Genetic Approaches for the Diagnosis and Treatment of Congenital Tooth Agenesis

dc.contributorMues, Gabriele
dc.creatorBonds, John Carless
dc.description.abstractCongenital tooth agenesis is the most common developmental anomaly in man. More severe forms of tooth agenesis (> 5 missing teeth) demand lengthy and expensive treatment approaches such as bone augmentation surgeries and placement of multiple implants. Tooth agenesis is caused by mutations in genes responsible for early tooth development; and ever since it had been shown that timely injections of functional recombinant gene products can overcome the corresponding, mutation-based developmental disorder, such new therapeutic strategies for the prevention of tooth agenesis should be attempted. In this research project I have pursued two objectives: 1.) Basic research into the molecular genetics and therapeutics of the tooth agenesis gene PAX9. Since PAX9 is an intra-cellular transcription factor which cannot be replaced directly, suitable downstream targets for therapy have to be identified by comparing wild type and Pax9 deficient tooth organs. 2.) Clinically oriented research into the molecular diagnostics of human tooth agenesis. We use candidate gene sequencing in large numbers of people with tooth agenesis to identify the majority of human tooth agenesis genes and to determine the molecular cause of tooth agenesis in individuals. In the first study I identify the genes and pathways that are affected by Pax9 deficiency using microarray and q-PCR technology, and find that the Fgf, Shh and Wnt pathways are more affected than Bmp4 which had previously been considered the main target of Pax9 in tooth development. The next study shows that it is possible to apply therapeutic approaches to unravel the complexity of molecular signaling within the developing craniofacial complex. Using small molecule Wnt therapies we are able to rescue palatal clefting in Pax9-deficient mice. Our third study presents a clinical aspect of human molecular genetics where we establish that tooth agenesis does not predispose women to ovarian cancer, as had been previously suggested. The last study shows that mutations in WNT10A, but not in WNT10B or WNT6, are highly prevalent in populations with tooth agenesis. We also suggest that there must be some kind of heterozygous advantage to retaining mutations in Wnt10a. However, that advantage has not been identified.
dc.subjecttooth agenesis
dc.subjectovarian cancer
dc.subjectcleft palate
dc.titleGenetic Approaches for the Diagnosis and Treatment of Congenital Tooth Agenesis