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School of Dentistry PhD Project Proposal Form 2017 entry
Project Title
Understanding the causes of developmental tooth defects using a highthroughput genomic screening approach
Dr Alan Mighell
Professor Chris Inglehearn
Project Summary
Dental enamel is the hardest tissue in the human body. The process of enamel formation is
called amelogenesis, and Amelogenesis imperfecta (AI) is the name given to a set of severe
defects of this process which are inherited as Mendelian conditions. AI occurs in up to 1:700
live births and presentation varies with the genetic mutation(s) involved. Over 20 genes
have been implicated so far by genetic studies, including many by the Leeds AI group (eg
Smith et al 2016, EJHG 11:1565; Parry et al 2016, AJHG 99:984 and many other published
papers). Clinical care is complex, demanding on patients and the dental team and requires
long-term specialist treatment. Patients have difficulty maintaining oral hygiene, suffer low
self-esteem and report an inferior quality-of-life.
Molar Incisor Hypoplasia (MIH) is another type of enamel defect which is similar to AI but
only involves some of the teeth in the adult dentition. Unlike AI it is not a Mendelian
condition, but there is evidence of both genetic and environmental contributions to
susceptibility. It is common, with frequency ranging from 2.4%-40.2% in different
populations. At optimum levels fluoride protects teeth from dental decay. Fluorosis is a third
category of dental development abnormality of variable severity. It is largely due to a single
environmental cause (excessive fluoride in drinking water) during tooth development, but
there is data that supports a genetic susceptibility that may influence the severity of the
enamel defects.
Aims & Objectives
This project aims to develop a screen for the genetic regions most frequently mutated in AI
patients using Multiple Inversion Probes (MIPS) technology, then test this as a pre-screen
on all of the new samples being collected by the Leeds AI group, through their network of
collaborators around the world. Those that prove negative will then be tested by whole
exome or whole genome next generation sequencing and bioinformatics analysis to find
new AI genes, which could then be characterised in cell or animal models. The pathology
of new forms of AI will be studied by micro-CT scanning, electron microscopy,
immunofluorescence and biochemical analysis. Meanwhile the MIPS pre-screen will be
applied to sets of patients with MIH and fluorosis to determine whether the same genes
contribute to risk of these much more common dental conditions as well. This project will
give the successful applicant the opportunity to train in and use a wide range of molecular
genetic, bioinformatic, cell biology and pathology techniques, to publish their work with this
highly successful group and to begin a career in dental research.
References (optional)