Tooth agenesis constitutes the most common anomalies of dental development in man. Despite this, little is known about the genetic defects responsible for this complex condition. To date, the only genes associated with the non-syndromic form of tooth agenesis are MSX1 and PAX9, which encode transcription factors that play a critical role during tooth development. This paper aims to review current literature about the molecular mechanisms responsible for selective tooth agenesis in humans.

Recent advances in understanding the molecular events underlying hypohidrotic ectodermal dysplasia (HED) caused by mutations of the genes encoding proteins of the tumor necrosis factor α (TNFα)-related signaling pathway have been presented. These proteins are involved in signal transduction from ectoderm to mesenchyme during development of the fetus and are indispensable for the differentiation of ectoderm-derived structures such as eccrine sweat glands, teeth, hair, skin, and/or nails. Novel data were reviewed and discussed on the structure and functions of the components of TNFα-related signaling pathway, the consequences of mutations of the genes encoding these proteins, and the prospect for further investigations, which might elucidate the origin of HED.

Tooth development is regulated through a series of reciprocal interactions between the dental epithelium and mesenchyme and requires protein products of a number of genes. It has been reported that selective tooth agenesis is associated with mutations in human MSX and PAX9 genes. Mutational analysis of the two genes was performed in 25 individuals with familial or sporadic form of permanent tooth agenesis. Single-stranded conformational polymorphism analysis revealed no mutations in the entire coding sequence of the MSX1 gene. In PAX9, a novel, heterozygous G151A transition in the sequence encoding the paired domain of the PAX9 protein was detected in a patient with agenesis of third molars, second premolars and incisors, but not in her parents, the remaining patients or 162 individuals with normal dentition. This is the first de novo mutation described in PAX9. Our results support the view that mutations in PAX9 could constitute a causative factor of oligodontia. We hypothesize that the G151A transition in PAX9 might be responsible for the sporadic form of tooth agenesis in this patient.

Large differences in relation to dental size, number, and morphology among and within modern human populations and between modern humans and other primate species have been observed. Molecular studies have demonstrated that tooth development is under strict genetic control, but, the genetic basis of primate tooth variation remains unknown. The PAX9 gene, which codes for a paired domain-containing transcription factor that plays an essential role in the development of mammal dentition, has been associated with selective tooth agenesis in humans and mice, which mainly involves the posterior teeth. To determine whether this gene is polymorphic in humans, we sequenced Ϸ2.1 kb of the entire four-exon region (exons 1, 2, 3 and 4; 1,026 bp) and exon-intron (1.1 kb) boundaries of 86 individuals sampled from Asian, European, and Native American populations. We provided evidence that human PAX9 polymorphisms are limited to exon 3 only and furnished details about the distribution of a mutation there in 350 Polish subjects. To investigate the pattern of selective pressure on exon 3, we sequenced ortholog regions of this exon in four species of New World monkeys and one gorilla. In addition, orthologous sequences of PAX9 available in public databases were also analyzed. Although several differences were identified between humans and other species, our findings support the view that strong purifying selection is acting on PAX9. New World and Old World primate lineages may, however, have different degrees of restriction for changes in this DNA region. human evolution ͉ tooth agenesis ͉ evolutionary window

Background and Purpose-Homocysteine (Hcy)-thiolactone mediates protein N-homocysteinylation in humans. Protein N-linked Hcy comprises a major pool of Hcy in human blood, greater that the "total" Hcy pool. N-homocysteinylated proteins are structurally different, compared with native proteins, and are thus likely to be recognized as neoself antigens and induce an autoimmune response. This study was undertaken to provide evidence for anti-N⑀-Hcy-Lys-protein antibody and to examine associations between the antibody level, Hcy, and stroke in humans. Methods-ELISA was used to quantify anti-⌵⑀-Hcy-Lys-protein antibodies in human serum. Results-We found that autoantibodies that specifically recognize N⑀-Hcy-Lys epitope on Hcy-containing proteins occur in humans. Serum levels of anti-N⑀-Hcy-Lys-protein autoantibodies positively correlate with plasma total Hcy levels, but not with plasma cysteine or methionine levels. In a group of exclusively male patients with stroke, mean level of anti-N⑀-Hcy-Lys-protein autoantibodies was Ϸ50% higher than in a group of healthy subjects. Conclusion-These findings support a hypothesis that N⑀-Hcy-Lys-protein is a neoself antigen, which may contribute to immune activation, an important modulator of atherogenesis.