Leeds Amelogenesis Imperfecta (AI) and Enamel Research Group

Members of the Leeds AI Genetics Research Group

Dr Alan Mighell (Joint Group Lead)

Prof Chris Inglehearn (Joint Group Lead)

Dr Claire Smith (Post Doctoral Scientist)

Georgios Nikolopoulos (PhD Student)

 

Mission statement

Leeds AI and Enamel Research Group aims to increase understanding of enamel formation. To do this, we aim to identify and study the mutations and mechanisms that cause amelogenesis imperfecta, as well as the development of the enamel and the evolutionary history of enamel.

 

What is Amelogenesis Imperfecta (AI)?

Amelogenesis Imperfecta (AI) is a variable group of inherited conditions of tooth enamel, in which both the quality and the quantity of enamel may be abnormal. AI mostly occurs in isolation of other health problems ("non-syndromic AI"), but can be associated with significant problems in other tissues or organs. 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. AI affects up to 1 in 700 people and can be inherited in an autosomal dominant, recessive or X-linked manner.

 AI Tooth images

Clinical images that illustrate the variability of AI. (A) Hypoplastic AI is characterised by teeth without the curves associated with a normal enamel volume. (B) In hypomaturation AI enamel volume can be near-normal, but opaque with structural weaknesses that result in rapid post-eruptive enamel loss with enamel fracturing away to exposure the underlying dentine. (C) Brown discolouration and early post-eruptive enamel loss is typical of hypomineralised forms of AI. (D) Mixed AI phenotypes are frequently encountered. In this example a near-normal enamel volume is characterised by multiple focal pits that are most evident on the inset image, with variable colouration that includes focal opacities, but without premature fracturing of the enamel to reveal dentine. Image reused with acknowledgement to Front. Physiol., 26 June 2017

 

Research

The group uses various sequencing methodologies, including exome and genome sequencing and downstream analyses to identify the underlying AI mutations in patients with amelogenesis imperfecta. We collect both DNA samples and teeth from patients and their families, via an ever-expanding clinical network across the UK and by collaboration with other national and international researchers. We have DNA from over 300 AI families, making our AI research cohort one of the largest in the world. We are also participate in an international consortium, GEnamel (Genes for Enamel), which through collaboration, shares AI genetics findings to expedite AI gene discovery and to perform functional studies on candidate genes.

Through sequencing studies, Leeds AI Genetics Research Group have already implicated a number of genes in AI pathogenesis, including GPR68, AMTN, PEX1, PEX6, AMBN, ITGB6, LAMB3, FAM20A, WDR72, C4orf26, SLC24A4 and CNNM4. This knowledge is the first step in elucidating roles for these proteins in enamel formation.

As well as DNA sequencing studies, we are also examining the evolutionary footprints of enamel genes in collaboration with Dr Mary O’Connell’s Computational and Molecular Evolutionary Biology Research Group. This will highlight genes important for enamel formation and therefore also candidate genes for AI. We also work to characterise the phenotypes of AI enamel resulting from particular genotypes through collaboration with the Leeds Biomineralisation Research Group. We use scanning electron microscopy, micro-computerised tomography, energy dispersive X-ray analysis and microhardness testing to characterise the enamel. This research will inform clinical treatments for AI and will help to focus research efforts on improving restorative techniques for the treatment of enamel pathology. We are also developing new methods to study how ameloblasts move during enamel formation to better understand how enamel is made, what goes wrong in AI, to highlight therapeutic targets and to aid development of new restorative treatments.

 

Impact and public engagement

Our research has helped to establish UK NHS diagnostic screening for AI and we have established and continue to curate a publically available database of published AI mutations for the benefit of fellow researchers.

We also review the Genomic England Clinical Amelogenesis Imperfecta panel app to aid clinical interpretation of variants identified and have published a comprehensivereview of AI genetics.

As part of the SMILE AIDER (Stakeholder Meaningful InvoLvement and Engagement Aiding Dental Research) oral health patients and public involvement forum and as international friends of the D3 (Developmental Dental Defects) group we participate in increasing the public understanding of developmental dental defects such as amelogenesis imperfecta, molar incisor hypomineralisation (MIH) and fluorosis.

As part of our efforts to encourage involvement in dentistry and research, we host undergraduate students for summer project placements and give further education students experience of research in a laboratory setting. We have also participated in Leeds Dental School Open Days and have run an innovative and exciting “Dental Disease Detectives” family activity programme at the Thackray Medical Museum. Some members of our group are also Science, Technology, Engineering and Mathematics (STEM) ambassadors who volunteer their time, enthusiasm and experiences to encourage and inspire young people to achieve more and progress further in science, technology, engineering and mathematics (STEM).

 

Contact

 

For further information, including information on PhD opportunities, collaboration or public engagement, please contact:

Dr Alan Mighell a.j.mighell@leeds.ac.uk +44 (0) 113 343 6121

Prof Chris Inglehearn c.inglehearn@leeds.ac.uk +44 (0) 113 343 8646

Dr Claire Smith c.e.l.smith@leeds.ac.uk +44 (0) 113 343 8445

Mr Georgios (George) Nikolopoulos bs16gn@leeds.ac.uk +44 (0) 113 343 8445

 

Links

Computational and Molecular Evolutionary Biology Research Group

Leeds Biomineralisation Research Group

Leeds AI Leiden Open Variant Database 

Genomic England Clinical Amelogenesis Imperfecta panel app 

Comprehensive review of AI genetics; Amelogenesis imperfecta: Genes, proteins and pathways

SMILE AIDER (Stakeholder Meaningful InvoLvement and Engagement Aiding Dental Research) oral health patients and public involvement forum 

D3 (Developmental Dental Defects) group

Leeds Dental School 

Thackray Medical Museum 

Science, Technology, Engineering and Mathematics (STEM) ambassadors