to study a cohort of over 500 families and ultimately aimed to translate diagnostic protocols developed from this research to an NHS clinical setting. The research better catalogued the scope of variants (including structural, copy number and intronic variants) within known disease genes, as well as the range of phenotypes that they cause but also identified new genes for IRDs through the use of large pre-screened cohorts. I used bioinformatics analyses including developing alignment, variant calling and filtering pipelines, to identify variants and assess their pathogenicity by in silico and in vitro analysis. The large amount of sequencing data were processed using the Medical Advanced Research Computing 1 large memory node cluster at the University of Leeds.


  • PhD supervisor: Georgios Nikolopoulos

Research interests

Drug screening to identify treatments for ciliopathies:

Ciliopathies are a heterogeneous collection of individually rare diseases that are collectively common, including Bardet-Biedl syndrome, Joubert syndrome, nephronophthisis, retinitis pigmentosa and polycystic kidney disease (PCKD). A major symptom of many ciliopathies is the development of polycystic kidneys which can result in end stage kidney disease, requiring regular dialysis or a kidney tranplant to treat. Currently available treatments for PCKD are limited, mainly relying on treating on the secondary symptoms. Tolvaptan, a vasopressin V2 receptor antagonist is one treatment that does slow cyst progression, however it may not be appropriate to treat everyone, meaning that these is a clinical need for novel and more effective therapeutics. 

As part of the Ciliopathy Research group led by Prof. Colin Johnson, I am screening 2160 compounds to try to identify a compound for further development and refinement as a starting point for testing of a chemical hit series for preclinical studies. To do this, I am using high throughput cell based screening methods (for example the Operetta high content imager) as well as a variety of model based platforms to further test any chemicals passing primary screening. This will utilise CRISPR engineered cells, mouse knockout embryonic fibroblast cell lines and patient urine derived endothelial cells.

Inherited Retinal Dystrophies (IRDs):

Inherited Retinal Dystrophies (IRDs) are a group of inherited defects affecting the retina, the part of the eye responsible for conversion of light to electrical signals that enables visual perception. IRDs affect up to 1 in 3000 people and include conditions such as retinitis pigmentosa, cone-rod dystrophies, macular dystrophies, Leber congenital amaurosis and congenital stationary nightblindness.

Sight loss has an immediate and obvious huge impact on the lives and wellbeing of affected individuals but is also estimated to cost the UK over £5 billion per year. Future treatments will be developed and their efficacy determined by the genetics of the conditions. This means that knowledge of the underlying mutation(s) will be the key to preventing sight loss and maintaining vision. Once identified, mutations are fed back to patients, who by knowing their mutation can get access to accurate genetic counselling and may choose in future to participate in clinical trials of treatments or prevention for future generations.

My research used a variety of different techniques to determine the underlying mutations responsible for IRDs, including molecular inversion probes, whole exome sequencing, whole genome sequencing, transcriptomics and metabolomics. The research aimed to better catalogue the scope of variants (including structural, copy number and intronic variants) within known disease genes but also aimed to identify new genes for IRDs through the use of large pre-screened cohorts. I used bioinformatics analyses including developing alignment, variant calling and filtering pipelines to identify variants and assess their pathogenicity by in silico and in vitro analysis. Research findings from a cohort of over 500 families were shared with colleagues at University College London, the University of Oxford, the University of Manchester and the University of Southampton. This means that even rare disease genes were more likely to be identified. The project ultimately aimed to translate diagnostic protocols developed from this research to an NHS clinical setting.

Amelogenesis Imperfecta (AI):

I retain a strong interest in amelogenesis imperfecta (AI) and am part of the Leeds Dental Genetics Group, led by Dr Alan Mighell. I also supervise a PhD student, Georgios Nikolopoulos, who is studying the evolutionary history of the proteins involved in AI. AI is a group of inherited defects in tooth enamel. Affected patients have either very thin enamel or very weak enamel, which in both cases does not function correctly. The impact of AI on affected individuals and their families is considerable since patients experience dental pain and sensitivity, poor aesthetics and are reported to experience a lower quality of life due to social anxiety. Treatment of AI is expensive since it requires ongoing clinical management to maintain function and aesthetics. The aim of the Leeds AI genetics group is to increase our understanding of this disorder by piecing together the molecular mechanisms involved in tooth enamel formation, a process known as amelogenesis. By identifying the causative mutation in a family, we can attempt to understand the underlying cause of the disorder and perhaps give an insight into potential treatments. Any mutations identified are fed back to patients, who by knowing their mutation can get access to accurate genetic counselling and may choose in future to participate in clinical trials of AI treatments or AI prevention for future generations.

My research previously focused on both the identification of new genes for AI and the analysis of the enamel formed in AI patients. Having first identified the AI-causing mutations in these patients, any extracted or exfoliated teeth donated by patients are analysed using micro-computerised tomography, scanning electron microscopy, energy dispersive X-ray and microhardness testing. The aim is to compile knowledge of the effect of each AI mutation on the enamel that is formed and to identify any common mechanism of disease. This information may inform future treatments for AI.

Other activities:

I am a member of the Genomics England Clinical Interpretation Partnership (GeCIP) Domain for Hearing and Sight and I have curated the genes included in the Genomics England Amelogenesis Imperfecta Panel App.

I have reviewed submissions to many journals, including Clinical Genetics, Application of Clinical Genetics, Scientific Reports and PLOS ONE.

I am also active in patient and public involvement in research through the Leeds SMILE AIDER forum, through the Leeds University Be Curious festival and through hosting students in further education and lower years of higher education. I am also an International Friend of the D3 (Developmental Dental Defects) Group that aims to provide information to everyone: scientists, clinicians, adults and children on developmental dental defects: http://www.thed3group.org/international.html


  • PhD Medicine (Genetics)
  • BSc (Hons) Biology

Student education

I have taught undergraduates, postgraduates and visiting AS/A2 level students. This experience includes supervising PhD students, giving seminars, practical demonstrating and marking assessed work on population and human genetics, evolution, biochemistry, microbiology, molecular biology and molecular medicine.

Research groups and institutes

  • Leeds Institute of Medical Research at St James's
  • Amelogenesis Research Group
  • Vision Research Group
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