Amelogenesis Research Group

What we do

The Leeds Amelogenesis Research Group aims to increase our understanding of enamel formation and function. To do this, we aim to identify and study the mechanisms that lead to conditions such as Amelogesis imperfecta, Molar Incisor hypomineralisation and dental fluorosis, as well as studying the normal processes involved in enamel development 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 the absence of other health problems (non-syndromic AI), but can also be associated with significant problems in other tissues or organs (syndromic AI). The impact of AI on affected individuals and their families is considerable. 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 and difficult 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.

Amelogenesis Imperfecta  Imagae

Amelogenesis Imperfecta

(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

Our 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.

Through sequencing studies, the 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 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 the ameloblast cells themselves and to understand how they move during enamel formation, to better understand how enamel is made, what goes wrong in AI, to highlight therapeutic targets 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 here.

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

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).

Key publications

Title Text

  1. Novel DLX3 variants in amelogenesis imperfecta with attenuated tricho-dento-osseous syndrome. Whitehouse LLE, Smith CEL, Poulter JA, Brown CJ, Patel A, Lamb T, Brown LR, O'Sullivan EA, Mitchell RE, Berry IR, Charlton R, Inglehearn CF, Mighell AJ. Oral Dis. 2018 Aug 10. doi: 10.1111/odi.12955.
  2. Amelogenesis Imperfecta; Genes, Proteins, and Pathways. Smith CEL, Poulter JA, Antanaviciute A, Kirkham J, Brookes SJ, Inglehearn CF, Mighell AJ. Front Physiol. 2017 Jun 26;8:435. doi: 10.3389/fphys.2017.00435.
  3. Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta. Smith CE, Whitehouse LL, Poulter JA, Brookes SJ, Day PF, Soldani F, Kirkham J, Inglehearn CF, Mighell AJ. Eur J Hum Genet. 2017 Aug;25(8):1015-1019.
  4. Amelogenesis imperfecta caused by N-terminal enamelin point mutations in mice and men is driven by endoplasmic reticulum stress. Brookes SJ, Barron MJ, Smith CEL, Poulter JA, Mighell AJ, Inglehearn CF, Brown CJ, Rodd H, Kirkham J, Dixon MJ. Hum Mol Genet. 2017 May 15;26 (10):1863-1876.
  5. Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta. Parry DA, Smith CE, El-Sayed W, Poulter JA, Shore RC, Logan CV, Mogi C, Sato K, Okajima F, Harada A, Zhang H, Koruyucu M, Seymen F, Hu JC, Simmer JP, Ahmed M, Jafri H, Johnson CA, Inglehearn CF, Mighell AJ. Am J Hum Genet. 2016 Oct 6;99 (4):984-990.
  6. Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta. Smith CE, Murillo G, Brookes SJ, Poulter JA, Silva S, Kirkham J, Inglehearn CF, Mighell AJ. Hum Mol Genet. 2016 Aug 15;25 (16):3578-3587.
  7. A homozygous STIM1 mutation impairs store-operated calcium entry and natural killer cell effector function without clinical immunodeficiency. Parry DA, Holmes TD, Gamper N, El-Sayed W, Hettiarachchi NT, Ahmed M, Cook GP, Logan CV, Johnson CA, Joss S, Peers C, Prescott K, Savic S, Inglehearn CF, Mighell AJ. J Allergy Clin Immunol. 2016 Mar;137 (3):955-7.e8.
  8. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Am J Hum Genet. 2015 Oct 1;97 (4):535-45.
  9. Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta. Poulter JA, Murillo G, Brookes SJ, Smith CE, Parry DA, Silva S, Kirkham J, Inglehearn CF, Mighell AJ. Hum Mol Genet. 2014 Oct 15;23 (20):5317-24.
  10. A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta. Poulter JA, Brookes SJ, Shore RC, Smith CE, Abi Farraj L, Kirkham J, Inglehearn CF, Mighell AJ. Hum Mol Genet. 2014 Apr 15;23 (8):2189-97.


Who we are


Group Leads
Dr Alan Mighell
Professor Chris Inglehearn

View our team members