Congenital, selective tooth agenesis (TA), also termed non-yndromic TA, affects up to ten percent of the population worldwide. The condition consists of a variable number of missing teeth without any other apparent abnormalities and poses not only an esthetic-psychological problem but often requires costly orthodontic and restorative treatment. New developments in two areas of investigation: 1) the genetics of selective TA and 2) the treatment of hypohidrotic ectodermal dysplasia (HED, MIM 305100) may soon lead to the application of molecular diagnostics and genetic counseling in TA and dentistry. HED, a well-known syndrome, is caused by a variety of mutations in the ectodysplasin-A (EDA) gene. HED encompasses TA as one of its features and dentists serve as consultants in patient treatment. Recently it has been shown that some EDA mutations do not cause the HED syndrome but isolated selective TA (MIM 300606). Individuals with the latter manifestation of EDA mutations are usually only seen by a dental care provider. As long as treatment of the dental condition was only symptomatic, a proper diagnosis didn't matter much. But now it has been shown that early postnatal treatment with recombinant EDA protein can prevent agenesis of permanent teeth in experimental animals with HED. In the near future postnatal treatment with recombinant EDA protein will probably be the curative treatment for EDA-caused TA and dental professionals will be responsible for early diagnosis of the condition. Since it may not be practical or desirable to send every patient with selective TA for genetic counseling, we propose to evaluate the scope of the problem by determining the prevalence, the range of phenotypes and the kind of mutations that are encountered in EDA-associated selective TA. Mutations in the EDA receptor EDAR can cause the same HED condition, so it is very likely that EDAR mutations can also cause isolated TA. Our goal is to determine the prevalence of both, EDA and EDAR-caused selective TA and the nature of the mutations, and to record the associated phenotypes. We have obtained preliminary in vitro evidence that manifestation of the HED syndrome requires a total absence of EDA/EDAR signaling while a mere reduction in EDA/EDAR signaling leads to isolated, selective TA. Thus we propose to sequence not only the coding areas but also non-coding regulatory regions of both genes in patients with different patterns of selective TA. Public Health Relevance: Inborn missing teeth are a relatively common problem which is caused by mutations in several different genes. We propose to investigate the role of two of these genes, EDA and EDAR, in greater detail because the gained knowledge would facilitate the identification of patients who could benefit from a promising, uncomplicated cure for missing teeth caused by deficits in these two genes.
Inborn missing teeth are a relatively common problem which is caused by mutations in several different genes. We propose to investigate the role of two of these genes, EDA and EDAR, in greater detail because the gained knowledge would facilitate the identification of patients who could benefit from a promising, uncomplicated cure for missing teeth caused by deficits in these two genes.
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